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Question: <p>Recently, I've been reading about the MyD88 dependent signalling pathway, with particular reference to its activation in Macrophages and other cells of the immune system on recognition of a pathogen. I understand that when a PAMP (Pathogen Associated Molecular Pattern) binds with a PRR (Pattern Recognition Receptor), the receptor undergoes a conformational change, which precipitates a cascade of chemical reactions between various proteins, which eventually leads (inter alia) to the translocation of NF-κB to the nucleus, which leads to the production of cytokines. My question is about the finer points, particularly with respect to TLR1 and TLR2.</p>
<p>My reading suggests that these generally form a heterodimer - is this always true? Are both required for a pathogen to be recognised and an immune response produced?</p>
<p>Upon the pathogen binding with TLR1 (whether in a complex with TLR2 or not) what precisely happens to the receptor. I understand that MyD88 is, ultimately, recruited, but by what means?</p>
<p>I believe I understand everything that happens after the recruitment of MyD88, but I am less clear on everything before that. I had initially understood that the recruitment of MyD88 was the immediate next step, but other sources make reference to two proteins which I was initially unaware of: TOLLIP and TIRAP. What, if anything, is their role?</p>
<p>I'm still a little new to stackexchange so I apologise if this question is not up to standard, in which case, let the question simply be: 'How do TLR1/TLR2 activate the MyD88 dependent pathway?'</p>
Answer: <p>The TLR are usually working as homodimers (<a href="http://www.sciencedirect.com/science/article/pii/S0960982211005975" rel="nofollow noreferrer">Toll-like receptors</a>), although TLR2 can cooperate with TLR1 or 6.
Upon binding of its ligand (this is called pathogen associated molecular pattern) the receptors change their conformation and allow binding of TIRAP (TIR adapter protein) to their Toll-interleukin 1 receptor (TIR) domain. TIRAP then recruits MYD88, which then recruits IRAK1 or 4. The signal is then passed down the pathway as shown in the figure below (taken from the Wikipedia article on <a href="http://en.wikipedia.org/wiki/Toll-like_receptor" rel="nofollow noreferrer">TLR</a>).</p>
<p><img src="https://i.sstatic.net/7o8zi.png" alt="enter image description here"></p>
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https://biology.stackexchange.com/questions/15509/how-do-tlr1-tlr2-activate-the-myd88-dependent-pathway
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Question: <p>ROR1 is currently under investigation as a therapeutic target for cancer (1). A number of studies show different cancers may have their metastatic potential reduced, or become apoptotic through targeting or abrogation of ROR1 (1-3). ROR1 itself is show to have a number interactions (either through crosstalk or interaction) with some known tumorigenic markers; these include c-Met, PI3K, Akt, Wnt5a, EGF, c-Src (4-7). In terms of metastatic potential, interactions with vimentin, Snail/Slug, cadherins, ß-catenin, and CXCR4/CXCL12 were also identified (1, 8). Some of these are via expression of CREB. In terms of ROR1 is tissue, abnormalities that lead to death were noted in newborn mice that has ROR1 knocked down (9). A notable mechanism for ROR1 in development was in neuroprogenitor cells in which ROR1 regulation status determined whether these cells differentiated into neurons or not (10). It's also found that neural, heart, lung and kidney tissue in adults express some form or another of ROR1 (11). More recent studies suggest ROR1 downmodulation may present toxicity for some subsets of normal tissues (<a href="http://www.ncbi.nlm.nih.gov/pubmed/20702778" rel="noreferrer">12</a>).</p>
<p>The question, now: Are there any empirical studies that illuminate the potential mechanism of ROR1 in healthy, adult tissues? This is from a treatment toxicity standpoint, since the subsets of affected cells seem to be rather slim. I can understand why the effect on metastatic potential can be significant from the fetal neural cortex development (the need to migrate the neurons into position). We also see a truncated version of ROR1 in some instances. If anyone can shed some light, thank you in advance!</p>
<p>References</p>
<ol>
<li>Cui B. et al. Targeting ROR1 inhibits epithelial-mesenchymal transition and metastasis. Cancer. Res. 73, 3649–3660 (2012).</li>
<li>Hojjat-Farsangi, M., Ghaemimanesh, F., Daneshmanesh, A. H., Bayat, A. A., Mahmoudian, J., Jeddi-Tehrani, M., … Mellstedt, H. (2013). Inhibition of the Receptor Tyrosine Kinase ROR1 by Anti-ROR1 Monoclonal Antibodies and siRNA Induced Apoptosis of Melanoma Cells. PLoS ONE, 8. doi:10.1371/journal.pone.0061167</li>
<li>Daneshmanesh AH, Hojjat-Farsangi M, Sandin A, Khan AS, Moshfegh A, et al.. (2012) Monoclonal Antibody Against ROR1 In Chronic Lymphocytic Leukemia Cells Induced Apoptosis Via PI3-kinase/AKT/CREB pathway. 54th American Society of hematology (ASH), Atlanta, USA, 8–11 December.</li>
<li>T. Yamaguchi, K. Yanagisawa, R. Sugiyama, Y. Hosono, Y. Shimada, C. Arima, S. Kato, S. Tomida, M. Suzuki, H. Osada, T. Takahashi. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell, 21 (2012), pp. 348–361</li>
<li>Fukuda T, Chen L, Endo T, Tang L, Lu D, Castro JE, Widhopf GF, II, Rassenti LZ, Cantwell MJ, Prussak CE, et al. Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc Natl Acad Sci USA. 2008;105:3047–3052. doi: 10.1073/pnas.0712148105.</li>
<li>Gentile A, Lazzari L, Benvenuti S, Trusolino L, Comoglio PM. Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res 2011;71:3132–41.</li>
<li>Zhang S, Chen L, Cui B, Chuang HY, Yu J, Wang-Rodriguez J, et al. ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS ONE 2012;7:e31127.</li>
<li>Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin CancerRes. 2010;16(11):2927-31.</li>
<li>Nomi M, Oishi I, Kani S, Suzuki H, Matsuda T, Yoda A, et al. Loss of mRor1 enhances the heart and skeletal abnormalities in mRor2-deficient mice: redundant and pleiotropic functions of mRor1 and mRor2 receptor tyrosine kinases. Mol Cell Biol 2001;21:8329–35.</li>
<li>Endo M, Doi R, Nishita M, Minami Y. Ror family receptor tyrosine kinases regulate the maintenance of neural progenitor cells in the developing neocortex. J Cell Sci 2012;125:2017–29.</li>
<li>Reddy UR, Phatak S, Pleasure D. Human neural tissues express a truncated Ror1 receptor tyrosine kinase, lacking both extracellular and transmembrane domains. Oncogene 1996;13:1555–9.</li>
<li>Linked in text.</li>
</ol>
Answer: <p>Examining the literature it'd seem that the ROR pathways incl. ROR1 and ROR2 are critical for developing tissues in the majority of cases. We also see relevance in the expression of ROR1/2, more specifically ROR2, in cases where taxic cell types are required to migrate, branch, etc. Most of the literature determines much of this occurs through a noncanonical Wnt signaling pathway.</p>
<p><a href="http://www.pnas.org/content/109/11/4044.abstract" rel="nofollow">Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis</a></p>
<p><a href="http://www.jbc.org/content/289/30/20664.abstract" rel="nofollow">Ror2 Receptor Mediates Wnt11 Ligand Signaling and Affects Convergence and Extension Movements in Zebrafish</a></p>
<p><a href="http://jcb.rupress.org/content/208/3/351.abstract" rel="nofollow">Ror2 regulates branching, differentiation, and actin-cytoskeletal dynamics within the mammary epithelium</a></p>
<p>Notwithstanding the abnormalities we see in neonates with knocked down ROR, is it wrong to assume we'd see developmental defects of branching tissues in developing (or juvenile) organisms such as lung, mammary, neural, glandular tissue, etc.? Some data in that respect would be interesting, but it's also illuminating given the presence of ROR in cancer metastasis and EMT events.</p>
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https://biology.stackexchange.com/questions/28464/expression-mechanism-of-ror1-in-healthy-tissue
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Question: <p><strong>The question</strong> is fairly simple - does formaldehyde or methanol fixation in preparation for immunocytochemistry/immunofluorescent staining affect the pH of the lysosomes?</p>
<p><strong>Some background:</strong> I'm trying to look at the intracellular trafficking of a fluorescently-labeled lysosomal enzyme. Cells are grown <em>in vitro</em> and treated with the labeled protein, which is taken up into the cells via <a href="https://en.wikipedia.org/wiki/Receptor-mediated_endocytosis" rel="nofollow">receptor-mediated endocytosis</a>. The protein-receptor complex targets the late endosome-lysosome pathway, where eventually the acidic pH of the lysosome causes the two to dissociate and the receptor to recycle, while the enzyme stays and does its thing. I've labeled the enzyme with two different dyes - Alexa Fluor 488, which is supposedly <a href="http://www.lifetechnologies.com/us/en/home/references/molecular-probes-the-handbook/fluorophores-and-their-amine-reactive-derivatives/alexa-fluor-dyes-spanning-the-visible-and-infrared-spectrum.html?icid=fr-alexa-3#head1" rel="nofollow">pH-insensitive between 4 and 10</a>, and <a href="https://www.lifetechnologies.com/us/en/home/references/newsletters-and-journals/bioprobes-journal-of-cell-biology-applications/bioprobes-issues-2012/bioprobes-68-november-2012/phrodo-ph-indicators.html" rel="nofollow">pHrodo Red</a>, which has greatly-increased fluorescence as the pH drops. Alexa488 is the brightest of the Alexa dyes, and is widely used in all sorts of applications. pHrodo is not as bright (as far as I can tell, it's been difficult to find comparisons), but its pH-dependence helps lower the effect of non-specific extracellular binding, and it seems to work in my system so far.</p>
<p><strong>So what's the problem?</strong> I'm developing an assay that will measure the ability of certain substances to block the uptake of this enzyme into the cell. Since I'll be measuring a lack of signal, the higher I can get the uninhibited signal to be, the better. Like I said, pHrodo works OK, but it could be better. The problem is that my Alexa-labeled protein has an extremely low signal to noise ratio, when I would have expected the exact opposite. I'm wondering if, in my system, the Alexa dye really <strong>is</strong> somewhat pH-sensitive, and is not fluorescing as well when in the acidic lysosome. I'm encountering a few other issues as well, and while before I was performing live-cell imaging, I'm starting to toy with the idea of fixing the cells first, as that will positively impact some other things I want to try.</p>
<p><strong>Hence my question:</strong> Will fixing the cells with 4% formaldehyde in PBS (standard ICC/IF protocol) affect the pH of the lysosomes? Would methanol fixation do the same thing? Any other suggestions for increasing signal?</p>
Answer: <p>In my opinion, cell fixation shouldn't change the pH. However unbuffered formalin will oxidize and lower the pH, but using PBS should buffer around pH 7.
Maybe Glutaraldehyde fixation would also be an option, if the others are not working...</p>
<p>I found this website by leica very useful, maybe it will also help you:</p>
<blockquote>
<p><a href="http://www.leicabiosystems.com/pathologyleaders/fixation-and-fixatives-2-factors-influencing-chemical-fixation-formaldehyde-and-glutaraldehyde/" rel="nofollow">http://www.leicabiosystems.com/pathologyleaders/fixation-and-fixatives-2-factors-influencing-chemical-fixation-formaldehyde-and-glutaraldehyde/</a></p>
</blockquote>
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https://biology.stackexchange.com/questions/10476/how-does-formaldehyde-pbs-or-methanol-fixation-of-cells-affect-lysosomal-ph
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Question: <p><a href="https://www.nature.com/articles/s41580-019-0199-y" rel="nofollow noreferrer">A 2020 review paper about mTOR</a> (ref. 1) says:</p>
<blockquote>
<p>because biomass accumulation demands vast reserves of energetic currency, mTORC1 enhances translation of nuclear-encoded mitochondrial transcripts through 4E-BP1 to expand the ATP production capacity of the cell</p>
</blockquote>
<p>The above quote cites <a href="https://www.sciencedirect.com/science/article/pii/S0092867409009143" rel="nofollow noreferrer">a 2009 paper</a> (ref. 2) that says:</p>
<blockquote>
<p>Upon DR mitochondrial protein density increased 25% in control flies, while in d4E-BP null mutant flies there was no change</p>
</blockquote>
<p>(DR stands for "dietary restriction", which is known to inhibit TOR, which is an inhibitor of d4E-BP, if I understand correctly.)</p>
<p>These two really confuse me, as it seems to me that ref. 1 cites ref. 2 but says the opposite.<br/>
To spell it out: It seems that everyone agrees that active (i.e., non-phosphorylated) 4E-BPs inhibit translation, but ref. 1 claims that the inhibition is strongest for nuclear-encoded mitochondrial transcripts, while ref. 2 claims the inhibition is weakest for these transcripts.</p>
<p>As far as I can tell, the claim by ref. 1 is also supported by two other papers: <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045806" rel="nofollow noreferrer">A 2012 paper</a> (ref. 3) that says:</p>
<blockquote>
<p>gene silencing of 4E-BP1 up-regulated the protein expressions of all RCs and the action of 4E-BP1 appeared to be specific to these mitochondrial proteins.</p>
</blockquote>
<p>And <a href="https://www.sciencedirect.com/science/article/pii/S1550413113004130" rel="nofollow noreferrer">a 2013 paper</a> (ref. 4) that says:</p>
<blockquote>
<p>Whereas 4E-BP1/2 depletion did not affect polysome distribution of β-actin mRNA (Figure 6B, upper), it prevented the Ink1341-induced shift of TFAM and ATP5O mRNAs toward lighter polysomes (Figure 6B, lower). Therefore, 4E-BPs act as major mediators of mTORC1 on translation of TFAM and ATP5O mRNAs. Accordingly, asTORi decreased ATP5O and TFAM protein levels in control, but not in 4E-BP1/2-depleted cells</p>
</blockquote>
<p>Finally, I found <a href="https://www.pnas.org/content/114/36/9737.long" rel="nofollow noreferrer">a 2017 paper</a> (ref. 5) that seems to make a claim similar to the one ref. 2 makes. It says:</p>
<blockquote>
<p>cold inhibits translation in general, but the synthesis of proteins destined to the mitochondria is selectively preserved, resulting in a cellular enrichment of these molecules.</p>
</blockquote>
<p>and:</p>
<blockquote>
<p>4E-BP can be phosphorylated at multiple sites but phosphorylation of Thr37/Thr46 by the mammalian target of rapamycin (mTOR) acts as a priming event required for further phosphorylation. Cold exposure increased the proportion of nonphosphorylated protein, largely at the expense of the primed fraction [...] Taken collectively, our observations suggest that reduced ambient temperature induces a physiological state comprising posttranslational modification of 4E-BP—resulting in a lower proportion of the phosphorylated isoform primed for inactivation—and a switch from global protein translation toward mitochondrial metabolism and efficiency.</p>
</blockquote>
<p>So my question is:<br/>
Is it really that refs 1,3,4 say one thing, and refs 2,5 say the opposite?<br/>
If yes: Has anyone offered an explanation to resolve the seemingly contradicting results?</p>
<p><strong>References</strong><br/></p>
<ol>
<li><a href="https://www.nature.com/articles/s41580-019-0199-y" rel="nofollow noreferrer">Liu, Grace Y., and David M. Sabatini. "mTOR at the nexus of nutrition, growth, ageing and disease." Nature Reviews Molecular Cell Biology 21.4 (2020): 183-203.</a></li>
<li><a href="https://www.sciencedirect.com/science/article/pii/S0092867409009143" rel="nofollow noreferrer">Zid, Brian M., et al. "4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila." Cell 139.1 (2009): 149-160.</a></li>
<li><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045806" rel="nofollow noreferrer">Goo, Chong Kiat, et al. "PTEN/Akt signaling controls mitochondrial respiratory capacity through 4E-BP1." (2012): e45806.</a></li>
<li><a href="https://www.sciencedirect.com/science/article/pii/S1550413113004130" rel="nofollow noreferrer">Morita, Masahiro, et al. "mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation." Cell metabolism 18.5 (2013): 698-711.</a></li>
<li><a href="https://www.pnas.org/content/114/36/9737.long" rel="nofollow noreferrer">Carvalho, Gil B., et al. "The 4E-BP growth pathway regulates the effect of ambient temperature on Drosophila metabolism and lifespan." Proceedings of the National Academy of Sciences 114.36 (2017): 9737-9742.</a></li>
</ol>
Answer:
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https://biology.stackexchange.com/questions/104524/how-does-the-phosphorylation-state-of-4e-bps-affect-translation-of-nuclear-encod
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Question: <p>Consider the following synaptic connections (<a href="http://www.apsubiology.org/anatomy/2010/2010_Exam_Reviews/Exam_3_Review/CH_11_Neuron-to-Neuron_Transmission.htm" rel="nofollow noreferrer">from here</a>):</p>
<blockquote>
<p><strong>axodendritic</strong> - A term pertaining to an excitatory or inhibitory synaptic connection between the presynaptic axon of a transmitting neuron and the postsynaptic dendrite(s) of a receiving neuron in a nerve impulse pathway; <em>such connections can influence whether or not a graded potential will be generated on a postsynaptic dendrite</em>.</p>
<p><strong>axosomatic</strong> - A term pertaining to an excitatory or inhibitory synaptic connection between the presynaptic axon of a transmitting neuron and the postsynaptic cell body/soma of a receiving neuron in a nerve impulse pathway; <em>such connections can influence whether or not an action potential will be generated in the postsynaptic axon trigger zone at the axon hillock</em>.</p>
<p><strong>axoaxonic</strong> - A term pertaining to an excitatory or inhibitory synaptic connection between the presynaptic axon of a transmitting neuron and the postsynaptic axon hillock or axon of a receiving neuron in a nerve impulse pathway; <em>such connections can influence whether or not an action potential will be generated in the postsynaptic axon trigger zone at the axon hillock</em>.</p>
</blockquote>
<p>What exactly are the differences between the connections in terms of their influence on the neuron?</p>
<p>To my understanding:</p>
<ul>
<li>axodendritic: influences a dendrite <span class="math-container">$\rightarrow$</span> hence influences the graded potential of the neuron</li>
<li>axosomatic: influences the graded potential of the neuron directly</li>
<li>axoaxonic: influences the axon only (independently of the neuron?)</li>
</ul>
<p>Hence, to my understanding the axodendritic and axosomatic connections yield the same result: they influence the graded potential of the neuron (<em>e.g. whether the neuron "fires"</em>), where the axoaxonic connection only influences whether the axon fires. Is this correct?</p>
<p>If so, then what is the purpose of dendrites? If axons can connect to the cell body directly, then why would they need dendrites (apart from yielding a larger connection surface to the neuron)?</p>
<p><strong>Note:</strong> I have read <a href="https://biology.stackexchange.com/questions/849/how-does-an-inhibitory-synapse-communicate-to-the-cell-body-of-a-neuron/852#852">this answer</a>, which partially explains the use of dendrites. However, it also states that the signal decay due to the synaptic location is compensated for by the local potential change. Therefore, IMO, the answer states that the main advantage of having dendrites is that inhibitory axosomatic synapses can capitalize on the location-dependence of the axodendritic synapses. Is that the <em>true and only purpose</em> of axosomatic synapses? (Please, correct me if my inference is wrong!)</p>
Answer: <p>Neurons are all about specialized structures having specialized roles. You've given a good justification for dendrites---an efficient way to fit lots of connections in a small space. A pyramidal neuron in cortex, for instance, will have tens of thousands of synapses. If you only had axosomatic connections, the soma would have to be enormous to fit all of them (and this would cause lots of other issues).</p>
<p>Dendritic structure also allows the cell more efficient electrical properties (see cable theory) and to process inputs independently. In fact, different parts of the dendrite are now thought of as independent computational compartments. For instance, the cell might want to selectively strengthen a single synapse or all the synapses on one dendritic branch. By physically isolating those synapses in small dendritic structures, it is easier to make those targeted changes without unwanted "crosstalk" on other synapses or cell activities. What's more, incoming connections from different areas often segregate into regions of the dendrite (e.g. in CA1 hippocampal pyramidal neurons, cortical connections to the most distant part of the dendrite, internal hippocampal connections to the part of the dendrite closer to the soma).</p>
<p>When a cell has a large dendrite (some neurons have no dendrites), its useful to think of axodendritic synapses as the normal inputs that contribute to fine-grained computation, and axosomatic and axoaxonic synapses as more global gates. These latter types take advantage of their location to short circuit the "normal" computation in the dendrites. An inhibitory axosomatic synapse, for example, will reduce the effect of <em>all</em> dendritic inputs when activated.</p>
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https://biology.stackexchange.com/questions/40144/differences-between-synaptic-connections
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Question: <p>So I've been reading a lot of papers on the reward pathway. But since I'm not schooled in any relevant knowledge I'm having trouble grasping the chain of events. Most papers detail just bits and pieces, but not the full sequence of events.</p>
<p>I'm trying to grasp how the error prediction signal works.</p>
<p>This is my guess so far:</p>
<p><strong>Players</strong>: </p>
<blockquote>
<p>Photosensitice cell <strong>A</strong><br>
Light processing neuron <strong>B</strong><br>
Dopamine neuron <strong>C</strong><br>
Motorneuron <strong>D</strong></p>
</blockquote>
<p><strong>Event</strong>:</p>
<blockquote>
<p>Light strikes <strong>A</strong><br>
<strong>A</strong> triggers <strong>B</strong><br>
<strong>B</strong> spikes after <em>N</em> triggers.<br>
<strong>B</strong> triggers <strong>C</strong><br>
<strong>C</strong> spikes after <em>N</em> triggers.<br>
<strong>C</strong> keeps repeadetly spiking for as long as its internally coded reward size/duration expectation.<br>
<strong>D</strong> receives predecition triggers spikes causing action.<br>
Reward comes, neural connections are strengthened.<br>
If reward doesnt come in predicted time connection degrades. </p>
</blockquote>
<p>Am I correct in this deduction or way off?</p>
<p>How does the actual reward get communicated? By dopamine release in blood?<br>
By the same neurons that coded the reward prediction? If so, how do those exact neurons get triggered to release reward?</p>
Answer: <p>Essentially that's what I remember, but there can be a lot more steps between A and C, i.e. more pathways interacting in different systems to produce an associative memory. Pavlov's dogs is the classic example:</p>
<p>1: Pavlov rings bell, dogs hear bell</p>
<p>2: Pavlov feeds dogs, (dogs rewarded)</p>
<p>3: Repeat 1 and 2 for a few days.</p>
<p>4: Ring bell, dogs will salivate and expect food, even if no food is on the way.</p>
<p>So, in the skull, the dogs are making a link between hearing a bell and a reward.</p>
<p>Dopamine is released at dopaminergic synapses, the <a href="https://en.wikipedia.org/wiki/Limbic_system" rel="nofollow noreferrer">limbic system</a> is probably the best understood part of the memory/reward system, particularly the <a href="http://neuroscience.mssm.edu/nestler/nidappg/brainrewardpathways.html" rel="nofollow noreferrer">mesolimbic</a> pathway for reward.</p>
<p>Neurons get triggered by presynaptic neurotransmitters, some require convergence of signals to reach threshold and trigger an action potential. Connections are strengthened by long-term potentiation, which has been argued to be the basis for memories, but that's a massive topic I'm not qualified to discuss.</p>
<p>I haven't heard of the "error prediction signal" before, might be a new discovery/thinking that I'm a bit behind on.</p>
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https://biology.stackexchange.com/questions/60294/reward-pathway-sequence-of-events
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Question: <p>I have been reading a fascinating paper: <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848041/">Valproate reopens critical-period learning of absolute pitch</a></p>
<p>18 individuals were given Sodium Valproate (VPA) for a fortnight during which they trained on a pitch-training game. Results suggest that VPA reopens the plasticity window that normally closes by adolescence.</p>
<p>However, the paper seems to suggest that the exact mechanism of action is unknown.</p>
<blockquote>
<p>Valproic acid is believed to have multiple pharmacological actions,
including acute blockade of GABA transaminase to enhance inhibitory
function in epileptic seizures and enduring effects on gene
transcription as an histone deacetlyase (HDAC) inhibitor (Monti et
al., 2009). Of relevance here is the epigenetic actions of this drug,
as enhancing inhibition does not reactivate brain plasticity in
adulthood (Fagiolini and Hensch, 2000), but reopening chromatin
structure does (Putignano et al., 2007). While systemic drug
application is a rather coarse treatment, the effects may differ
dramatically by individual cell type (TK Hensch and P Carninci,
unpublished observations). VPA treatment mimics Nogo receptor deletion
to reopen plasticity for acoustic preference in mice (Yang et al.,
2012), suggesting a common pathway through the regulation of
myelin-related signaling which normally closes critical period
plasticity (McGee et al., 2005). Future work will address the cellular
actions of VPA treatment in the process of reactivating critical
periods. Future MRI studies will also be needed to establish whether
HDAC inhibition by VPA induces hyperconnectivity of myelinated,
long-range connections concurrent with renewed AP ability (Loui et
al., 2011).</p>
</blockquote>
<p>So it is saying that the standard use of VPA is to increase GABA levels (which keeps firing rate down -- it is used as an antiepileptic), however it also acts as an HDAC inhibitor, which means it causes unwrapping of chromatin and consequently increased mRNA transcription, maybe even transcription of genes that would normally be entirely deactivated in an adult.</p>
<p>So my guess is that some protein is getting produced that messages neurons to generate new axon/dendrite growth and/or new synaptic connections.</p>
<p>Can anyone clarify how VPA might accomplish plasticity?</p>
<p>EDIT (one month later): I have more detail, but I still can't quite make the connection. Here goes:</p>
<p>Neurites get wrapped by myelin/oligodendrocyte, which produces and exudes some of the chemical messagers {Nogo, OMgp, MAG}. The membrane surface of the neurite contains nogo 66 receptors (NgR-s) that get triggered by these messagers and inform the neuron to inhibit axon-growth. Somehow the 'HDAC inhibition' property of VPA is unwinding DNA enough to alter transcription rates of certain proteins, and one of these must be disabling the NgR.</p>
<p>But how is this happening?</p>
Answer: <p>As far as I can see this paper is being a little misleading, by saying "VPA mimics Nogo-66 receptor deletion".</p>
<p>The action of VPA doesn't seem to be related to this receptor.</p>
<p>It seems that blocking this receptor and applying VPA both increase plasticity, but via different mechanisms.</p>
<p>VPA seems to facilitate LTP through increased availability of relevant proteins (as an HDAC inhibitor, it "loosens/unwinds" DNA, allowing for increase in protein transcription). And by increasing protein transcription across the board, it may be increasing the availability of proteins that promote synapse formation.</p>
<p>The principal problem with growing new structure is, as hinted at the end of the question, that the adolescent/adult brain secretes a chemical that gets picked up by Nogo 66 receptor, which signals to collapse the axon growth cone.</p>
<p>It's why adult humans can't recover from spinal injuries. The axons won't reconnect.</p>
<p>It so happens that a small molecule Nogo Antagonist has recently been developed by Professor Strittmatter. He was kind to reply to my query, and I learned that this molecule is currently in the early stages of FDA approval. It's a very exciting discovery!</p>
<p>I would caution anyone considering taking VPA to balance it with a beta-blocker (e.g. omeprazole). It is an acid, and if not balanced with something to reduce the stomach's ability to produce acid, risks acid reflux, which may force a change of diet, and be longterm/permanent. So, DYOR.</p>
<p>Also of note is that (again discovered by Strittmatter) Ibuprofen has been found to also interrupt the signalling pathway that leads to axon growth collapse. But it requires a high dosage, and ibuprofen also causes a similar imbalance.</p>
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https://biology.stackexchange.com/questions/19856/how-does-sodium-valproate-cause-neural-plasticity
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Question: <p><strong>[EDIT]</strong> - Have just found not <a href="http://www.uniprot.org/citations/7791872" rel="nofollow">one</a> but <a href="http://www.nature.com/nsmb/journal/v3/n8/abs/nsb0896-723.html" rel="nofollow">two</a> papers that address my structure problem. However they concern RAP-1A, so I guess my question is now what is the difference in structure and function of RAP-1A and RAP-5? Does anyone know of X-ray structure analysis being used to examine RAP-5? </p>
<hr>
<h2>original question</h2>
<p>I'm a University Physics student writing a mock review article on what to me feels like a very 'un-physicsy' antibody - RAP-5. </p>
<p>Although my knowledge of Biology is pretty poor, research is going quite well. I've found a lot of papers from the 80s talking about conducting immunohisto(/cyto)chemistry experiments, most of them finding that RAP-5 can be used to determine whether a cell has the ras in it, so they are able to measure the percentage of cells that are neoplastic (I believe this means cancerous) and contain ras and the percentage of cells which are normal and contain ras. (the ras-gene being a proto-oncogene which on mutation can result in permanently switched on ras proteins (p21?), which results in proliferation of cells and therefore can cause tumors). This is all very nice but on first glance immunohistochemistry doesn't seem to involve a huge amount of physics (for my bio-physics assignment), apart from using an optical microscope. </p>
<p>I was hoping to be able focus a section of my article on the physical techniques involved in determining the structure of RAP-5. Although there seems to be plenty of literature on uses of RAP-5, I am struggling to find anything on the details on why it is able to be used in such experiments. In other words, I presume that its function is to bind on to an epitode specific to the ras protein (amino acids 10 -17 have popped up a few times) but I don't know if there is any imaging one can do to have a look at the structure and conclude 'yes this is why it binds to ras proteins and not to others'. Is there a technique that is likely to have been used to examine the structure of RAP-5? Is it's tertiary structure likely to be 'Y' shaped like other antibodies? Does it differ in structure from RAP1-4? (<a href="http://books.google.co.uk/books?id=Ht1bypUY7c8C&pg=PA298&lpg=PA298&dq=ras%20Adenylate%20cyclase%20rap&source=bl&ots=WXvSq69THL&sig=ijXnD_UdHlkBumk2DmSOQUy3fu8&hl=en&sa=X&ei=LABlT_eeGeOy0QWLg8iWCA&ved=0CDcQ6AEwAg#v=onepage&q=ras%20Adenylate%20cyclase%20rap&f=false" rel="nofollow">this book</a> informs me that RAP1 and RAP2 have 60% sequence identity, but most sources seem to leave out RAP3-to-5, some evening telling me that the RAP family consists of RAP1A/B, RAP2A/B/C and no others!).</p>
<p>Also, if RAP-5 is an antibody, does this mean that it is produced in the body and gets involved in the ras protein signal pathway in order to reduce too much ras expression? (am I right in saying the amount of expression is the amount of protein the ras-gene is producing?) or is it only synthetically produced and used in experiments to measure the amount and location of ras proteins? </p>
<p>Also there seems to be little differentiation between the differences in the functions of each RAP. RAP-5 seems to be used quite a bit in experiments involving Ha-ras - but not exclusively. Do the different RAPs bind to different variants of ras? Ha-ras being the one unique to RAP-5. </p>
Answer: <p>The confusion that you're facing is because RAP-5 is actually known as <a href="http://en.wikipedia.org/wiki/RAB5C" rel="nofollow">RAB5C</a> (<a href="http://www.ncbi.nlm.nih.gov/gene/5878" rel="nofollow">GENEID</a>). The <a href="http://en.wikipedia.org/wiki/Ras_superfamily" rel="nofollow">ras superfamily</a> (<a href="http://www.ncbi.nlm.nih.gov/pubmed/3145021" rel="nofollow">review</a>) is divided into Ras, Rho, Rab, and Rap. But the Rap GTPases are divided only into two categories, <a href="http://www.ncbi.nlm.nih.gov/pubmed/14570053" rel="nofollow">RAP1 and RAP2</a>. On the other hand, there are multiple <a href="http://en.wikipedia.org/wiki/Rab_%28G-protein%29" rel="nofollow">Rab GTPases</a> which include <a href="http://www.ncbi.nlm.nih.gov/gene/5868" rel="nofollow">RAB5A</a> and <a href="http://www.ncbi.nlm.nih.gov/gene/5878" rel="nofollow">RAB5C</a>.</p>
<p>There are a few crystal structures of both Rab5A and Rab5C in both human and murine forms.</p>
<p>Now, for RAP-5. <a href="http://www.nature.com/bjc/journal/v54/n6/abs/bjc1986256a.html" rel="nofollow">RAP-5</a> <strong>is</strong> a monoclonal murine antibody which has no relationship to the RAP family of proteins. It's probably called RAP because Spandidos and Wilkie weren't thinking clearly when they named their antibodies RAP1-5. In this case, you're probably better off looking at the antibody Y13-259 which is probably called that since its the 259th antibody they tried.</p>
<p>To answer your questions, specifically, very few people have attempted to get a structure since it is an antibody and everyone knows what they look like. Secondly, the antibody is produced in a mouse and added to tissue. And yes, the RAP antibodies bind to different variants of Ras. Also, no one uses RAP-5 since anti-Ras <a href="http://www.abcam.com/Ras-antibody-EP1125Y-ab52939.html" rel="nofollow">EP1125Y</a> seems to be more popular.</p>
<p>If you still want a crystal structure, I would hunt down the RAP5 patent and look up the peptide sequence. From there, you can look up similar structures in the <a href="http://www.imgt.org/" rel="nofollow">IMGT database</a></p>
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https://biology.stackexchange.com/questions/1469/structure-of-rap-antibodies-specifically-rap-5
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Question: <p>Membrane insertion of transmembrane proteins typically requires highly hydrophobic alpha helixes at the N-terminus, N-terminal signal peptides, tail anchors, or a combination of the three.</p>
<p>Byun, H., Gou, Y., Zook, A., Lozano, M., & Dudley, J. (n.d). ERAD and how viruses exploit it. Frontiers In Microbiology, 5</p>
<p>These processes occur co-translationally and are mediated by the SEC translocon and associated factors (especially GPI anchor transferases for tail-anchored proteins). However, my undergraduate research is focused on a viral protein which appears to be translated in association with SRP and co-translationally translocated to the ER by the translocon, but is not anchored to the membrane during translocation. This was shown (by others) by purification of the ER-associated fraction of the protein and centrifugation showing the majority pelleted with the dense, soluble fraction. A small fraction pelleted with the low density membrane-associated fraction, and my research further suggests that this membrane-associated fraction is important for its escape from the ER.</p>
<p>The protein I am studying functions in the cytoplasm, not in the ER or in the secretory pathway, and therefore its escape from the ER is essential for its function. The typical ERAD pathway for soluble proteins involves retrotranslocation through the Sec61 translocon channel (the same channel involved in co-translational translocation, but with different associated factors during ERAD), but this would result in unfolding of the protein prior to its retrotranslocation to the cytosol. On the other hand, the ERAD pathway for membrane proteins (the "dislocation pathway") appears to dislocate folded membrane proteins while retaining most or all of their tertiary/quaternary structure (previous citation and below).</p>
<p>Avci, D., & Lemberg, M. K. (2015). Clipping or Extracting: Two Ways to Membrane Protein Degradation. Trends In Cell Biology, (10), 611. doi:10.1016/j.tcb.2015.07.003</p>
<p>Knowing that the protein is not co-translationally inserted into the membrane because only a small fraction is membrane associated, and suspecting that the small membrane-associated fraction is important for its escape from the ER because the dislocation pathway allows folded protein to exit the ER, my question is:</p>
<p>How could the retrotranslocation pathway for soluble proteins be disrupted such that it would (infrequently) result in membrane insertion of this protein <strong>at an early step in retrotranslocation-coupled unfolding, such that the folded protein could follow the dislocation pathway into the cytoplasm</strong>?</p>
<p>I would appreciate any examples of similar processes in viruses or in eukaryotes, but any speculation on possible mechanisms - based on understanding of ERAD but lacking supporting examples - would also be greatly appreciated.</p>
<p>As this is unpublished research, I can't be too specific about what virus or even what model system I'm working in, but if there is additional information that would help, I'll be happy to provide it - if I can.</p>
<p>One final piece of information that is also relevant is that I suspect the protein's transmembrane or membrane-anchored domain is very close to its C-terminus. Another important question that this raises is <strong>whether retrotranslocation exclusively proceeds by feeding the N-terminus of a protein into the Sec61 channel, or if the C-terminus can be fed directly into the channel?</strong> If only the N-terminus could be fed into the channel, this would suggest most of the protein would have to be unfolded before the C-terminal domain became associated with the channel and was able to become membrane-associated, which voids the main benefit of the dislocation pathway; maintaining the folded state of the protein.</p>
<p>If somebody can answer only this question regarding the translocon (and provide some relevant reading), I would be incredibly grateful because it would suggest further literature search to help support the mechanism I am proposing.</p>
<p>Thank you!</p>
Answer:
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https://biology.stackexchange.com/questions/45666/are-there-well-studied-examples-of-erad-mediated-membrane-insertion-especially
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Question: <p>So there was this video of a cat killing a snake: <a href="https://youtube.com/shorts/ygJb5skuTPM?feature=share" rel="nofollow noreferrer">Cat reaction time</a><br>
and another of a bobcat killing a rattlesnake <a href="https://youtu.be/QUH3Sxcprws" rel="nofollow noreferrer">Bobcat kills rattlesnake</a><br>
And then this from <a href="https://en.m.wikipedia.org/wiki/Sand_cat" rel="nofollow noreferrer">wikipedia on sand cats:</a></p>
<blockquote>
<p>In the Ténéré, a desert region in south central Sahara, sand cats were observed preying foremost on small rodents, and the young of cape hare (Lepus capensis), but also hunting greater hoopoe lark (Alaemon alaudipes), desert monitor (Varanus griseus), sandfish (Scincus scincus) and venomous Cerastes vipers.<br>
This paper claims that <a href="https://louisiana.edu/news/vipers-lose-rep-snakes-fastest-strike" rel="nofollow noreferrer">vipers and rattlesnakes have fastest strike rate</a><br>Mongoose are known predators of cobra.<br><br></p>
</blockquote>
<p>These mammals are able to hunt them because of their faster reaction time and/or relex velocity.</p>
<p><strong>So how is it that these animals have faster reaction times given that the length of signal transmission is actually lesser in those reptiles?</strong></p>
<p>From wikipedia:<br></p>
<blockquote>
<p><a href="https://en.m.wikipedia.org/wiki/Myelin" rel="nofollow noreferrer"> Myelin </a> is considered a defining characteristic of the jawed vertebrates (gnathostomes), though axons are ensheathed by a type of cell, called glial cells, in invertebrates.<br><br>
A <a href="https://en.m.wikipedia.org/wiki/Reflex_arc" rel="nofollow noreferrer">reflex arc</a> is a neural pathway that controls a reflex. In vertebrates, most sensory neurons do not pass directly into the brain, but synapse in the spinal cord. This allows for faster reflex actions to occur by activating spinal motor neurons.</p>
</blockquote>
<p>So those factors are eliminated. For the mentioned case, it might be that those reptiles don't have as good of a perception as their predators but again they have a higher ratio of electrical:chemical synapses.<br> (In case of a fly it is probably the smaller body and electrical synapses)</p>
<p><strong>So what are the general factors affecting the speed of a reflex/reaction time? If a specific system is of help, the visual reflex system of the feline will do just fine.</strong></p>
<p><strong>Why was the snake unable to escape being hit by the paw?</strong><br><em>(The snake has an extremely fast strike velocity and the most likely factors are eliminated. At such close ranges, stimulus perception should not differ much either)</em></p>
Answer:
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https://biology.stackexchange.com/questions/112263/what-are-the-factors-affecting-reaction-time-and-or-reflex-velocity
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Question: <p>This question pertains to the <a href="https://en.wikipedia.org/wiki/KRAS" rel="nofollow noreferrer">KRAS wikipedia page</a>, and I just want to double check and clarify my own understanding of how this mutation works in cancer.</p>
<p>It states:</p>
<blockquote>
<p><em>K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules.</em></p>
</blockquote>
<p>So if K-Ras is a switch, does that mean that when there is K-Ras mutation, it functions defectively so that it does not shut off? So for example when it binds to GTP and converts it to GDP, KRAS does not shut off regardless of GTP is converted to GDP and this would lead to / cause cancer.</p>
<p>So I guess I have several questions to my reasoning above..</p>
<ol>
<li><p>Why does excess conversion of GTP to GDP lead to cancer? Is it because this is specifically pertaining to the the RAS pathway?</p>
</li>
<li><p>When I referenced above "it" is the K-Ras binding event the K-Ras protein binding to GTP then converting to GDP caused by the K-RAS gene not being able to function correctly? I'm just confused if its the K-Ras gene causing the problem or the K-Ras protein being the problem, or is it both?</p>
</li>
<li><p>If K-Ras acts as a molecular switch, how to GEFs/GAPs effect K-Ras mutations? Because I know GEFS activate the conversion of of GTP to GDP, but what is its relationship to KRAS/K-Ras?</p>
</li>
</ol>
<p>In the next line it states:</p>
<blockquote>
<p><em>When the protein is bound to GDP, it does not relay signals to the cell's nucleus.</em></p>
</blockquote>
<ol start="4">
<li>Is this saying when K-Ras is bound to GDP, that the conversion of GTP to GDP won't ever stop? I kind of just don't understand why this was written or what its relevance is. Or is it simply stating K-Ras can only turn on GTP to convert it in to GDP but not the other way around?</li>
</ol>
Answer: <p>NRAS is indeed a molecular switch, as part of the MAP-Kinase signaltransduction pathway it acts in controling the signal which goes downstream and finally will cause the expression of genes. In the case of NRAS this includes genes for proliferation, which is important for tumors. In principle, this looks like shown on this figure (from <a href="https://de.wikipedia.org/wiki/Datei:MAPKpathway_diagram.svg" rel="nofollow noreferrer">here</a>):</p>
<p><a href="https://i.sstatic.net/yk7BL.png" rel="nofollow noreferrer"><img src="https://i.sstatic.net/yk7BL.png" alt="enter image description here"></a></p>
<p>RAS (this is the same for all three RAS family members) needs to be activated so it can signal downstream, this happens, when GTP is bound to the protein. Since permanent activation is obviously not a good idea, RAS itself has an intrinsic, but slow GTPase activity, which is activated by GTPase-activating proteins (GAP) and will eventually cleave the terminal phosphate group group from the GTP to make GDP + P. GDP bound RAS is inactive. GDP stays bound to the RAS protein and needs to be exchanged against GTP by Nucleotide Exchange factors (NEF) to activate RAS again.</p>
<p>The general principle is shown in this figure (from <a href="https://www.frontiersin.org/articles/10.3389/fonc.2014.00160/full" rel="nofollow noreferrer">here</a>):</p>
<p><a href="https://i.sstatic.net/emdNV.jpg" rel="nofollow noreferrer"><img src="https://i.sstatic.net/emdNV.jpg" alt="enter image description here"></a></p>
<p>Mutations in RAS proteins occur in 98% of the time in three locations (see reference 1): In codons 12, 13 and 61. All three mutation affect the ability of the protein to break down GTP by abolishing the intrinsic GTPase activity by the GAP (see reference 2). This leads to the accumulation of RAS protein which is permanently bound to GTP and therefore activated, subsequently activation transcription of genes for proliferation (amongst others). This process can lead to the formation of cancer.</p>
<p>Your questions: </p>
<ol>
<li><p>The conversation of GTP to GDP does not lead to cancer. This process stops the activation of RAS proteins. It is the permanent activation which causes the problems.</p></li>
<li><p>You have the mutation in the KRAS gene, which is the origin of the problem. The wrong activation is of course done by the KRAS protein.</p></li>
<li><p>GEFs facilitate the exchange of GDP to GTP, the break down of GTP is supported by the GAPs. The mutation hinders the GAP to fulfill their role, so they are useless in the mutated form of the protein.</p></li>
<li><p>The other way round. If RAS proteins are bound to GDP, they are rendered inactive, unless a GEF exchanges it again to GTP.</p></li>
</ol>
<p>References:</p>
<ol>
<li><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869631/" rel="nofollow noreferrer">RAS isoforms and mutations in cancer at a glance</a></li>
<li><a href="https://www.ncbi.nlm.nih.gov/pubmed/2833817" rel="nofollow noreferrer">Guanosine triphosphatase activating protein (GAP) interacts with the
p21 ras effector binding domain.</a></li>
</ol>
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https://biology.stackexchange.com/questions/89598/kras-gene-and-k-ras-mutations
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Question: <p>For someone who is interested in learning about the discovery of epigenetics, which are the foundational defining papers in the area?</p>
Answer: <p>I understand that Robin Holliday was the first to discuss the possible role of DNA methylation
in the control of Gene expression. In his paper "<a href="http://www.ncbi.nlm.nih.gov/pubmed/3310230">The inheritance of epigenetic defects</a>"
he presents what is one of the first modern formulations of what we now regard as epigenetics. The term "epigenetics" itself was coined by Conrad Waddington although this predated our modern understanding of heredity.</p>
<p>Holliday, R., <strong>The inheritance of epigenetic defects</strong>, 1987, Science, 238, 4824</p>
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https://biology.stackexchange.com/questions/264/defining-papers-in-epigenetics
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Question: <p>Gene regulation is aided by epigenetics. Epigenetics determines which genes are turned off and which are switched on, and it varies throughout our lifetimes. Is it feasible that epigenetic modifications switch off the genes that determine whether a muscle cell or a neuron is a muscle cell or a neuron? I have searched this question but I could not find an explanation.</p>
Answer: <p>Correct me if I am wrong but it seems you are asking 'do epigenetic mechanisms influence cell fate/determination?'. If this is your question, the answer is yes. Epigenetic modifications play a key role in 'deciding' what type of cell a given stem cell will differentiate into. Here is some more information: <a href="https://www.nature.com/articles/pr2006122" rel="nofollow noreferrer">https://www.nature.com/articles/pr2006122</a></p>
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https://biology.stackexchange.com/questions/101301/gene-regulation-and-epigenetics-in-specialized-cells
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Question: <p><em><strong>Background:</strong></em> While classical genetics deals with how DNA sequences directly code for traits, epigenetics involves chemical modifications to DNA and associated proteins that can switch genes on or off without changing the underlying DNA sequence (including DNA methylation, histone modifications, and chromatin accessibility, etc).</p>
<p><em><strong>Question:</strong></em> Is it possible to quantitatively measure and compare the impact of DNA and epigenetics on expression? Which one is more important and by how much? If so,</p>
<blockquote>
<p>What is the proportional contribution of epigenetic modifications
versus DNA sequence variation to gene expression variance in human
somatic cells, expressed as percentages of total phenotypic variance?</p>
</blockquote>
<p><em><strong>Example equation:</strong></em></p>
<p><span class="math-container">$\text{Total Phenotypic Variance} = \sigma^2_G + \sigma^2_E + \sigma^2_{G \times E} + \sigma^2_{\text{error}}$</span></p>
<p>Here, G means genetics, E means epigenetics, and the third term is covariance.</p>
<p><em><strong>Example result:</strong></em> I wonder if there are already results like this: Genetic sequence variation explains about 25-40% of expression variance in a sample. Epigenetic variation accounts for approximately 10-30% of expression variance. The remaining variance is attributed to environmental factors, measurement noise, and gene-environment interactions</p>
<p>There are surely a lot of loopholes and drawbacks in this approach, so I wonder if there are better approaches. I think this quantitative analysis would be very important, because it can guide us in many areas. For example, in genetic engineering, we need to know if it is more efficient to edit the gene or to deal with the epigenetics.</p>
Answer: <p>There is extensive work attempting to decompose phenotypic variance into genetic, epigenetic etc. terms. Here are just three random examples from the last 10 years that I got by googling this:</p>
<ul>
<li><a href="https://www.nature.com/articles/s41437-019-0261-8" rel="nofollow noreferrer">https://www.nature.com/articles/s41437-019-0261-8</a></li>
<li><a href="https://www.nature.com/articles/s41467-020-16520-1" rel="nofollow noreferrer">https://www.nature.com/articles/s41467-020-16520-1</a> (focuses specifically on DNA methylation, which is possibly dubious from a classic interpretation of epigenetics)</li>
<li><a href="https://www.nature.com/articles/s41437-018-0114-x.pdf" rel="nofollow noreferrer">https://www.nature.com/articles/s41437-018-0114-x.pdf</a> (theoretical review)</li>
</ul>
<p>In some cases phenotypes show >50% of variance could be explained by epigenetic causes (see review). In other cases it is much less.</p>
<p>However, as always when considering these variance decomposition approaches, <a href="https://academic.oup.com/ije/article/35/3/520/735787" rel="nofollow noreferrer">variance decomposition does not substitute for a causal analysis</a>. Heritability is far too unstable of an estimator to be informative except in very well designed cases- that are more or less impossible to find for humans, because we can't breed humans for ethical reasons.</p>
<p>Epigenetic analysis only complicates this ambiguous approach, given its intimate relationship to both genetic and environmental contributors to phenotype.</p>
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https://biology.stackexchange.com/questions/115592/quantitatively-measure-the-impact-of-dna-vs-epigenetics
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Question: <p>I'm having trouble understanding what epigenetics is in a simple sense.</p>
<p>How I imagine it is that if we had 2 twins with identical DNA and we let them live we will see that they'll develop differently. Their DNA will stay the same (unless the DNA gains mutations, which could lead to cancer...) but their epigenetic tags will differ. These epigenetics tags determine the execution of parts of the DNA and the way the twins live their lives determine how the tags will be distributed. It's hard for me to find an example.</p>
<p>Another way I think of epigenetics is for example the cells in the muscles have a specific epigenetic tags to produce the specific proteins needed to create the muscle and the cells in the skin for example have different tags, produce different proteins which produce the skin.</p>
<p>Is my understanding of epigenetics anywhere close to the truth?</p>
Answer: <p><strong>Short answer:</strong> Yes, epigenetics play a role in determining gene expression, therefore protein expression and function.</p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752894/" rel="nofollow noreferrer">Lifestyle factors</a> like diet, smoking, alcohol consumption, and stress can change one's epigenome. A historical example of this might be the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579375/" rel="nofollow noreferrer">Dutch Hunger Winter of 1944-45</a>; there is evidence that after the parents' generation suffered during World War II, the children who were conceived during this time and exposed in utero to famine had different epigenetic marks than their siblings who were conceived <em>not</em> during the famine.</p>
<p>Epigenetic regulation is also essential for <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229506/" rel="nofollow noreferrer">cell differentiation</a> in vivo and in vitro. Embryonic stem cells undergo many changes to their epigenome in order to become mature cells. One interesting example for further reading is the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718001/" rel="nofollow noreferrer">transcription factor NeuroD1</a>, which binds to targets in the DNA to cause widespread changes in gene expression that are <em>specific</em> to neurons, and commits cells to a neuronal fate. It doesn't bind to thousands of neuronal genes; instead, it causes a "ripple effect" thanks to epigenetic mechanisms.</p>
<p><strong>Longer answer:</strong> Epigenetic marks are added to the genome for many reasons, including the two you just listed, and I think it is helpful to understand what happens at a molecular level in order to understand "why" we have them and to better visualize what the epigenetic marks ("tags") are. This might help you to think of better examples on your own.</p>
<p>DNA spends most of its time wrapped around proteins called <em>histones.</em> A complex of DNA and histones is called a <em>nucleosome.</em> DNA-in-nucleosomes is called <em>chromatin.</em> Chromatin can then either be "loose" (called <em>euchromatin</em>) or "compact" (called <em>heterochromatin</em>). There are more detailed ways to define how accessible chromatin is, but this is the basic idea. Intuitively, loose chromatin is more easily accessible and the genes there can be transcribed actively. Compact chromatin is less active.</p>
<p>The looseness of chromatin is determined by how closely the nucleosomes interact, which is controlled by the histones' molecular properties. Whether or not the histone proteins interact to make the chromatin compact, or repel each other to make the chromatin loose, depends on what modifications they possess. These modifications are added by <em>histone-modifying enzymes.</em></p>
<p>Histone-modifying enzymes are regulated by transcription factors (i.e. during the process of differentiation) as well as signals generated by extrinsic factors (i.e. during the organism's lifetime). The balance of activating and silencing activity is what adds and removes these marks to give a cell its individual epigenome.</p>
<p>So, in simple terms, epigenetic marks determine how <strong>accessible</strong> different parts of the DNA are, and a whole lot of factors (like cell identity and lifestyle) can determine where those epigenetic marks are.</p>
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https://biology.stackexchange.com/questions/80065/do-epigenetics-determine-the-proteins-a-cell-produces-and-therefore-its-functio
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Question: <p>I know that epigenetics have capacity to affect and degrade the genes thereby inducing problems/illness/degradation in body functions. </p>
<p>Can they also make better genes or have positive impact on genes or body? If yes, can someone give some examples?</p>
Answer: <p>First, let me qualify the idea of "problematic" epigenetic modifications by saying that the impact of a modification on an organism is often dependent on the environment. That is to say that outcome is dependent on the interaction of genetics (or epigenetics) and the environment in which the associated genes are expressed; <em>e.g.</em> a mutation or modification that confers an advantage in a nutrient-limiting environment may be detrimental when nutrients are plentiful. </p>
<p>Second, it is helpful to think of epigenetic modifications as reversible switches rather than entities that "degrade the genes". In fact, the <a href="https://en.wiktionary.org/wiki/epi-#English" rel="nofollow noreferrer">etymology</a> of "epigenetic" implies that such changes work at a level above that of the gene sequence, <em>i.e.</em> gene expression. Canonically, DNA methylation and histone modifications (acetylation and methylation) modify the expression of a gene by regulating the ability of RNA polymerase to access that gene, either by directly influencing transcription factor binding or modulating the associations of nucleosomes and DNA. Read up on <a href="https://en.wikipedia.org/wiki/Heterochromatin#Facultative_heterochromatin" rel="nofollow noreferrer">facultative heterochromatin</a>. </p>
<p>As for examples, I point you to a set of papers that show associations between human starvation, epigenetics, and disease / mortality outcomes across generations. </p>
<p><strong><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792223/" rel="nofollow noreferrer">DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood</a></strong></p>
<blockquote>
<p>[DNA methylation] at six CpGs, including at previously [serum triglyceride]-associated CpGs at TXNIP and ABCG1, mediated the association between famine exposure and [serum triglyceride]. [DNA methylation] at these CpGs was likewise associated with the expression of genes implicated in cell growth and energy metabolism. </p>
</blockquote>
<p>Note that the authors present caveats to their analyses in the discussion. The New York Times also <a href="https://www.nytimes.com/2018/01/31/science/dutch-famine-genes.html" rel="nofollow noreferrer">covered</a> this publication. </p>
<p><strong><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290014/" rel="nofollow noreferrer">Paternal grandfather’s access to food predicts all-cause and cancer mortality in grandsons</a></strong></p>
<p>This publication is essentially a replication of the <a href="https://www.ncbi.nlm.nih.gov/pubmed/16391557" rel="nofollow noreferrer">published works</a> concerning transgenerational epigenetics in the <a href="https://en.wikipedia.org/wiki/%C3%96verkalix_study" rel="nofollow noreferrer">Överkalix cohort</a>. They give a concise summary of how epigenetic changes caused by environmental stress may be heritable:</p>
<blockquote>
<p>An intriguing aspect of these studies is the conjecture that an epigenetic pathway, carrying information across generations, may open up just before puberty, during the so-called slow growth period (SGP). Pre-puberty may be one of several “windows” for germline reprogramming in response to nutritional signals. A number of mechanisms for transmission across generations have been suggested, usually involving DNA methylation, chromatin formation or small noncoding RNAs. After fertilization, in the preimplantation embryo, epigenetic modifications acquired early in life are then usually erased, but not fully. Imprinting on specific loci may resist the post fertilization wave of reprogramming, eventually causing changes in offspring phenotype that are not driven by changes of the DNA sequence.</p>
</blockquote>
<p>If you're looking for more examples, research <a href="https://en.wikipedia.org/wiki/Genomic_imprinting#Disorders_associated_with_imprinting" rel="nofollow noreferrer">genomic imprinting</a>. </p>
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https://biology.stackexchange.com/questions/88325/can-epigenetics-have-positive-impact-on-the-genes-are-development
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Question: <p>I am currently studying a textbook that presents the following definition of <strong>epigenetics</strong>:</p>
<blockquote>
<p>Epigenetics is defined as heritable changes in gene expression without changes in the DNA sequence. </p>
</blockquote>
<p>The authors then claim the following:</p>
<blockquote>
<p>DNA methylation is a stable and inheritable epigenetic mark. This genetically programmed modification is almost exclusively found on the 5' position of the pyrimidine ring of cytosines (5mC) adjacent to a guanine. </p>
</blockquote>
<p>Given these two excerpts, it seems somewhat contradictory to define epigenetics as heritable changes in gene expression <strong>without</strong> changes in the DNA sequence. After all, the DNA sequence is comprised of nucleotides, and it is these nucleotides that are modified during methylation (for instance, the addition of the methyl group on the 5' position of the pyrimidine ring of cytosines adjacent to a guanine), right? So, is it not technically true that the DNA sequence is changed? Or is what they're saying that, although the nucleotide is changed (such as in DNA methylation), the base pairs are unchanged (I'm unsure if this is true, just hypothesising)? </p>
<p>I would greatly appreciate it if people would please take the time to clarify this.</p>
Answer: <p>A methylated nucleotide is the same nucleotide, for the purposes of base-pairing events. The methylated base will be paired with its Watson-Crick opposite after replication, for instance (and methylation will even persist after replication).</p>
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https://biology.stackexchange.com/questions/90676/dna-methylation-and-the-validity-of-the-definition-of-epigenetics
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Question: <p>In a documentary, they were saying that epigenetics changes caused by the environment in an individual can be transferred to the following generations. I have some questions on that:</p>
<ol>
<li><p>How many generations are affected by an epigenetic change? can this be permanent?</p>
</li>
<li><p>Can drugs cause epigenetics changes in the current population that are visible in the following generations in the form of disease and birth defects?</p>
</li>
<li><p>Do epigenetic play any role in evolution? For example, is it possible that an epigenetic change becomes a permanent genetic change after a certain number of generations?</p>
</li>
</ol>
Answer: <p>Generally speaking, epigenetic modifications are not inherited as they are reset during embryogenesis. However, subsequent epigenetic modifications can be acquired during the period of pregnancy, which as a mechanism depends on the epigenetic state before the reset and on the physiological conditions of the mother including nutrition, health, stress, etc.. Obviously drug-intake years before pregnancy can still affect the mothers health-state.</p>
<p>Answering your first question: Epigenetic modifications generally cannot be directly passed, but indirect effects could theoretically pass through multiple generations without hard limit.</p>
<blockquote>
<p>A major barrier to transgenerational epigenetic inheritance is germline reprogramming, during which histone variants and their modifications, as well as small RNAs and DNA methylation, are all reset. In mammals reprogramming occurs both in the germline and in the zygote immediately after fertilization. (Source: Heard & Martienssen 2014 <a href="https://www.doi.org/10.1016/j.cell.2014.02.045" rel="nofollow noreferrer">doi: 10.1016/j.cell.2014.02.045</a>)</p>
</blockquote>
<p>2: The great <a href="https://vocal.media/longevity/the-irish-potato-famine-and-epigenetics" rel="nofollow noreferrer">potato famine</a> is said to still have epigenetic effects, generations later. 3.: Epigenetic changes cannot directly "become permanent" as genetic changes, although hypothetically speaking, epigenetic states can lead to viability of certain mutations that would otherwise be lethal and can therefore in theory influence evolution.</p>
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https://biology.stackexchange.com/questions/95332/role-of-epigenetics-in-evolution-and-transmission-of-defects-caused-by-drugs
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Question: <p>I am not a biologist. But googling "epigenetics lamarck", I find many different opinions:</p>
<ul>
<li>For: <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/brv.12322" rel="nofollow noreferrer">Lamarck rises from his grave</a>, <a href="https://www.acsh.org/news/2016/06/10/epigenetics-lamarcks-revenge" rel="nofollow noreferrer">Epigenetics: Lamarck’s Revenge?</a>, <a href="https://aeon.co/essays/on-epigenetics-we-need-both-darwin-s-and-lamarck-s-theories" rel="nofollow noreferrer">Darwin’s theory ... is incomplete without input from evolution’s anti-hero: Lamarck</a>;</li>
<li>Against: <a href="https://platofootnote.wordpress.com/2017/09/19/one-more-time-no-epigenetics-is-not-lamarckism/" rel="nofollow noreferrer">One more time: no, epigenetics is not Lamarckism</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/27139147/" rel="nofollow noreferrer">Why epigenetics is not a vindication of Lamarckism</a>.</li>
</ul>
<p>This is highly confusing to laypersons such as myself and I'm hoping an expert here can explain to me why there seem to be such vehement disagreements on this matter.</p>
<p>Here's my simplistic layperson understanding of the matter:</p>
<ul>
<li>Lamarck: Variations transmitted from parent to child can be influenced by the experiences of the parent.</li>
<li>Darwin: Lamarck is wrong, variations transmitted from parent to child are purely random and cannot be influenced by the experiences of the parent.</li>
</ul>
<p>Based on my above simplistic understanding (correct me if I've made any errors), it seems to me that epigenetics suggests that there is at least some element of truth to Lamarckism. Am I mistaken?</p>
Answer:
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https://biology.stackexchange.com/questions/94160/does-epigenetics-suggest-there-is-at-least-some-element-of-truth-to-lamarckism
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Question: <p>I was lately researching epigenetics and the current research on age reversal. Because epigenetic processes are influenced by the environment and can vary over time, I wanted to know if all epigenetic marks and mechanisms, including those that play a key part in cell differentiation, are reversible?
I am extremely keen to learn about this and any assistance would be greatly appreciated.</p>
Answer:
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https://biology.stackexchange.com/questions/101323/epigenetic-marks
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Question: <p><a href="http://www.ajsc.us/files/ajsc0030217.pdf" rel="nofollow">Recent study</a> has shown that epigenetics can play role in male-caused infertility and it cites for example studies which showed an enhancing of silent genes when drinking alcohol. Since the study argues this as a reason to the negative newborns' conditions, it has to act negatively on the organism somehow.</p>
<p>I would call an epigenetic influence on the fetuses an influence that is meant to prepare the fetus on the change in the conditions. Does the evolution of the enhanced genes any relate to the alcohol consumption, or is it just a negative coincidence?</p>
Answer:
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https://biology.stackexchange.com/questions/46228/how-does-epigenetics-affect-the-birth-conditions-via-alcohol
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Question: <p>This is prompted by niallhaslam's answer to this question [<a href="https://biology.stackexchange.com/questions/3771/since-darwinian-times-has-there-been-any-striking-notable-effects-of-evolution">Since Darwinian times, has there been any striking/notable effects of evolution on humans?</a>]. A comment by Alan Boyd asks whether epigenetic changes count as evolution. </p>
<p>Transgenerational epigenetic inheritance can occur, and does increase the natural variation of a species (although this review is more about plants, this does apply to animals too) [<a href="http://dx.doi.org/10.1016/j.pbi.2012.08.004" rel="nofollow noreferrer">1</a>]. Based on this alone I'm inclined to say that epigenetics can affect the fitness of a species, and thus could contribute to evolution.</p>
<p>I am interested to know if, in practise, this does occur, and whether epigenetics have been shown to affect the reproductive success of a species? Because the changes are not permanent I could imagine that they actually have very little impact "species-wide", as environmental effects (infections, toxic exposures) also affect epigenetics. So, is there any evidence for epigenetics affecting the reproductive success of a species? This also includes whether epigenetics can influence traits enough to create a new sub-species.</p>
<ol>
<li>Becker, C., & Weigel, D. (2012). Epigenetic variation: origin and transgenerational inheritance. Current opinion in plant biology. doi:<a href="http://dx.doi.org/10.1016/j.pbi.2012.08.004" rel="nofollow noreferrer">10.1016/j.pbi.2012.08.004</a>.</li>
</ol>
Answer: <p><a href="http://rd.springer.com/static-content/0.5415/pdf/672/art%253A10.1186%252F1471-2164-13-59.pdf?token=1349547201563--df67f8e33c10393eeb2a5501673869cd27643eebc78b8e9ae9a8ba858d30b45062d36922685bb45cdc0fe9cfa3cbe814e638131409957240b1103900fa7df04a&doi=10.1186/1471-2164-13-59&contentType=article" rel="nofollow noreferrer">This article</a> deals with the effect of phenotypic variation brought on by epigenetic patterns, and how these are inherited to the next generation. Their conclusions?</p>
<blockquote>
<p>Our results show that epigenetic variation is inherited in chickens, and we suggest that selection of
favourable epigenomes, either by selection of genotypes affecting epigenetic states, or by selection of methylation
states which are inherited independently of sequence differences, may have been an important aspect of chicken
domestication.</p>
</blockquote>
<p>However, I personally prefer <a href="http://www.cell.com/AJHG/abstract/S0002-9297%2812%2900410-7" rel="nofollow noreferrer">this article</a>, as it has a more profound implication on reproductive success and addresses your question <strong>specifically</strong>. They found the there is a species-level difference in DNA methylation between humans and chimps, but more importantly that <em>this difference is responsible for the causation of numerous lethal diseases/conditions</em>, which has a direct impact of the fitness of the species as a whole.</p>
<blockquote>
<p>Finally, we found that differentially methylated genes are strikingly enriched with loci associated with neurological disorders, psychological disorders, and cancers. Our results demonstrate that differential DNA methylation might be an important molecular mechanism driving gene-expression divergence between human and chimpanzee brains and might potentially contribute to the evolution of disease vulnerabilities. Thus, comparative studies of humans and chimpanzees stand to identify key epigenomic modifications underlying the evolution of human-specific traits.</p>
</blockquote>
<p>In summary, evidence has shown that epigenetics does seem to play an active role in the evolution of species, although the exact mode of inheritance of DNA methylation from generation to generation is unknown.</p>
<hr />
<h1>References</h1>
<ul>
<li><p><strong>Nätt, Daniel, Carl-Johan Rubin, Dominic Wright, Martin Johnsson, Johan Beltéky, Leif Andersson, and Per Jensen.</strong> <em>“Heritable Genome-wide Variation of Gene Expression and Promoter Methylation Between Wild and Domesticated Chickens.”</em> BMC Genomics 13, no. 1 (February 4, 2012): 59.</p>
</li>
<li><p><strong>Zeng, Jia, Genevieve Konopka, Brendan G. Hunt, Todd M. Preuss, Dan Geschwind, and Soojin V. Yi.</strong> <em>“Divergent Whole-Genome Methylation Maps of Human and Chimpanzee Brains Reveal Epigenetic Basis of Human Regulatory Evolution.”</em> The American Journal of Human Genetics 91, no. 3 (September 7, 2012): 455–465.</p>
</li>
</ul>
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https://biology.stackexchange.com/questions/3789/can-epigenetic-changes-affect-reproductive-success
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Question: <p>I know the basics of epigenetics, but I do not know how epigenetic mechanisms are transmitted from parents to children (or if there is even enough literature to derive a consensus). My question is relates to surrogate motherhood, in which an egg is fertilized <em>in vitro</em> and then implanted in the womb of a woman other than the egg donor. </p>
<p>Are all the factors that affect epigenetic mechanisms encoded in the genome? Is it possible for the surrogate mother's epigenetics to influence the epigenetics of the child/children?</p>
Answer: <p>Epigenetic information is information that can be inherited through cell division that is not encoded in the DNA sequence. This includes, but is not limited to, DNA methylation and histone modifications (there is also non-chromatin based epigenetic information). A nice example is the centromere, the chromosomal region that binds the kinetochore and is important to attach chromosomes to the mitotic spindle during cell division. The location of the centromere on the chromosome is encoded by a specific nucleosome composition and does not seem to rely on the DNA that wraps around those nucleosomes: The DNA sequence at centromeres is not even conserved from chromosome to chromosome (with the exception of budding yeast), and there are several known examples of people and families where the centromere is in a different place. However, all the mechanisms for maintaining this epigenetic mark are encoded genetically. </p>
<p>As epigenetic information is transmitted through cell division, it is directly inherited from the biological mother (with the exception of e.g. the centromere, most epigenetic marks from the father's chromosomes are removed when sperm is created). </p>
<p>However, (some) epigenetic information can be <em>modified</em>. This is obviously important during development where gene expression patterns of a liver cell need to be stable but different from gene expression patterns of a neuron, even though both descend from the same cell. </p>
<p>There is evidence that the metabolism of the mother will influence the epigenetic program of the child; diet being one of the determinants. It has also been suggested that epigenetic changes may influence behavior. Thus, it is indeed possible for the surrogate mother's epigenetic state to influence the epigenetic information of the children.</p>
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https://biology.stackexchange.com/questions/33/transmission-of-epigenetic-regulation-through-surrogate-mother
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Question: <p>How is epigenetics used in the differentiation of cells and is this the only thing that is used? I've seen that transcription factors play a role but are these simply proteins that initially write the epigenetic code or something different altogether?</p>
<p>I've written this explanation of how I understand it currently. Please tell me if this is right or wrong.</p>
<p>How do our cells become specialised if they have the same genome? The answer lies in the fact that gametes have most of their epigenetic information taken off at fertilisation, (apart from small sections like at IAP retrotransposons) so it’s like a clean slate. The zygote cells divide to form many identical cells that have the capacity to become any cell in the body.
Proteins in the egg then bind to certain genes and regulate their expression by adding epigenetic markers like methyl groups and histone modifications. The proteins created from these genes then go to control the regulation of other genes and so on, until all the cells have different epigenetic markers put on them that mean they produce different proteins in different quantities to serve different functions in the body.</p>
Answer:
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https://biology.stackexchange.com/questions/66370/how-do-cells-become-differentiated-using-epigenetics-despite-having-the-same-gen
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Question: <p>Evolution leads to phenotypic changes through changes in DNA such as mutations. Mutations are transmitted to offspring. Cumulative mutational changes across many generations may cause evolution and speciation. </p>
<p>As far as I know, <strong>epigenetic changes</strong> causes an individual to change in how it appears (<em>phenotypic changes</em>). In turn, epigenetic changes may be transmitted to offspring, just as DNA mutations can be. </p>
<p><strong><em>Is epigenetics a factor in evolution</em></strong>?</p>
Answer: <p><strong>To start I will repost some of an answer I have previously posted, which will explain what evolution is:</strong></p>
<p>Evolution is simply <strong><a href="http://evolution.berkeley.edu/evolibrary/article/0_0_0/evo_02" rel="nofollow">a process of change</a></strong>. It is a change in trait values of populations over time. It results from four mechanisms: mutation, migration, drift, and selection. </p>
<blockquote>
<p>"Evolution means change, change in the form and behaviour of organisms
between generations. ... When members of a population breed and
produce the next generation we can imagine a lineage of populations,
made up of a series of populations through time. Each population is
ancestral to the descendant population in the next generation: a
lineage is an ancestor-descendent series of populations. Evolution is
then change between generations within a population lineage." - <a href="https://www.blackwellpublishing.com/ridley/" rel="nofollow"><em>Ridley,
Evolution</em></a></p>
</blockquote>
<p><strong>Your Answer:</strong></p>
<p>Evolution depends on the inheritance of information from the ancestral population to the descendant population. Much of the time we talk about information in the form of genetic variation, the information contained within the <a href="https://en.wikipedia.org/wiki/DNA" rel="nofollow">DNA</a>. However, more and more we are realising that other forms of information transmission can occur, including epigenetic effects, and that these can contribute to evolution. </p>
<blockquote>
<p>"Epigenetic modifications are a bit like ornaments on a Christmas
tree; the tree (the DNA sequence) is still the same, but the
decorations (epigenetic modifications) change how it's perceived." ...</p>
<p>"Over the past few years, several studies have compared the epigenetic
modifications of our genome with that of other great apes, leading to
an emerging picture of the importance of epigenetics in our recent
evolutionary history." ...</p>
<p>"The role of epigenetics in evolution (particularly primate evolution)
is an active and exciting area of research..." - <a href="http://www.nature.com/scitable/blog/accumulating-glitches/epigenetics_and_evolution" rel="nofollow"><em>Nature Scitable</em></a></p>
</blockquote>
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https://biology.stackexchange.com/questions/41192/are-epigenetic-changes-involved-in-evolution
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Question: <p>In an <a href="https://newatlas.com/child-abuse-dna-genetic-biomarker/56588/" rel="nofollow noreferrer">article on biomarkers of child abuse</a>, the author referred to an "epigenetic mark on a person's DNA". It's a popular science article, so the language may reflect a combination of the journalist's scientific competency and his or her desire to communicate complex topics efficiently to a lay audience. Is that an example of such language?</p>
<p>My understanding was that anything in the realm of "epigenetics" is happening to something other than DNA. Is it technically correct to refer to an "epigenetic mark on a person's DNA"? Correct enough? Only potentially misleading? I'm trying to wrap my head around the whole epigenetics concept.</p>
Answer: <p>We may restrict your definition of epigenetics as heritable changes in an organism's phenotype that occur without a change in the <em>sequence of DNA bases</em>. That is, changes to the DNA molecule itself is permitted, as long as the sequence of ATCGs are not affected.</p>
<p>In this sense, it would not be wrong to refer to an "epigenetic mark on a person's DNA". For example, a mechanism of epigenetics that does directly change the DNA molecule would be something like <a href="https://en.wikipedia.org/wiki/DNA_methylation" rel="nofollow noreferrer">DNA methylation</a>.</p>
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https://biology.stackexchange.com/questions/77956/semantics-question-epigenetic-mark-on-a-persons-dna
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Question: <p>So, I'm trying to study the effects of epigenetic variability on the brain structure. Can I use SNPs associated with a gene's higher expression to compute the likelihood of that gene being expressed in the brain region? I don't have environmental data, just the SNP information. </p>
<p>Since epigenetics refers to the variations in the gene expression without changing the DNA sequence, I don't really understand if there could be a connection. </p>
<p>Any help would be appreciated, thank you!</p>
Answer: <p>Starting from what appears to be your main question:</p>
<blockquote>
<p>Can I use SNPs associated with a gene's higher expression to compute the likelihood of that gene being expressed in the brain region?</p>
</blockquote>
<p>I would strongly advise against using SNPs determine if genes are expressed (at all) in a given tissue.For one thing SNPs that affect expression (then often called <a href="https://en.wikipedia.org/wiki/Expression_quantitative_trait_loci" rel="nofollow noreferrer">eQTLs</a>) will usually only have small +- effects on expression instead of switching it on/off and also have that effect in many/all cell types. Unless an (individual) SNP has clearly described /and validated effects on gene expression in a specific tissue/brain region, you should assume it has global effects.</p>
<p>Now, luckily for you gene expression in different cell types, tissues etc is a relatively well studied area and there are resources for gene expression in the brain available (<a href="http://portal.brain-map.org" rel="nofollow noreferrer">brain atlas</a> is probably closest to what you might look for).<br>
You can uses these resources to determine which genes are expressed in your regions of interest and from there on check if SNPs associated with these genes correlate with certain structural brain features you are interest in.</p>
<p>One more thing you note:<br>
The title of your questions (as well es comments) mention that you are interested in epigenetics. Neither gene expression nor SNPs/eQTLS are diretcly linked to epigenetics, so if this is your actual focus you should also look for availbale ChIP-seq data or similar and also include this into your analysis (correlation of SNPs with epigenetic marks is difficult but not impossible)</p>
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https://biology.stackexchange.com/questions/85168/studying-the-epigenetic-variability-can-i-use-snps
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Question: <p>Carl Jung has long ago proposed a rather controversial notion of <em>collective unconsciousness</em><a href="http://www.britannica.com/EBchecked/topic/125572/collective-unconscious" rel="nofollow"> [1</a>, <a href="http://www.thefreedictionary.com/collective+unconscious" rel="nofollow">2</a>, <a href="http://en.wikipedia.org/wiki/Collective_unconscious" rel="nofollow">3],
</a></p>
<blockquote>
<p>a form of the unconscious (that part of the mind containing memories
and impulses of which the individual is not aware) common to mankind
as a whole and originating in the inherited structure of the brain. It
is distinct from the personal unconscious, which arises from the
experience of the individual.</p>
</blockquote>
<p>While the complete original formulation of the idea may be interpreted as unfalsifiable and hence unscientific, suppose that we try to redefine it to some more modest idea, e.g. a set of inheritable subconscious memories, impulses and reactions present in populations/groups, with some expected degree of variation. </p>
<p>Now, it has been shown that memories reside in specific brain cells<a href="http://newsoffice.mit.edu/2012/conjuring-memories-artificially-0322" rel="nofollow"> [4]</a>. What is also known is the direct impact of environment (which - as far as I understand it - also includes our thoughts, feelings and expectations) on gene expression and epigenetic inheritance. In the light of these insights, could the notion of collective unconsciousness be revitalized and interpreted in some non-trivial way that could be used to better understand the way we dream, feel, identify with characters in stories etc.?</p>
<p>In other words, do new discoveries in neurobiology, evolutionary biology and epigenetics shed any new light on Jung's writings (e.g. timescale for such structures to adapt between generations etc.) and perhaps confirm some of his ideas? If not, could experiments be performed that would provide some new insights? Or is the idea so trivial at its core that basic evolution is enough to explain it in its entirety?</p>
Answer: <p>Jung's premise is rather plausible: consciousness evolved rather than appeared suddenly, and therefore carries "pre-conscious" elements common to humans as a species. However, Jung goes very far in his interpretation of what may be hidden in subconscious, bordering on open mysticism - predicting accidents, wars, etc. I doubt there may be any evidence for that.</p>
<p>Among the more plausible of Jung's arguments are his comparative studies of the similarities between fairy-tales, legends and other folcloric features between cultures. This however does not necessarily prove that these existed in subconscious - they could evolve as a part of different human cultures encountering similar problems, e.g., dealing with incest (Edip), reaching sexual maturity (Beauty and the beast), etc. - which was already Freud's view. Essentially, Jung attributes to <em>collective subconscious</em> many of the things that Freud attributes to <em>superego</em>, that is to the cultural influences.</p>
<p>Less far reaching claims are made by modern theoretical linguistics, since all the existing languages are shown to obey similar <a href="https://en.wikipedia.org/wiki/Generative_grammar" rel="nofollow noreferrer"><em>generative grammar</em></a>, <a href="https://en.wikipedia.org/wiki/Generative_grammar" rel="nofollow noreferrer">see my post about the subject</a>. While I am not aware of any conclusive results for this view from neuroscience, the evidence collected by linguists is rather strong.</p>
<p><strong>References</strong></p>
<ul>
<li>K. Jung, <a href="https://en.wikipedia.org/wiki/Man_and_His_Symbols" rel="nofollow noreferrer">Man and his symbols</a></li>
<li>S. Freud <a href="https://en.wikipedia.org/wiki/Totem_and_Taboo" rel="nofollow noreferrer">Totem and taboo</a></li>
<li>S. Freud <a href="https://en.wikipedia.org/wiki/The_Psychopathology_of_Everyday_Life" rel="nofollow noreferrer">The psychopathology of everyday life</a></li>
<li>S. Freud <a href="https://rads.stackoverflow.com/amzn/click/com/039300743X" rel="nofollow noreferrer" rel="nofollow noreferrer">New introductory lectures on psychoanalysis</a></li>
<li>D. Isac and Ch. Reiss, <a href="https://rads.stackoverflow.com/amzn/click/com/0199660174" rel="nofollow noreferrer" rel="nofollow noreferrer">I-Language: An Introduction to Linguistics as Cognitive Science</a></li>
</ul>
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https://biology.stackexchange.com/questions/21982/does-the-jungian-notion-of-collective-unconsciousness-have-any-legitimacy-in-the
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Question: <p>It seems that during reproduction particular genes are targeted for modification (mutation, deletion, insertion, etc.) given environmental inputs of either or both of the parents.</p>
<p>If a creature was fit given its environment, its <em>seems</em> there is little mutation. However, if the creature becomes less fit (i.e, due to increasingly becoming prey to a predator) it will undergo increased rate of mutation to find a successful adaption to the new environment. But it <em>seems</em> that the mutation is also targeted to particular genes that maybe most beneficial to mutate (i.e, to develop camouflage).</p>
<p>This begs the question - <strong>given environmental inputs, is there something that controls gene modification during reproduction? More specifically, is there a process that targets a specific gene or trait?</strong></p>
Answer: <p>Mutations are not performed targeting a specific new phenotype. There is no way an organism can "know" the impact of a specific future mutation anyway. A mutation is just a mistake in the replication process. As a consequence the majority of mutations are deleterious and only a handful of mutations are beneficial.</p>
<p>It is true though that the mutation rate can be affected by the environment or the stress induced by an individual (<a href="http://onlinelibrary.wiley.com/doi/10.1046/j.1420-9101.2002.00464.x/full" rel="nofollow noreferrer">Agrawal 2002</a>). It seems more intuitive that these are just a consequences of the cost of the DNA replication machinery and DNA repair machinery but it is not impossible that such changes in mutation rate could eventually evolve as a <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842822/" rel="nofollow noreferrer">bet-hedging</a> strategy. In the extreme case where the same types of environmental change happen over and over again, it is not impossible that a lineage could evolve the ability to modify the mutation rate at a particular <a href="https://en.wikipedia.org/wiki/Locus_(genetics)" rel="nofollow noreferrer">locus</a>. However, to my knowledge this has never been found.</p>
<p>You might want to follow an introductory course to evolutionary biology. You might also want to read <a href="https://biology.stackexchange.com/questions/36647/is-mutation-theory-still-valid-for-complex-organisms/36650#36650">this post</a> too that gives a mixture of related information</p>
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https://biology.stackexchange.com/questions/46074/determination-of-genes-to-be-modified-in-epigenetics
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Question: <p><strong>Development of human average height</strong></p>
<p>Human average height has fluctuated significantly throughout history. For instance, in the last 100 years or so, it has increased sharply by about 10cm. OWID (Our World in Data) has data and figures on, among other measures, the <a href="https://ourworldindata.org/grapher/human-heights-over-the-long-run" rel="nofollow noreferrer">average height over the last 18K years</a>, <a href="https://ourworldindata.org/grapher/average-height-of-men-for-selected-countries" rel="nofollow noreferrer">average male height by country over the last 200 years</a>, <a href="https://ourworldindata.org/grapher/annual-change-in-average-male-height" rel="nofollow noreferrer">annual change in average male height</a>, and <a href="https://ourworldindata.org/grapher/annual-change-in-average-female-height" rel="nofollow noreferrer">annual change in average female height</a>.</p>
<p><strong>Regulation of human height</strong></p>
<p>Already the genetics of human height seem to be complicated and to involve a large number of different genes (and hundreds of loci) according to, e.g., <a href="https://doi.org/10.1007/s00439-011-0969-x" rel="nofollow noreferrer">this article by Lettre (2011)</a>. However, since the time spans are too short for significant purely genetic effects, there must be either developmental or epigenetic effects at play or both. Developmental effects have been linked to socio-economic status, perhaps via steady and good nutrition before birth and during childhood. <a href="https://doi.org/10.1016/S0363-3268(07)25003-7" rel="nofollow noreferrer">This paper by Komlos (2007)</a> (without paywall <a href="https://epub.ub.uni-muenchen.de/573/1/children_youth.pdf" rel="nofollow noreferrer">here</a>) shows data for English youths in the 1700s and 1800s by socio-economic status and finds a height gap of up to 22.6cm, his sample sizes are a couple of thousands for the lower-class group and less than that for the upper-class group.</p>
<p><strong>Epigenetics human height</strong></p>
<p>Carey reports in <a href="https://cup.columbia.edu/book/the-epigenetics-revolution/9780231161169" rel="nofollow noreferrer">her book "The Epigenetics Revolution" (2012)</a> that people born after the <a href="https://en.wikipedia.org/wiki/Dutch_famine_of_1944%E2%80%9345" rel="nofollow noreferrer">Dutch Hunger Winter</a> would not only remain small for their entire lives but that there was still a significant difference in their children, born decades later. She does not seem to refer to height differences though (I guess?), but to differences in the risk to develop certain diseases as reported in <a href="https://doi.org/10.1073/pnas.0806560105" rel="nofollow noreferrer">this paper by Heijmans et al. (2008)</a> (not sure if there's a paywall; <a href="http://www.leidenlangleven.nl/uploads/publicaties/2008/2008%20Heijmans%20PNAS.pdf" rel="nofollow noreferrer">same paper is also here</a>). <a href="https://doi.org/10.1073/pnas.0806560105" rel="nofollow noreferrer">They trace this</a> to differences in the expression of a certain gene (IGF2) because of <a href="https://en.wikipedia.org/wiki/DNA_methylation" rel="nofollow noreferrer">hypomethylation</a> of that region.</p>
<p>Since other phenomena are thus shown to be subject to epigenetic effects, it is possible that the regulation of human height is too. To be clear, I am not aware of any study that suggests this (or investigates this). It would certainly be very difficult to identify, so I suspect this has not been thoroughly investigated. Note that the epigenetic effects shown in <a href="https://doi.org/10.1073/pnas.0806560105" rel="nofollow noreferrer">Heijmans et al. (2008)</a> could only be shown because of the very specific conditions of the <a href="https://en.wikipedia.org/wiki/Dutch_famine_of_1944%E2%80%9345" rel="nofollow noreferrer">Dutch Hunger Winter</a>, a short but horribly severe famine with intact medical records. But I am hoping there is some information out there.</p>
<p><strong>So my question is</strong></p>
<p>Are there indications that epigenetic effects may be present in the regulation of human height and its rather interesting development in recorded history? (Or is this unlikely, e.g. because the variation is sufficiently explained by other factors or because studies have tried and failed to find epigenetic effects? Or has this not been investigated so far?)</p>
Answer:
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https://biology.stackexchange.com/questions/98516/are-there-epigenetic-effects-in-the-regulation-of-human-height
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Question: <p>For example, how are histone code patterns passed down?</p>
<p>This question was asked a few years ago in this thread:</p>
<p><a href="https://biology.stackexchange.com/questions/5342/how-are-epigenetic-marks-transmitted-during-cell-division">How are epigenetic marks transmitted during cell division?</a></p>
<p>However, it has been a few years now, and I'd like to know if researchers have made any progress.</p>
<p><strong>Clarification:</strong>
I'm specifically interested in figuring out how chromatin modifications are epigenetically inherited. There seems to be some evidence that it can be inherited, but there doesn't seem to be a full explanation as to how.</p>
<p>A good source for what I'm talking about is a article published in 2010 called: "Epigenetics and the Origins of Paternal Effects", which goes into detail on experiments done on rats that show epigenetic traits being inherited across offspring. However, the article ended on a note saying that the evidence is speculative, and further research needs to be done. Here's the link:</p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975825/" rel="nofollow noreferrer">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975825/</a></p>
Answer:
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https://biology.stackexchange.com/questions/60218/have-researchers-discovered-how-epigenetic-information-is-passed-down-during-cel
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Question: <p>I'm trying to understand the difference between epigenetic and environmental factors. For example, if gene A increases the risk of lung cancer by 50% and smoking increases the risk by another 75% when combined with gene A (just throwing out numbers) person X now has a higher chance of developing lung cancer. However, if for example, certain epigenetic factors are inhibiting the expression of gene A than that 50% higher genetic risk has now decreased because those high-risk genes aren't being fully expressed. The environmental risk factor of smoking still plays a role but it too could be decreased because that 75% increased risk was associated with gene A being fully expressed and not inhibited by epigenetic factors. Am I thinking about this correctly? </p>
Answer: <p>If I understand you correctly what you are saying is</p>
<blockquote>
<p>There is envrionmental variance and epigenetic variance underlying the phenotypic variance. There can even be a covariance between the envrionment and epigenetics.</p>
</blockquote>
<p>Yes, this is true. You might want to have a look at <a href="https://biology.stackexchange.com/questions/42273/why-is-a-heritability-coefficient-not-an-index-of-how-genetic-something-is">this intro post to quantitative genetics</a>.</p>
<p>Note, there are several definitions of epigenetics. Epigenetic effects are some kind of factors that affect phenotypic variance and that are external to the DNA sequence. Often we think of modification directly on the nucleotides on on the histones (such as a methylation on the histon tail) but we sometimes also extend this context to include all the stuff that is the in the zygote or sometimes even further. In its broadest sense, the term "epigenetics" would be a synonym of "environment".</p>
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https://biology.stackexchange.com/questions/71802/epigenetic-vs-environmental-factors
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Question: <p>Do mutations in regulatory gene sequences lead to changes in epigenetic alterations in cancer, and if so which ones? I know abnormal hypermethylation of GCP islands occurs in promoters of tumour supressors, but what drives the abnormal methylation? Thanks </p>
Answer:
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https://biology.stackexchange.com/questions/84701/what-causes-epigenetic-dysregulation-in-cancer
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Question: <p>Can epigenetic structures cause a trait to manifest in a person if the trait is not already in the DNA? In all my readings I have yet to find a definitive statement that it is impossible.</p>
Answer: <p>Yes, epigenetic changes does affect the phenotype. This is here the whole interest behind epigenetic. Environmental variation (incl. parental care) affect epigenetics which in turn affect the phenotype (incl. behaviour) of an individual. It is pretty much clear from the <a href="https://en.wikipedia.org/wiki/Epigenetics" rel="nofollow noreferrer">wikipedia</a> definition of epigenetics</p>
<blockquote>
<p>Epigenetics studies stably heritable traits (or "phenotypes") that cannot be explained by changes in DNA sequence.</p>
</blockquote>
<p>The term "phenotype" (or "phenotypic") is actually present 3 times is the first small paragraph of the wikipedia article.</p>
<p>For example, you can read <a href="https://en.wikipedia.org/wiki/Behavioral_epigenetics#Research_into_epigenetics_in_psychology" rel="nofollow noreferrer">here</a> on wikipedia an example of a study showing that maternal care affect epigenetic variations which in turn affects stress level later in life as measured by <a href="https://en.wikipedia.org/wiki/Hypothalamic%E2%80%93pituitary%E2%80%93adrenal_axis" rel="nofollow noreferrer">HPA</a>.</p>
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https://biology.stackexchange.com/questions/55298/can-epigenetic-structures-carry-a-trait
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Question: <p>(EDITED - a lot of what I am saying is implicit and simplified. I'm not looking to recreate the numerous textbooks and scientific papers on how DNA works). </p>
<p>As far as I can understand it, an organisms basic building blocks (proteins) are made up of DNA, Genes, and Chromosomes. The most basic form of this is DNA, made up of molecules in double helix strands. DNA carries all the instructions for the body in a simple 'database' or 'blueprint' form. Genes are chunks, or sequences, of the DNA telling the body 'what to do'(1) by reading the 'DNA database' in a myriad of unique coding sequences. Genes naturally(2) switch on and off throughout an organisms lifespan allowing amongst other things for an organism to grow from young to old. DNA is essentially(3) stored in Chromosomes. </p>
<p>External and environmental factors can influence the expression of genes, and the information stored in the DNA (4) - the study of which is Epigenetics. These Epigenetic factors can change over time, switching genes on and off. (5)</p>
<p><strong>Does the body store a history of these expressions? Do the chromosomes (or some other part) of an older organism store a 'user-history' of which genes where previously activated when the organism was younger?</strong> eg, can you tell which genes where active when a person was 12, from the cells of an 80 year old?</p>
<p>Apologies, I do not have a background in Biology. (6)</p>
<hr>
<p>EDIT NOTES</p>
<p>(1) what to do, how to do it, when to do it. not necessarily all life supporting instructions but also the minute-to-minute, day-to-day processes etc.</p>
<p>(2) naturally. there is no black and white in nature, only shades of grey. </p>
<p>(3) essentially. not exactly and not in all cases but mostly. </p>
<p>(4) As in, factors influence the expression of genes (which in turn are made up of DNA information). I am not suggesting that external factors can influence the 'DNA database' itself but rather just how they are 'read', sequenced and expressed as genes.</p>
<p>(5) again, naturally. no sharp on/offs but variations of concentrations.</p>
<p>(6) I may not have used the correct terminology.</p>
Answer: <h2>Main question</h2>
<blockquote>
<p>Does the body store a history of these expressions? Do the chromosomes
(or some other part) of an older organism store a 'user-history' of
which genes where previously activated when the organism was younger?</p>
</blockquote>
<p>Cells can sometimes have a "memory" of the gene expression state which allows the cell to perpetuate its gene expression programme. This is facilitated by epigenetic mechanisms. Cells can also maintain a short term memory via feedbacks and switches (<a href="http://dx.doi.org/10.1002/bies.10102" rel="nofollow">Casadesús and D'Ari, 2002</a>). Immune cells store the memory of previous exposures to a certain pathogen (in this case each clonal population stores one piece of history which is unlike one cell storing the entire history). However, I don't think there is an explicit "user history" kind of mechanism. Most responses are dynamic (and memoryless); there are only a very few situations (such as immune response) that really need a history log. Usually the cellular memory is just one level deep. Storing deeper than that would cost the cell a lot.</p>
<hr>
<h3>Other corrections not directly related to the question</h3>
<blockquote>
<p>As far as I can understand it, an organisms basic building blocks
(proteins) are made up of DNA, Genes, and Chromosomes.</p>
</blockquote>
<p>This statement is extreme oversimplification. As a matter of fact, water is the most abundant molecule in the bodies of most (if not all) organisms. RNAs and proteins are essential molecules required for cellular functions. Lipids are also important as they constitute the cell membrane. Moreover, proteins are not made up of "DNA, genes and chromosomes". Your subsequent explanation of how the genes work is correct but this statement is quite wrong. </p>
<blockquote>
<p>The most basic form of this is DNA, made up of molecules in double
helix strands.</p>
</blockquote>
<p>Misleading again. It is not correct to call DNA as "most basic form". In what way? This statement is also opinion-based.</p>
<blockquote>
<p>DNA is essentially(3) stored in Chromosomes.</p>
</blockquote>
<p>Chromosome is an assembly consisting of the DNA and some proteins. In a way, DNA is contained in the chromosomes. As also pointed out by Remi, your statement can have misleading interpretations.</p>
<blockquote>
<p>External and environmental factors can influence the expression of
genes, and the information stored in the DNA (4) - the study of which
is Epigenetics. These Epigenetic factors can change over time,
switching genes on and off.</p>
</blockquote>
<p>This process is simply called "gene regulation" or "regulation of gene expression". Epigenetic mechanisms (such as DNA methylation and histone modifications) are one of the mechanisms of gene regulation but they are not the only one. You can simply google "gene regulation" and you'll get plenty of resources on this topic.</p>
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https://biology.stackexchange.com/questions/52372/can-a-gene-expression-or-epigenetic-user-history-be-found-in-the-body
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Question: <p>My question relates to the prospect of (near?) future control of biological aging.
As I understand, it has been recently demonstrated by Prof. David Sinclair's group that epigenetic drift appears to be a major driver of aging, and demonstrated it may be reversed by applying a certain subset of Yamanaka factors. In particular, upon fixing DNA aberrations, epigenetic information tends to be restored with less fidelity than the DNA itself. In the mice in the experiment, the degree of epigenetic changes corresponded well to an aged phenotype in these mice, which was also apparently reversed by applying the above said Yamanaka factors.
See <a href="https://www.sciencedirect.com/science/article/abs/pii/S0092867422015707" rel="nofollow noreferrer">https://www.sciencedirect.com/science/article/abs/pii/S0092867422015707</a> for more details..</p>
<p>My question is regarding on the existence of "Horvath clocks" that provide a certain measure of epigenetic drift that can be compared across species. That is, do we have some kind a way to measure more of an "absolute" amount of epigenetic drift, allowing to compare this amount in say, mice, dogs and humans? My hope is that this absolute amount would be much greater in shorter lived species, to an extent providing an approximate explanation to the major differences between the lifespans of these species, to further support Sinclair's theory.</p>
<p>Maybe this measure can not be summarized by a single number, even, but rather depend on epigenetic drift in particular DNA regions/presence of certain methylation patterns etc.?</p>
Answer:
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https://biology.stackexchange.com/questions/111946/variance-in-epigenetic-drift-rate-between-different-species
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Question: <p>Are enhancers and silencers considered as epigenetic modifications? I am confused as it seems like enhancers and silencers are sequences on the DNA and how they work is through binding with proteins, while epigenetic changes seem to be changes made to the bases for instance adding a methyl group.</p>
Answer: <p>No. </p>
<p>Epigenetic information is (by definition) NOT included in the nucleotide sequence, but affects genetic expression.</p>
<p>Enhancers/silencers are themselves nucleotide sequences, and therefore not epigenetic information.</p>
<p>Methylation is an example of epigenetic information, but a DNA sequence itself is genetic information, even if it affects a gene.</p>
<p>CgATgCCAg= Genetic</p>
<p>Acetylation of a histone/DNA methylation= epigenetic</p>
<p>Hope that helps! </p>
<p>Further reading: <a href="http://www.whatisepigenetics.com/fundamentals/" rel="nofollow">http://www.whatisepigenetics.com/fundamentals/</a></p>
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https://biology.stackexchange.com/questions/51963/are-enhancers-and-silencers-considered-as-epigenetic-modifications
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Question: <p>As far as I know, this is one of the biggest questions in the epigenetic field: how are the epigenetic marks like histone modifications propagated through cell division? A lot is already known about DNA methylation (e.g. as in <a href="https://biology.stackexchange.com/questions/3450/how-does-inheritance-of-methylation-of-dna-and-or-histones-work">How does “inheritance of methylation” of DNA and/or histones work?</a>), but very little about histone modifications. What is the current state of knowledge? </p>
Answer: <p>I can get the ball rolling..</p>
<p>Found a nice paper which looks at this phenomenon <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028980" rel="nofollow noreferrer">in yeast</a>.</p>
<p>So as a primer, 8 histone proteins come together to make a spool of sorts which DNA wraps around:</p>
<p><img src="https://i.sstatic.net/pjs5a.png" alt="the histone core from wikipedia" /></p>
<p>Histone <a href="http://en.wikipedia.org/wiki/Histone#Classes" rel="nofollow noreferrer">proteins have many sequence variants</a>, and each one of them can be covalently modified with methyl, acyl, phospho, SUMO, adp and many other sorts of <a href="http://en.wikipedia.org/wiki/Histone#Functions_of_histone_modifications" rel="nofollow noreferrer">chemical groups via a chemical bond</a>. Although its not yet clear exactly how it works its clear that these modifications can change the behavior of the histones which prevent transcription of the gene when they have the chromosomal DNA all wrapped up.</p>
<p>So as to the question a pattern of inheritance of modified histone patterns is indeed seen and has epigenetic effects. (that is, it modifies the genetic phenotype of daughter cells which retain the histone modifications of the parent cells). In this paper, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028980" rel="nofollow noreferrer">newly synthesized (and labelled) yeast histone can be found incorporated into certain segments of the genome, which demonstrates that large segments of the histones are carried forward from the parent cell</a>.</p>
<p>They also found a particular case of histone epigenetic labeling carried forward through division:</p>
<blockquote>
<p>Furthermore, if the heterochromatin-binding protein Sir3 is unavailable during DNA replication, histone H3-K4</p>
</blockquote>
<p>So there's evidence that histone configurations <em>are</em> transmitted epigenetically, In this 2011 paper, the author support a 'conservative distribution model' and compare it to a 'semi-conservative' model:</p>
<blockquote>
<p>The conservative distribution model proposes that newly synthesized histone molecules form nucleosomes that are randomly inserted among preexisting parental nucleosomes.</p>
<p>The semi-conservative distribution model proposes that a hybrid nucleosome that contains both newly synthesized and parental histone H3-H4 dimers is formed, which facilitates the transmission of epigenetic information within the basic nucleosome unit.</p>
</blockquote>
<p>They go on to say that a conservative model of histone inheritance allows for strong epigenetic inheritance as the remaining parent histones will tend to attract similarly labelled histones as the new histones incorporate themselves among the parental histones on the daughter chromosome.</p>
<p>Its still being worked out though...</p>
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https://biology.stackexchange.com/questions/5342/how-are-epigenetic-marks-transmitted-during-cell-division
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Question: <p>Is the firstborn son biologically different in any way from the sons that follow?</p>
<p>Perhaps his epigenome is different? I have heard that a man's testosterone levels decrease when he becomes a father -- could this then have implications for the epigenetics of subsequent sons?</p>
Answer: <p>There are lots of cases reported now that suggest that overall the firstborn child is usually more intelligent. The <a href="http://jhr.uwpress.org/content/early/2016/11/01/jhr.53.1.0816-8177.abstract" rel="nofollow noreferrer">articles supporting this</a> are based on behavioural and economic study though, so the biological basis is a little lacking.</p>
<p>It's also not clear if this is nature or nurture. The firstborn may benefit from their parents undivided attention disproportionately.</p>
<p>Here's the <a href="http://www.ed.ac.uk/news/2017/first-borns-have-mental-edge-study-shows" rel="nofollow noreferrer">press release</a> for it. And the coverage from the <a href="http://www.independent.co.uk/life-style/health-and-families/health-news/first-born-child-more-intelligent-smarter-siblings-younger-eldest-sibling-university-of-edinburgh-a7570606.html" rel="nofollow noreferrer">Independent</a>
and <a href="https://www.forbes.com/sites/brucelee/2017/02/12/study-says-the-oldest-child-is-the-smartest/#4ab539e24d9c" rel="nofollow noreferrer">Forbes</a></p>
<p>I read somewhere that the firstborn is more likely to be overweight too, but I can't find the article now. Other people may know other traits that are supposed to differ between children.</p>
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https://biology.stackexchange.com/questions/64695/is-there-any-biological-basis-for-the-emphasis-on-the-value-of-the-firstborn-son
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Question: <p>I was reading up on KCNQ1, which encodes a voltage-gated potassium channel, and I discovered that it happens to be only maternally expressed. This is regulated by KCNQ1OT1, a non-coding RNA, which is also epigenetically regulated (expressed only paternally). Mutations in KCNQ1OT1 are associated with Beckwith-Wiedemann Syndrome (BWS).</p>
<p>Further reading led to the discovery that there are <a href="http://humrep.oxfordjournals.org/content/18/12/2508.long" rel="nofollow">ART-related (assisted reproductive technology) cases of BWS due to loss of methylation at KCNQ1</a>.</p>
<p>However, <a href="http://journals2005.pasteur.ac.ir/NG2005/NG37%286%29/585%20-%20587.pdf" rel="nofollow">this article</a> found epigenetic stability of KCNQ1OT1 methylation in cultured human embryonic stem cells, which leads me to think that KCNQ1 might also have been properly methylated.</p>
<p>So what exactly are assisted reproductive technologies doing that can disrupt inheritance of epigenetic marks (that culturing hESCs doesn't do)? (Is this understood for any gene?)</p>
Answer: <p>I was at a talk last year where some geneticists were starting to look at the effect of IVF techniques on genetic issues. Because of the work being done and the inclinations of the clients involved, this has not been studied very much. One presumes that since zygotes are still used, there will not be much epigenetic effects due to methylation patterns - its the same cell stocks being used in vitro and in vivo. </p>
<p>There may be an effect on genetics because the natural selection process. Spermatogenesis and oogenesis is a highly selective process; only a small fraction of the ova generated by the ovaries ever mature and a large percentage of sperm generated are not motile or have other irregularities. During fertilization, sperm competition obviously throws out all but <a href="http://en.wikipedia.org/wiki/Semen_analysis#Total_sperm_count" rel="nofollow">one in 250 million</a>. It also appears that there are processes in the fallopian tubes that can store the <a href="http://humupd.oxfordjournals.org/content/12/1/23.full" rel="nofollow">sperm for several (up to 5) days before fertilization</a>. </p>
<p>So while its not strongly established one can see how various IVF processes vary from in vivo fertilization. This could have an impact on epigenetic factors, although different sperm vary genetically due to Meiosis and this would be a big source of genetic variation in the outcome. </p>
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https://biology.stackexchange.com/questions/7691/how-might-ivf-and-related-technologies-alter-epigenetic-marks
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Question: <p>Isolating a gene or sets of genes in diseases sometimes isn't enough to determine penetrance - epigenetic factors can have a significant effect. What are the criteria in determining whether epigenetic factors are significant?</p>
Answer: <p>First of all, the nature of penetrance is almost entirely unknown. Likely it's a combination of epistasis and gene interactions, induced gene regulatory pathways, developmental noise, and other factors. Epigenetics (imprinting, etc) may have little to do with penetrance, while chromatin structure may be a consequence of other things (most now regard histone modifications, etc, as consequence of transcription rather than heritable regulatory mechanism). Currently, the field of epigenetics is undergoing a (long-overdue) reassessment. Until that happens, anyone who wants to make claims of "epigenetics" is free to, so spurious claims are rampant.</p>
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https://biology.stackexchange.com/questions/202/what-are-the-criteria-for-determining-the-influence-of-epigenetic-factors
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Question: <p>Is post-transcriptional regulation of gene expression (for example regulation by microRNAs) a type of epigenetic gene expression regulation? </p>
<p>I think we can categorize it as epigenetic since the DNA sequence is not changed, but I have never come across that terming in any papers. Does someone have any idea, or know of any papers that categorize post-transcriptional regulation as epigenetic?</p>
Answer: <p>miRNAs and other post-transcriptional regulators are very well "genetic". They are encoded by genetic elements, are expressed and are affected by mutations. Just because this mode of regulation was not well known previously, it should not be classified as an epigenetic mechanism while the traditional protein based transcription factors (TF) are not. </p>
<p>Epigenetics, as it is originally defined (the "formal definition") is about mechanisms that can perpetuate the state of a cell to its next generation. Inheritance of gene expression programmes is therefore epigenetic. Although the gene expression programmes themselves can be implemented via different factors including protein and RNA based regulators, they would not necessarily constitute the epigenetic mechanisms that lead to inheritance of this state. </p>
<p>rg255's point of view is that any mechanism that causes a variation in the functional aspects of the genome without altering the genome sequence itself, would be epigenetic. This is technically correct but in that case all gene expression regulators including TFs should constitute epigenetic mechanisms.</p>
<hr>
<p>Now, the main issue is where to draw the line between <em>gene regulation</em> and <em>epigenetics</em>?</p>
<p>In my opinion, the <em>epigenetic</em> mechanisms are one of the ways to regulate the gene expression. Although histone modifications and DNA methylation regulate gene expression and also confer heritability to the gene expression programme, the heritability can be implemented without them as well. </p>
<p>You can imagine a cell as a vessel which runs a system of biochemical reactions. This system can have multiple steady states (for e.g. multiple fates of a stem cell). To perpetuate a state, the new cell just needs to have the right initial conditions. This can be proved mathematically too. Such a system can be implemented via the traditional transcription factors as well. So <em>what is epigenetic?</em></p>
<p>IMHO <em>epigenetic</em> was a loose term to denote something that people were not fully aware of, at that time. Anything that was not directly mediated by transcription factors was termed as epigenetic, including long distance regulators, non-coding RNA etc.</p>
<hr>
<p><strong>BOTTOMLINE</strong></p>
<p>I <strong>would not</strong> classify non-coding RNAs as "epigenetic" for the very reason that they are encoded by genes and have more or less a direct effect on the target genes, just like TFs (which are apparently <em>not epigenetic</em>). As for the papers, there were many papers that used to assign these under epigenetic mechanisms, but that is IMO just too vaguely arbitrary. (Ironically, I happened to come across miRNAs and lncRNAs while I was doing a summer project on <em>epigenetics</em> and was reading relevant papers.)</p>
<p>What <em>should be</em> considered <em>epigenetic</em> would be a subject of another debate. </p>
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https://biology.stackexchange.com/questions/50788/is-post-transcriptional-regulation-of-gene-expression-an-epigenetic-process
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Question: <p>I’m a little bit confused about DNA methlyation reprogramming and about the nature of an epigenetic phenomenon. According to <a href="https://en.wikipedia.org/wiki/Reprogramming" rel="nofollow noreferrer">Wikipedia</a>:</p>
<blockquote>
<p>After fertilization the paternal and maternal genomes are once again demethylated and remethylated (except for differentially methylated regions associated with imprinted genes). This reprogramming is likely required for totipotency of the newly formed embryo and <strong>erasure of acquired epigenetic changes</strong>.</p>
</blockquote>
<p>I don't understand how something can be thought to be both heritable and erasable. Any help would be greatly appreciated.</p>
Answer: <p>I have done a presentation in epigenetics and the main topic was imprinting.
This paper will answer all your questions <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941233/" rel="nofollow noreferrer">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941233/</a>
I am adding some glimpses from this paper here
Mammals are diploid organisms whose cells possess two
matched sets of chromosomes, one inherited from the mother
and one from the father. Thus, mammals have two copies of
every gene. Normally both the maternal and paternal copy of
each gene has the same potential to be active in any cell.
Genomic imprinting is an epigenetic mechanism that changes
this potential because it restricts the expression of a gene to
one of the two parental chromosomes. It is a phenomenon
displayed by only a few hundred of the approximately 25,000
genes in our genome, the majority being expressed equally
when inherited from either parent. Genomic imprinting affects
both male and female offspring and is, therefore,<a href="https://i.sstatic.net/jdCPQ.png" rel="nofollow noreferrer"><img src="https://i.sstatic.net/jdCPQ.png" alt="enter image description here"></a> a consequence
of parental inheritance, not of sex. As an example of
what is meant by this, an imprinted gene that is active on a
maternally inherited chromosome will be active on the maternal
chromosome and silent on the paternal chromosome in
all males and females.</p>
<p>Hope this help and please ask if you do not understand the paper.Thank you</p>
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https://biology.stackexchange.com/questions/70090/how-can-epigenetic-changes-be-erased-if-they-are-inherited
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Question: <p>I'm an amateur when it comes to genetics, I'm hoping to learn something from the corrections. I am taking epigenetics into account (kind of); all 3 entities are susceptible to external physical influences.</p>
<p>Kind regards,</p>
<p>Frank</p>
Answer: <p>Alleles are passed down (to individuals) and created by individuals (although not fully under their control). But individuals are not passed out or created by the governments (I suppose), although individuals are influenced by the governments and they can influence governments, whereas individuals can not necessarily influence the allele of the gene they already have unless you take epi-genetics into account. Also, the creation of an allele is not entirely influenced by individuals due to <a href="http://www.nature.com/scitable/definition/principle-of-independent-assortment-law-of-independent-302" rel="nofollow noreferrer">independent assortment</a> and <a href="http://en.wikipedia.org/wiki/Chromosomal_crossover" rel="nofollow noreferrer">chromosomal crossover</a>, but individuals can more or less influence governments.</p>
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https://biology.stackexchange.com/questions/20020/what-is-wrong-with-this-analogy-individuals-are-to-alleles-what-governments-are
|
Question: <p>Lamarckism is a pre-darwinian theory according to which an organism's traits acquired to adapt to the environment are passed onto its offspring. A couple of years ago, I attended an event with Richard Dawkins and Jerry Coyne, both preeminent evolutionary biologists, in which I remember them agreeing that it is basically B.S. and that acquired traits don't get passed but instead propagate themselves through natural selection. As a non expert in biology, it does not make sense to me that acquired traits would make their way into the genotype and then get passed on, which coincides with what Dawkins was saying. But I am a non expert.</p>
<p>I also have read a few things about epigenetics and it sounds strangely similar to lamarckism. Steven Pinker also discusses all these things in The Blank Slate and he gives a notion that thare is some idealistic ideology behind promoting ideas that we can radically change an organism by environmental conditioning and "save" those changes into the genotype. He says that ideology is to justify government programs aimed at rapidly enhancing mankind whereas natural selection, which proponents of such ideas may deem reactionary, simply is not so optimistic.</p>
<p>My questions are:</p>
<ol>
<li>Is lamarckism, or inheritance of acquired traits, been conclusively discredited?</li>
<li>What does lamarckism relate to epigenetics</li>
</ol>
Answer: <p>The question is interesting at many levels. Of course, in biology and in any other science there is no absolute or 'objective' truth about some given phenomenon if we really care to look at the nuances. Lamarck seems to be vindicated mainly by a wave of empirical work on patterns of <a href="https://scholar.google.com/scholar?hl=en&as_sdt=0,11&as_ylo=2016&q=transgenerational%20inheritance" rel="nofollow noreferrer">transgenerational inheritance</a>, particularly in the field that is known as <a href="https://en.wikipedia.org/wiki/Epigenetics" rel="nofollow noreferrer">epigenetics</a>. You can read a good intro-level review <a href="https://science.sciencemag.org/content/354/6308/59" rel="nofollow noreferrer">here</a> for some recent developments, some particular examples <a href="https://academic.oup.com/eep/article/2/1/dvw002/2464897" rel="nofollow noreferrer">here</a>, or a more conceptual reading <a href="https://books.google.com/books?hl=en&lr=&id=NDFjDwAAQBAJ&oi=fnd&pg=PT7&dq=lamarck%20epigenetics&ots=dzYMRav0hj&sig=-ayJGP6j_BDRslISQxrU1a1-NH0#v=onepage&q=lamarck%20epigenetics&f=false" rel="nofollow noreferrer">here</a>. </p>
<p>As an evolutionary biologist myself, I will say that most other biologists acknowledge that epigenetics and transgenerational inheritance are important and have solid empirical support, but (for various reasons) some of them are hesitant of calling that 'Lamarckian'. </p>
<p>By the way, Dawkins was a very effective science popularizer, but he does not practice science nowadays, and many of his ideas lie in what is known as '<a href="https://en.wikipedia.org/wiki/Scientism" rel="nofollow noreferrer">scientism</a>', which is a blind confidence in science as an absolute truth that is inflexible. The same applies to many positions of Steven Pinker, deGrasse Tyson, etc. </p>
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https://biology.stackexchange.com/questions/92317/has-lamarckism-been-discredited
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Question: <p>I recently dived into the topic of <strong>instincts</strong> and now I have a question, where I haven't found anything about.</p>
<p>There's this thesis (I think mentioned <a href="https://link.springer.com/article/10.3758/BF03200077" rel="nofollow noreferrer">here</a> amongst others) that, through epigenetics, learned instincts <strong>can</strong> be passed along in genes and <strong>can</strong> over time be permanently integrated into the genome.</p>
<p>But...</p>
<p>Why is there no mentioning about how instincts can disappear over time, if they're simply not useful anymore? Or is it just not possible?</p>
Answer: <p>If it is like any other genetic trait, it will only be weeded out if there exists selective pressure that makes it counter-productive. Merely not being useful is not necessarily sufficient. Though I suppose over extremely long periods of time, it may get diluted out by mutation and propagation of those mutations if it persists in having no beneficial or detrimental effects.</p>
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https://biology.stackexchange.com/questions/114020/can-instincts-disappear-after-a-long-period-of-non-usefulness
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Question: <p>Are there any studies of epigenetic difference between twins during their lifespan ? I ask because I wonder if there exist phases during lifespan, when environmental factors plays major role (expecially in early adulthood) - twins study should allow to distinguish between changes in epigenetic profile caused by external factors and that from "inner dynamics" of organism.</p>
Answer: <p>I would think there have to be, though do you mean collecting samples on a regular basis and plotting out the difference at each point? Or do you simply mean the total accumulated change. If it is the latter, the answer is certainly "yes". You have probably seen the Nova documentary "<a href="http://www.youtube.com/watch?v=0o9f0VlyP5o" rel="nofollow">Ghost in Your Genes</a>" (The US, not BBC one). In it they show comparison of accumulated epigenetic change between a pair of identical twin Spanish women. I'm guessing you are more looking at measuring this change on a regular basis and looking for points of rapid divergence.... I don't know if this has been done for individuals, but it appears that it has been done for sample sets (see the same documentary). They discuss accumulated genetic change in younger twins vs older ones...</p>
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https://biology.stackexchange.com/questions/7380/are-there-any-studies-of-epigenetic-difference-between-twins-during-their-lifesp
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Question: <p>Wondering what the general take is on what are the molecular mechanisms that are mostly responsible for cell type differentiation stability; ie, for a cell's identity to actually become 'locked in' and progressively less susceptible to extracellular cues (for example, in heterotopic transplantation experiments such as Sue McConnell's).</p>
<p>I'm pretty convinced it really comes down to DNA methylation / chromatin remodelling / histone modifications in order to reach those truly stable, self-perpetuating, differentiated cell identities, but haven't been able to find a paper or review that actually discusses this. Your suggestions and opinions are welcome.</p>
<p>Also posted on <a href="https://www.reddit.com/r/labrats/comments/brk7ws/do_you_think_epigenetic_modifications_are_the/" rel="nofollow noreferrer">reddit/labrats</a></p>
<p>Edit: I suppose another way to ask this is: Are Waddington's stable "attractor cell states" most likely or most easily explained by epigenetic modifications such as DNA methylation?</p>
Answer: <p>Epigenetic marks are reversible (you might be aware of <a href="https://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell" rel="nofollow noreferrer">induced pluripotent cells</a>). Many animals can regenerate organs with high tissue complexity (such as a limb) and this involves de-differentiation in some species (<a href="https://doi.org/10.1016/j.stem.2013.11.007" rel="nofollow noreferrer">Sandoval-Guzman et al., 2014</a>). Even otherwise, cells can respond to extracellular/environmental cues to modify their epigenetic state (for e.g. <a href="https://en.wikipedia.org/wiki/Epithelial%E2%80%93mesenchymal_transition" rel="nofollow noreferrer">EMT</a> involved in wound healing). I would still consider epigenetic marks to be more "stable" than simple regulatory mechanisms.</p>
<p>Only way for a <em>cell's identity to actually become 'locked in'</em> is by genetic changes. The maturation of lymphocytes (especially the B-cells), would be a good example. These genetic changes happen via <a href="https://en.wikipedia.org/wiki/V(D)J_recombination" rel="nofollow noreferrer">V(D)J recombination</a>, <a href="https://en.wikipedia.org/wiki/Immunoglobulin_class_switching" rel="nofollow noreferrer">class-switching</a> recombination and <a href="https://en.wikipedia.org/wiki/Somatic_hypermutation" rel="nofollow noreferrer">somatic hypermutation</a>. </p>
<p>L1 retrotransposons are also known to contribute to somatic heterogeneity in the brain neurons. However, the frequency of insertions is not very high (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567441/" rel="nofollow noreferrer">Evrony et al., 2012</a>). </p>
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https://biology.stackexchange.com/questions/84534/are-epigenetic-modifications-the-most-stable-mechanisms-for-cell-differentiation
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Question: <p>Is anyone aware of a good data source to look at epigenetic patterns of human tissue at the gene level? I am trying to perform genetic mapping from DNA I am having sequenced. I want to be able to determine from which tissue, e.g., lung, the DNA sequence originates from.</p>
<p>Where might I find some good data?</p>
<p>Also happy to take any tips surrounding the data. I am not a biologist, but rather a data scientist.</p>
Answer: <p>Here's an atlas of <a href="https://www.nature.com/articles/s41586-022-05580-6" rel="nofollow noreferrer">whole-genome bisulfite sequencing</a> for sorted cell types. I haven't looked closely, but I think this one incorporated data from <a href="https://www.nature.com/articles/nature14248" rel="nofollow noreferrer">Roadmap</a> and <a href="https://www.nature.com/articles/s41586-020-2493-4" rel="nofollow noreferrer">ENCODE</a>, which preceded it. There's <em>lots, lots more</em> indexed at <a href="https://epigenie.com/epigenetic-tools-and-databases/" rel="nofollow noreferrer">Epigenie</a>.</p>
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https://biology.stackexchange.com/questions/116212/data-for-epigenetic-patterns-of-human-tissue-at-the-gene-level
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Question: <p>Many trees first reproduce decades after germination. Many pests of trees reproduce in under a year. It would seem that the pests have an advantage in the evolutionary arms-race, as they can evolve a means of attack far faster than the tree can evolve a defense (<em>cf.</em> <a href="https://biology.stackexchange.com/q/48769">Does an increased reproduction/mortality rate provide an evolutionary advantage?</a>).</p>
<p>I once read a speculation that trees might mitigate this by varying the genetics (or perhaps only epigenetics?) of different branches within an individual. The branches that do better produce more seeds. The seeds produced by a branch carry information specific to the branch. This means evolution (or the epigenetic equivalent) happens at the level of the organ, not the individual.</p>
<p>Is there any research supporting this speculation? If it has been refuted, how <em>do</em> trees compete effectively in the arms-race?</p>
Answer:
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https://biology.stackexchange.com/questions/94661/tree-pest-coevolution
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Question: <p>In a sitation of a mother-father conflict of interests, the mother <a href="https://www.researchgate.net/publication/5985782_Parental_conflict_does_not_necessarily_lead_to_the_evolution_of_imprinting" rel="nofollow noreferrer">might use</a> epigenetics to turn off some genes only advantageous for the father's genes and not her own. I thought a logical father's contra-strategy would be to bind the functions only advantageous to him to some of the genes crucial for them both, so that the mother couldn't turn these genes off.</p>
<p>Is there any evidence for a similar mechanism of "taking some genes hostage" in a situation of a conflict of interests?</p>
Answer:
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https://biology.stackexchange.com/questions/98869/does-parental-conflict-lead-to-genes-combining-important-functions-with-function
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Question: <p>Epigenetics, 2. ed, Chapter 3.6:</p>
<blockquote>
<p>Similarly, methylated lysine residues embedded in histone tails can be
read by “aromatic cages” present in chromodomains, or similar domains
(e.g., MBT, Tudor) contained within complexes that facilitate
downstream chromatin modulating events (see Ch. 7 [Patel 2014] for
structural insights</p>
</blockquote>
<p>I understand it is something like a protein motif, but I cannot find a good definition using google.</p>
Answer: <p>It refers to the structures in the <a href="https://en.wikibooks.org/wiki/Structural_Biochemistry/PHD_Finger" rel="nofollow noreferrer">PHD-finger domain</a> and chromodomains. The aromatic amino acid residues form a cage like structure which covers and interacts with the methylated ammonium of lysine via a cation-pi interaction.</p>
<blockquote>
<p>The BPTF-PHD structures reveal the main characteristics of PHD fingers that can read H3K4me3. The binding occurs through an aromatic cage where a trimethyl ammonium group is stabilized by van der Waals and cation-–π interaction, which is similar to the ones observed in <strong>chromodomain</strong>, MBT, PWWP, and Tudor domains. This aromatic cage is composed of one Trp and three Tyr residues; and it has three faces and a 'lid' that is beyond the tip of H3K4me3. Subsequently determined structures of other fingers in complex with the H3K4me3 peptides show that the cage varies and can contain a combination of two to four aromatic and hydrophobic residues. </p>
</blockquote>
<p><a href="https://i.sstatic.net/Cjrxb.jpg" rel="nofollow noreferrer"><img src="https://i.sstatic.net/Cjrxb.jpg" alt="enter image description here"></a>
<strong><em><sup> <a href="http://dx.doi.org/10.1038/nature08398" rel="nofollow noreferrer">Margueron et al., 2009</a></sup></em></strong></p>
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https://biology.stackexchange.com/questions/52664/what-is-an-aromatic-cage-and-what-does-it-do
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Question: <p>A neuroscientist told me (according to my hazy memory) that the brain/nervous system can have an epigenetic function, ie directly regulate gene expression. </p>
<p>I'm not a biologist, but she talked me through how it worked, and I know enough of the basics to follow along and think it sounded reasonable. I think the conversation was based on some post-doc research she was doing.</p>
<p>A quick google search (Maybe I don't know enough jargon to get a productive answer) brings up a chap called Bruce Lipton, who completely agrees, but who also, according to wikipedia "remains on the sidelines of conventional discussions of epigenetics, basically ignored by mainstream science".</p>
<p>So what gives?</p>
<p>Are there (a possible chain of) mechanisms by which the subconscious mind can affect gene expression?</p>
Answer: <p>As has been pointed out in comments, the brain can certainly affect gene expression; but so can <em>anything</em> in our bodies, because the blood stream is super good at carrying stuff around the body to wreak havoc.</p>
<p>But I'm going to take a somewhat uncharitable view of this question<sup>1</sup>; and assume that what you are asking about is high-level mental processes affecting gene expression throughout the body, which is not a thing that happens.</p>
<p>The basic concept to bring forwards here is that the brain is hell-a layered. The brain is an extremely complicated organ, and while it's not a <em>complete</em> mystery, it's not an organ that we generally can be said to understand, at least not on the level that we can be said to understand in major terms how, say, the liver, kidney or spleen works.</p>
<p>What we do know is this: The brain forms a massive network of neurons; the shape of which informs our personality, memory and cognitive functions. Even our simplest thoughts involve, by necessity, thousands of neurons, and anything more complicated than 'Fire!' involves tens, hundreds or thousands of thousands (millions) of neurons.</p>
<p>At the same time, it's important to understand that our brain does a lot of things that we're not directly cognisant of. For one, our brain controls our breathing. As you're reading this, you'll discover that you take control of your breath, but also that you haven't done so for several hours at the very least, and maybe not for days or weeks, and you haven't died from hypoxia yet. Our brains do these kinds of things all the time, and we hardly ever notice.</p>
<p>Genetics are a very, very, <em>very</em> low-level thing. Way lower of a level than mere breathing, genetics is the engine that drives decision making at a cellular level; which is so far removed from consciousness that it's hardly imaginable.</p>
<p>And this is where layering really comes into play: While recent research indicates that brain cells have hijacked DNA replication techniques to store memories, most of our actual thoughts exist only on levels that are so much higher than the nuts-and-bolts of our brains that the physical structure of our brains don't even come into play.</p>
<p>Essentially, thought as we understand it doesn't exist within individual neurons, but only within the relationship <em>between</em> neurons. When it comes to cognitive or metacognitive processes, things like genetics becomes an implementation detail isolated from the higher-level system as a whole. The underlying physical structures can affect gene expression, but do so not as a response to thoughts or subconscious desires, since these don't exist in the individual neurons; but as a response to primal needs like "more sugar for the brain!" or "more oxygen for the brain!" or "more protein for the brain!".</p>
<p>In other words: While the (sub)conscious mind can affect gene expression, it does so in terms of resource management, not in terms of how body tissues act, because the mind as it is has no physical concept of bodily function.</p>
<hr>
<p>1: Uncharitable, yes, but it <em>does</em> make the question more illuminating and interesting, IMHO.</p>
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https://biology.stackexchange.com/questions/50441/can-the-brain-influence-gene-expression
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Question: <p>I would like you to point me out some literature about putative epigenetic state changes in mouse/mammal sequences after cloning steps in <em>Escherichia coli</em>.</p>
<p>This are the last search details I used in NCBI PubMed:</p>
<blockquote>
<p>"epigenomics"[MeSH Terms] AND "cloning, molecular"[MeSH Terms] OR
"molecular cloning"[All Fields] AND "sequence"[All Fields] AND
("escherichia coli"[All Fields] OR "e. coli"[All Fields])</p>
</blockquote>
Answer: <p><em>E.coli</em> strains that have <em>dam</em> or <em>dcm</em> methylases can methylate plasmid at adenines or cytosines respectively. See <a href="https://www.neb.com/tools-and-resources/usage-guidelines/dam-and-dcm-methylases-of-e-coli" rel="nofollow">here</a> — It is a NEB web page but has links to the cited references.</p>
<p>DH5α has both the methylases- <em>dam<sup>+</sup> dcm<sup>+</sup></em> , BL21 is <em>dam<sup>+</sup> dcm<sup>−</sup></em> and ET12567 is <em>dam<sup>−</sup> dcm<sup>−</sup></em></p>
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https://biology.stackexchange.com/questions/3432/literature-about-putative-epigenetic-state-changes-in-mammal-sequences-after-clo
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Question: <p>Will monozygotic twins defecate at the same time if fed at the same time during the first weeks of life?</p>
<p>They should have the same genetics (and epigenetics) since they are monozygotic and the same environment since they live in the same house and they are just born.</p>
<p>I looked if metabolism (assuming it is correlated to defecating) is a genetic trait. I found <a href="http://doi.org/10.1001/archpedi.1941.02000170061005" rel="nofollow noreferrer">this review</a> about basal metabolism of infants but it stated that the methods aren't good and not comparable.</p>
<p>If there is no information for humans, what about other mammals?</p>
Answer: <p>I like admire your interest.</p>
<p>Organisms in development rely not only on their <a href="https://en.wikipedia.org/wiki/Nature_versus_nurture" rel="nofollow noreferrer">genetic make-up but also: their environment and epigenetics</a> (no matter how early in development).</p>
<p>In addition to variables other than the ones stated...</p>
<p><em>In reality if we were to test this</em> - the twins <em>wont</em> eat at the same speed, expend the same amount of energy, stay the same temperature, eat the same amount, or drink the same amount as each other.</p>
<p>With so many extraneous variables, it leads one to believe that it is <em><strong>very unlikely</strong></em> identical humans or other organisms would defecate at the same time.</p>
<p>I can direct you toward some (no-pay wall) literature on <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515707/" rel="nofollow noreferrer">the Nature/Nurture debate</a> or <a href="https://academic.oup.com/ageing/article/41/5/581/47543" rel="nofollow noreferrer">Twin studies</a>.</p>
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https://biology.stackexchange.com/questions/95066/do-identical-twins-have-the-same-metabolism-rate-at-birth
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Question: <p>I know that epiphyseal growth plates seal up once people become young adults and that it is currently impossible to restore them to actively produce new bone growth but, is it theoretically possible via genetic or epigenetic means to reactivate them to produce new bone?</p>
Answer:
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https://biology.stackexchange.com/questions/23153/can-sealed-epiphyseal-growth-plates-theoretically-be-restored-via-epigenetic-or
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Question: <p>Are all genes capable of being switched on or off or only some genes? Are there some genes that permanently do not have the functionality that enables them to be switched on or off?</p>
<p>Everything I have found in response to this question seems to assume that ALL genes are capable of being switched on or off.</p>
<p>When I have searched for the answer to this question all I find are explanations about how things like epigenetics, gene regulation and expression work. I understand at the basic level how these things work and that there are different ways by which they are accomplished.</p>
<p>I realize the answer may be "as far as we know" or "we don't know" or "it's complicated" and that's fine and definitely understandable.</p>
Answer: <p>I cannot think of a mechanism that would entirely <em>prevent</em> a gene from being regulated. For example, consider mechanisms like <a href="https://en.wikipedia.org/wiki/Histone#Modification" rel="nofollow noreferrer">histone modification</a>: there is very little about the sequence of a single underlying gene that can itself cause or prevent histone modification, yet those changes regulate the expression of associated genes. However, you can really only provide evidence in science for things that happen; providing evidence that things <em>do not happen</em> is often questionable. If you have some example gene and you'd like to say "this gene is not regulated", the best you can ever get to is "I haven't yet found a circumstance in which this gene is regulated by any manipulation I know of".</p>
<p>In practice, there are some genes that are <em>not typically</em> "switched on/off" and always expressed at fairly constant rates, we call these <a href="https://en.wikipedia.org/wiki/Housekeeping_gene" rel="nofollow noreferrer">housekeeping genes</a>. For many of these, the consequence of 'switching them off' would be death of the cell. However, I would not consider that these genes are "not capable" of being regulated, rather, I would say that they are <em>specifically regulated to be always active</em>, and that there is very strong evolutionary pressure for this to occur. To show that I mean by this, consider some quoted lines from Wikipedia:</p>
<blockquote>
<p>The housekeeping gene expression levels are fine-tuned to meet the metabolic requirements in various tissues. Biochemical studies on transcription initiation of the housekeeping gene promoters have been difficult, partly due to the less-characterized promoter motifs and transcription initiation process.</p>
</blockquote>
<blockquote>
<p>Little is known about how the dispersed transcription initiation of housekeeping gene is established. There are transcription factors that are specifically enriched on and regulate housekeeping gene promoters.[12][13] Furthermore, housekeeping promoters are regulated by housekeeping enhancers but not developmentally regulated enhancers.[14]</p>
</blockquote>
<p>In summary, steady activity is carefully controlled, and difficult to study. Comparatively, if a gene has very different expression in different environments, you can follow an iterative process to look at cells in each environment and see what is different: if you find another protein is phosphorylated or otherwise modified, or has also changed expression, you might be looking at a transcription factor involved in your gene of interest. On the other hand, if something never changes, where do you start? Trickier problem for an experimentalist.</p>
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https://biology.stackexchange.com/questions/108155/are-all-genes-capable-of-being-switched-on-or-off
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Question: <p>We know that all extant bacteria use the operon system as their mode of regulating gene expression, in contrast to eukaryotes, which use individual gene promoters as well as epigenetic mechanisms, supporting the idea that the first eukaryotes came from archaea as the 'host' in endosymbiosis, not bacteria [2]. However, the endosymbiont bacteria is suspected to be a bacterial phylum, supported by various lines of evidence: in short, an archaea enveloped a bacteria to make a eukarya.</p>
<p>An obscure group of protists was found to have mitochondrial DNA that used operon [1], but other than that, pretty much all eukaryotic cells have mitochondria whose mtDNA does not use operon, instead using similar regulatory mechanisms to eukarya including some basic epigenetics (methylation) [3]. A few operons, mainly for nuclear rRNA genes, have been found in chordates. But clearly it is not the norm.</p>
<p>Based on this, it would seem that operon evolved in prokaryotes some time after the endosymbiosis event, since the two are present mostly exclusively in independent domains of life. But recent research finds that operon seems to be fairly primitive (if I am interpreting [4] and [5] correctly) and could have arisen easily as a de novo insertion sequence, suggesting it would have come about earlier.</p>
<p>Does anyone have any expertise on whether this is the case? Did operon or mitochondria come first?</p>
<p><strong>References</strong></p>
<p>[1] Gray MW. Mitochondrial evolution. Cold Spring Harb Perspect Biol. 2012 Sep 1;4(9):a011403. doi: 10.1101/cshperspect.a011403. PMID: 22952398; PMCID: PMC3428767. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428767/" rel="nofollow noreferrer">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428767/</a></p>
<p>[2] Gautam Dey, Mukund Thattai, Buzz Baum, On the Archaeal Origins of Eukaryotes and the Challenges of Inferring Phenotype from Genotype, Trends in Cell Biology, Volume 26, Issue 7, 2016,
Pages 476-485, <a href="https://www.sciencedirect.com/science/article/pii/S0962892416300022" rel="nofollow noreferrer">https://www.sciencedirect.com/science/article/pii/S0962892416300022</a></p>
<p>[3] Sharma N, Pasala MS, Prakash A. Mitochondrial DNA: Epigenetics and environment. Environ Mol Mutagen. 2019 Oct;60(8):668-682. doi: 10.1002/em.22319. Epub 2019 Aug 6. PMID: 31335990; PMCID: PMC6941438. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941438/" rel="nofollow noreferrer">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941438/</a></p>
<p>[4] Yuki Kanai, Saburo Tsuru, Chikara Furusawa, Experimental demonstration of operon formation catalyzed by insertion sequence, Nucleic Acids Research, Volume 50, Issue 3, 22 February 2022, Pages 1673–1686, <a href="https://academic.oup.com/nar/article/50/3/1673/6511971" rel="nofollow noreferrer">https://academic.oup.com/nar/article/50/3/1673/6511971</a></p>
<p>[5] Marco Fondi, Giovanni Emiliani, Renato Fani, Origin and evolution of operons and metabolic pathways, Research in Microbiology, Volume 160, Issue 7, 2009, Pages 502-512, ISSN 0923-2508, <a href="https://www.sciencedirect.com/science/article/pii/S0923250809000539" rel="nofollow noreferrer">https://www.sciencedirect.com/science/article/pii/S0923250809000539</a></p>
Answer:
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https://biology.stackexchange.com/questions/114042/did-operon-evolve-after-endosymbiosis-and-specialisation-of-mitochondria
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Question: <p>It does not seem possible that these two processes can coexist: </p>
<p>1) Genetic imprinting is the phenomenon where genes are expressed differently depending on the parent of origin: </p>
<p>1a. Methylated stretches of DNA are not transcribed. </p>
<p>1b. If the gene copy originating with mom is methylated but dad's copy is not, then only dad's copy will be expressed (e.g. Prader Willi syndrome).</p>
<p>1c. Methylation is preserved during cell divisions. </p>
<p>1d. Methylation is wiped at gametogenesis, when females will erase dad's imprints and re-imprint according to maternal imprint before meiosis. </p>
<p>But now I'm reading about the role of epigenetics in cell differentiation, and I discover: </p>
<p>2) Cell differentiation occurs with lineage-specific patterns of methylation.</p>
<p>2a. Immediately after fertilization (prior to the first cell division), the paternal genome undergoes demethylation. </p>
<p>2b. The maternal genome undergoes demethylation during the first few cell divisions. </p>
<p>2c. Cell differentiation is accompanied and perhaps even accomplished by progressive re-methylation following these "wipes."</p>
<p>Source for 2): <a href="http://labs.genetics.ucla.edu/fan/papers/HuangK_RM2010.pdf" rel="nofollow">http://labs.genetics.ucla.edu/fan/papers/HuangK_RM2010.pdf</a>
"DNA methylation in cell differentiation and reprogramming: an emerging systematic view" Huang & Fan (2010). Regen Med. 5(4):531-44.</p>
<p>I suspect that there is no conflict and I merely misunderstand one, the other, or both. Otherwise, how can a pattern of methylation be wiped both during gametogenesis and early embryonic stages and still be inherited? </p>
Answer: <p>What if imprinted regions are immune to being wiped? Also, you may be confusing DNA methylation, and histone methylation (?). Classical biochemistry posits that DNA methylation states can be transmitted from a dividing mother cell to both daughter cells because after DNA replication the two daughter chromosomes will each be hemi-methylated, and a DNA methylase that finds a hemi-methylated site will methylate the other strand (like a corrective editing mechanism).
The third thing to consider in your question is that parental imprinting is established in the germ line. In terms of wiping other epigenetic marks during early embryogenesis, the only ones present would be the ones involved in gametogenesis. In other words, as far as we know, genes activated in muscle development are never expressed after fertilization in the zygotic cells that will give rise to the primordial germ cells, so those muscle-specific epigenetic marks don't need to be wiped off in the embryo. Neither the sperm nor the egg ever expressed muscle myosin, etc.</p>
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https://biology.stackexchange.com/questions/31186/genetic-imprinting-and-cell-differentiation
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Question: <p>Cytosine residues in DNA that can be methylated (i.e. CpG sites) are likely to be in the same methylation state if they are geographically (proximally) close together. </p>
<p>I can only find one paper that states this empirically (1), that 90% of CpG sites within 50bp of one another are in the same methylation state - see below graph.</p>
<p><img src="https://i.sstatic.net/6r46G.png" alt="Relationship between methylation status and geographical proximity"></p>
<p>However this study is quite dated now (in the fields of epigenetics at least), and is very general. </p>
<p>I would like to know whether CpG's in different regions of the genome are more/less likely to be correlated than in other regions (say, exons vs. promoter regions). It would also be interesting to know whether the correlations change with age, and whether this is related to any disease processes? </p>
<p>Thanks for the input. </p>
<hr>
<ol>
<li>Eckhardt, et al, 2006. Nature Genetics. doi: <a href="http://dx.doi.org/10.1038/ng1909" rel="nofollow noreferrer">2010.1038/ng1909</a></li>
</ol>
Answer: <p>I've got to dash off so I won't be able to give a fully in-depth answer today, but this basically boils down to the concept of CpG islands. Something like 70-80% of CpGs are methylated in humans, so if they were randomly scattered around the genome there is already a pretty high chance nearby CpGs are in the same state. However, because of CpG islands, CpGs of similar state are indeed grouped together, depending on promoter activity (to simplify things a bit).</p>
<p>That being said, if you look for articles that <em>cite</em> your article, a plethora of useful references show up. In particular, <a href="http://www.nature.com/nrg/journal/v9/n6/full/nrg2341.html" rel="nofollow noreferrer">this bad boy</a> has a handy figure 1 which displays the overall landscape. Maybe that's too broad of a view, but in general, like methylation patterns cluster together; otherwise, there'd be no such thing as a methylation pattern! <a href="http://www.sciencedirect.com/science/article/pii/S0006291X09007049" rel="nofollow noreferrer">This paper</a> has a neat figure which sums it all up nicely:</p>
<p><img src="https://i.sstatic.net/okUSL.jpg" alt="enter image description here"></p>
<p>Basically, it's usually high-methylation or low-methylation; rarely is there anything in between. There's a lot more in there so I'd recommend going through some of them; I'll try to get back to this later.</p>
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https://biology.stackexchange.com/questions/10365/how-correlated-are-proximally-related-cpg-sites-in-human-dna
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Question: <p>Let's assume that I am searching for gene editing candidates for curing human adiposis. Are there computational frameworks that can allow me to select the best candidate-genes for editing via some CRISPR-like tools? I guess, that extensive databases of already performed experiments are available and human mind is required to select candidate genes for experiments. But maybe there are some methods, that allow computational select, planning of experiment, e.g. using: 1) already known biological pathways for different biological processes or incomplete pathways for the process under consideration; 2) protein-protein interaction models to predict some pathways and to select genes from them. Etc.</p>
<p>I am complete novice for this field, coming from computer science and only starting to read books about molecular cell biology, epigenetics and protein-protein interaction. Maybe there are special terms that allow me to Google for the subject of this question</p>
Answer: <p>I suspect that what you are asking for is years in the future yet. Bear in mind that the use of CRISPR-CAS9 is <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769084/" rel="nofollow noreferrer">just entering clinical trials for a very few, well studied diseases</a>. Almost all the work with CRISPR-CAS9 is still limited to model organisms and tissue cultures.</p>
<p>Are you referring to <a href="https://www.genome.gov/17516629/learning-about-dercum-disease/" rel="nofollow noreferrer">Adiposis Dolorosa</a>? Apparently the cause is not actually known yet. It's thought to be heritable, but it isn't known to be associated with a single gene or family of genes. The most common technique for analyzing what genes and gene mutations cause disease is <a href="https://en.wikipedia.org/wiki/Genome-wide_association_study" rel="nofollow noreferrer">Genome Wide Association Studies (GWAS)</a>, so you might use that as a staring point for your searches.</p>
<p>There are <a href="https://www.bsc.es/medicahead/scientific-outputs/pmut-%E2%80%93-pathogenic-mutation-prediction" rel="nofollow noreferrer">several computer programs that try to model what pathological effects a given mutation will have</a>, but these are pure research at this point, and typically require extensive training for each gene or protein product. Try searching for "sequence based pathology prediction". However you may not find much related to Adiposis Dolorosa since the causative genes are apparently not known yet.</p>
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https://biology.stackexchange.com/questions/82878/computational-approaches-for-making-hypotheses-about-the-effects-of-genetic-engi
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Question: <p>Given two multi-cellular species with obviously different phenotypes. The reason for the different phenotypes reflects their <em>different DNA</em>.</p>
<p>However two types of cells in an adult organism may have clearly different phenotypes (e.g. morphology), but the <em>same DNA</em>, with a different set of genes expressed. </p>
<p>To explain this it would seem that there must be some molecules to modulate the expression of the DNA in different cell types. In my reading I have found one such type of molecules the presence of which is prerequisite for one type of differentiation – <a href="https://en.wikipedia.org/wiki/Histone_code" rel="nofollow noreferrer">modification of histons</a> – methyl, phosphate, acetyl, ubiquitin. Another class of molecules is the <a href="https://en.wikipedia.org/wiki/Transcription_factor" rel="nofollow noreferrer">transcription factors</a>.</p>
<p>My question: </p>
<p><strong>What would one look at to tell the differentiated type of a cell (ignoring its phenotype)?</strong></p>
<hr>
<p><strong>Addendum</strong>: After having delved a little bit deeper into the topic of epigenetics, I'd like to suggest as a possible answer: it's the <a href="https://en.wikipedia.org/wiki/Histone_code" rel="nofollow noreferrer">histone code</a> one has to look at, something like: how the DNA is wrapped around which sequence (!) of (modified) histones.</p>
Answer:
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https://biology.stackexchange.com/questions/67642/what-determines-the-differences-between-differentiated-cells
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Question: <p>After puberty, can certain diets, exercise, and/or possible drugs affect masculine/feminine dimorphism in adults? We know dimorphism and/or morphology is a product of genes, but to what extent can this be altered through environment? Like, can chewing more give a more masculine jaw shape/angle? Can talking a certain way make a more deep, manlier voice? Can squinting give hunter eyes?</p>
<p>For women, can eating soy-based products increase hip-to-waist ratio? Estradiol? Feminization of the face, cheeks and etc.? Likewise, in males, can vigorous exercise, drugs/diet and etc. masculinize?</p>
<p>Sexual dimorphism I mean as in how they look and what makes assure genetic/reproductive value.</p>
<p>Aside from genes, basically, what extent can diet, foods, exercise and etc. affect epigenetics, morphology and sexual dimorphism in animals, namely humans? Any evidence/studies/work on this?</p>
<p>This isn't intended to be a medical/personal question thing -- more so, broad on any means a human and/or animal may use their environment to try and improve dimorphism and morphology/phenotype.</p>
Answer: <p>There is a slight inaccuracy in your title question. Let's clarify to begin with:</p>
<p>I think you are asking whether environmental factors can affect sexually dimorphic <strong>traits</strong>. I don't think you are aiming to ask about dimorphism itself (i.e. the presence of apparent differences between the sexes) specifically. You're not interested in whether, say, food will affect sex dimorphism in humans but rather whether it can affect phenotypes which are sex-specific. It's a good correction to start with.</p>
<blockquote>
<p>Can diet affect sexual dimorphism?</p>
</blockquote>
<p>Of course. This is the case with all sexually dimorphic animals. A good example is nutritional deficiency, sub-optimal calorie intake or ingesting hormones or metabolically-active natural products from food. For instance, a male stag's antlers will not grow very much if the stag does not ingest enough phosphorus or calcium. This has drastic effects on its ability to reproduce, as often antlers are a key element in sexual selection in deer species.</p>
<p>Also, in some nutrient deficiencies, the body's ability to produce sex hormones is affected, which in turn affects secondary sexual characteristics such as jaw shape and the storage of fat. In bulimia and anorexia, periods become irregular due to the body's state of chronic starvation and inability to regulate menstruation with hormone cycles. Thirdly, diet can affect the ethology of disease (diabetes is a good example) which can indirectly affect sexual characteristics. There are many complex examples in which disease has an endocrinological (hormonal) component.</p>
<p>In addition, regular exercise, for instance, is well-demonstrated to affect testosterone levels.</p>
<p>It's important to keep in mind that not all traits which are sexually dimorphic are visible. For instance, smoking has an effect on sperm count, which is something not visible but still constitutes a sex-specific phenotype.</p>
<blockquote>
<p>Can supplementation and drug-use affect sexual dimorphism?</p>
</blockquote>
<p>Of course. I think taking steroids and hormones is an obvious example. I don't think this one needs explaining - a search engine can help here.</p>
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https://biology.stackexchange.com/questions/79868/can-diet-supplementation-and-or-drugs-affect-sexual-dimorphism
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Question: <p>Coming from computer science with an interest in genetic programming (a process emulating evolution) I'm curious about whether the rate of mutation is homogeneous across the whole genome, or if some parts of the genome differ in the rate of mutation.</p>
<p>For example we could imagine, without going to into details that could invalidate the example, that parts of the genome associated with the immune system could have a relatively higher mutation rate, because this would allow for a quicker adaptation to quickly evolving pathogens.</p>
<p>Is there any empirical support for that different part of a genome of some species have different mutation rates, that would give us empirical support for the possibility that some species under evolution have the ability to adjust (by NS itself or even epigenetics) the mutation rate of specific parts of the genome?</p>
<p><em>Clarification</em></p>
<p>I'm only interested in the mutations happening in the scope of the lifetime of a individual organism, I'm not interested in whether the mutations persisted under NS are equally distributed over the genome.</p>
Answer: <p>Well, for start, there are "mutational hot spots", regions that are more prone to mutation than others.</p>
<p>As for immune system genes, first of all, lung cells and heart cells and retina cells don't need to mutate those genes, because they don't use them.</p>
<p>But you are right that in immune cells there is a lot of DNA futzing in the sequences for the heavy and light chains, in order to generate diversity in T and B-cell receptors. Those receptor sequences are built in a mix-and match fashion, like building an outfit from a closet with a few pairs of pants and a few shirts. Add in some messiness in cutting out the specific sequences, and you have a fair bit of diversity in receptor sequences possible from a single genome.</p>
<p>Later, once a B-cell or T-cell meets a matching antigen, the cell multiplies, and each descendant cell is subject to somatic hypermutation, in the hopes that one of the tweaked sequences will better match the antigen.</p>
<p>But none of that is going to be very evolutionary relevant, since only mutations in gametes or gamete stem cells are passed on to the next generation.</p>
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https://biology.stackexchange.com/questions/21145/is-the-mutation-rate-in-organisms-in-general-consistent-over-the-genome
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Question: <p>From '<strong>Protein and DNA Sequence Determinants of Thermophilic Adaptation</strong>', by Konstantin B Zeldovich, Igor N Berezovsky and Eugene I Shakhnovich (Published: January 12, 2007 | <a href="https://doi.org/10.1371/journal.pcbi.0030005" rel="nofollow noreferrer">https://doi.org/10.1371/journal.pcbi.0030005</a>):</p>
<blockquote>
<p>Proteins are encoded in the nucleotide sequences of their genes, and
thermal adaptation presumably leads to increased stability of both
proteins and DNA. Therefore, signatures of thermal adaptation in
protein sequences can be due to the specific biases in nucleotide
sequences and vice versa. In other words, one has to explore whether a
specific composition of nucleotide (amino acid) sequences shapes the
content of amino acid (nucleotide) ones, or thermal adaptation of
proteins and DNA (at the level of sequence compositions) are
independent processes.</p>
<p>To resolve this crucial issue, we applied the following logic. If
amino acid biases are a consequence of just nucleotide biases and not
protein adaptation, then proteomes translated from randomly reshuffled
genomes will feature similar “thermal adaptation” trends in amino acid
composition as observed in real proteomes. In contrast, if amino acid
compositions are selected independently, then such control calculation
will result in apparently different amino acid “trends” in randomly
reshuffled genomes than observed in reality.</p>
</blockquote>
<hr />
<p>Can someone explain the <em>logic</em> of these authors in the second paragraph? Because I do not understand.</p>
<p>Firstly, I understand that DNA can adapt somewhat independently from proteins due to codon bias, and protein expression can adapt independently from DNA due to epigenetic factors (epigenetics is not mentioned in the article). However,
<strong>how does comparing the amino acid composition of a proteome translated from a randomly shuffled genome to the original, unshuffled proteome provide insights into independent protein adaptation?</strong></p>
Answer:
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https://biology.stackexchange.com/questions/113390/how-does-comparing-shuffled-proteomes-to-the-unshuffled-ones-help-us-understand
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Question: <p>I recently read several articles that believe that environment can affect gene expression and this change will transfer down to the children. Some theorists believe that random mutations are more rare and time consuming than a mutation that develops as a response to change of the environment the organism is in.
Epigenetics could be the key to how animals adapted and evolved so fast.</p>
<p>So does this mean a couple living in say, Siberia (both of whom migrated from say, Congo) will have higher probability of transferring gene variations to their children or grand children that will allow them to adapt better to the cold (as compared to the offsprings randomly developing mutations that help them adapt to the cold, and then passing it on to future generations)</p>
<p>Does that explain how humans were able to evolve quickly to their travels from Africa to the rest of the world and still survived the drastic changes in environment, rather than conclude that random gene variations led to adaptation?</p>
<p>Is this genetic adaptation as a response to the environment biologically proven?</p>
<p><a href="http://dukemagazine.duke.edu/article/big-question-can-your-environment-change-your-dna" rel="nofollow noreferrer">http://dukemagazine.duke.edu/article/big-question-can-your-environment-change-your-dna</a></p>
Answer: <p><strong>Generalities</strong></p>
<p>You have misread the articles (or read misleading articles). </p>
<p>Epigenetic modifications are, by definition, any modification to the DNA and proteins attach to DNA that does not affect the nucleotidic sequence (note that I here ignore some of the difficulties defining the term epigenetics). Such modification include methylation of histon tails for example (a histon is a protein around which the DNA is wrapped). Those epigenetic modification can appears in reaction to the environment and can be passed on to the offspring giving it a seemingly Lamarckian style of inheritence.</p>
<p>A mutation is, by definition, a change in the sequence of nucleotides. An epigenetic modification is therefore not a mutation (and a mutation is not an epigenetic change).</p>
<p><strong>Comments in the text</strong></p>
<blockquote>
<p>Some theorists believe that random mutations are more rare and time consuming than a mutation that develops as a response to change of the environment the organism is in.</p>
</blockquote>
<p>You might want to avoid calling "mutations" "random mutations" because it feels like you might not understand how unclear this phrasing is. Have a look at the post <a href="https://biology.stackexchange.com/questions/66183/are-mutations-random">Are mutations random?</a></p>
<p>Epigenetics change are NOT mutations.</p>
<p>The claim is too general and unclear and is impossible to comment about it without knowing what process you are interested in. One might claim that most genetic variance in populations is caused by epigenetic variation or make other claim that can be discussed but the above claim is too broad and unclear.</p>
<blockquote>
<p>So does this mean a couple living in say, Siberia (both of whom migrated from say, Congo) will have higher probability of transferring gene variations to their children or grand children that will allow them to adapt better to the cold.</p>
</blockquote>
<p>I don't understand what you mean here. And it feels to me that explaining everything that is unclear and going through all possible ways of understanding this sentence would take too much time!</p>
<blockquote>
<p>Does that explain how humans were able to evolve quickly to their travels from Africa to the rest of the world and still survived the drastic changes in environment, rather than conclude that random gene variations led to adaptation?</p>
</blockquote>
<p>You are really not using the term random correctly, which makes your question hard to understanding. Also, instead of gene variation I suppose you might want to use the term allele.</p>
<p>It is possible that epigenetics has played a role to allowing faster range expansion / range shift of human populations. I don't know if this is the case and I don't how important of an effect it would have.</p>
<blockquote>
<p>Is this genetic adaptation as a response to the environment biologically proven?</p>
</blockquote>
<p>Epigenetic, not genetic. Yes, epigenetic modifications do exist. We have plenty of evidences. I don't know how much we know about their impact on population range shift and survival but I would notice that it depends upon what mechanism exactly we want to consider into the broad term of epigenetics. For example, everybody will consider histon modification as part of epigenetic modifications. However, not everybody will want to consider fat content in the egg as an epigenetic modification. There is also a blurry border between what would be environmental effect (such as maternal effect) and epigenetic effect. But this is a discussion for another time.</p>
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https://biology.stackexchange.com/questions/74035/can-the-environment-affect-genes-and-adaptation-in-offspring
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Question: <p>I understand that in our lifetime, our experiences affect the expression of our genes. Some get switched on, while others switched off. Our experiences, diet, lifestyle etc. determines this expression of genes, but my question is, how long does it roughly take for such an expression to take place? Let's say you are a raging alcoholic suffering from chronic stress. Because of this lifestyle, certain genes get turned on. Then after a decade or two, you decide to change. You start eating healthy, you exercise, you change your lifestyle completely. How long would it now take for your new lifestyle to cause a different gene expression?</p>
<p>I realize this could be a silly question, but this is my understanding of how things work.</p>
Answer:
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https://biology.stackexchange.com/questions/112507/how-long-does-it-take-for-a-gene-to-be-switched-on-or-off-through-the-process-of
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Question: <p>I'm looking for an epigenetic database which includes for each example the psychological history of the persons DNA. Right now I can only find DNA and epigenetic databases. Sadly none of the databases provide "thick data" (qualitative data eg. history of person) to the sequenced DNA. </p>
<p>I want to investigate the effects of psychology on epigenetic and vice versa.</p>
Answer: <p>You might want to look at the Danish Data archive: </p>
<p><a href="http://www.sa.dk/content/us/about_us/danish_data_archive" rel="nofollow">http://www.sa.dk/content/us/about_us/danish_data_archive</a></p>
<p>I have never used their data and I don't know what barriers there might be to accessing it, but the impression I got at a talk by Soren Brunak (<a href="http://ctbr.hunter.cuny.edu/Brunak" rel="nofollow">http://ctbr.hunter.cuny.edu/Brunak</a>), was that this was one of the most complete databases for studying relationships between people's DNA records and other health information that might be available about them.</p>
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https://biology.stackexchange.com/questions/16861/psychological-database-with-sequenced-dna-records
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Question: <p>My main focus is transcriptomics analysis and very recently I have also started working on metabolomics. From my transcriptomic data it looks like there is a gene/protein that could potentially generate epigenetic modifications. I also have untargeted metabolomics data of equivalent experimental conditions that I plan to analyse soon hoping it will complete the picture. However, I have searched for publications linking specific metabolites with hyper/hypomethylation or chromatin structure and I have only been able to find a few references (see link below) and I got the feeling that untargeted metabolomics does not seem to be an obvious technique to observe epigenetic signatures.
<a href="https://www.ncbi.nlm.nih.gov/pubmed/30125527" rel="nofollow noreferrer">https://www.ncbi.nlm.nih.gov/pubmed/30125527</a></p>
<p>What metabolites would be regulated under epigenetic circumstances?
Does anybody have any experience or know of any particular study that looks into this relationship between untargeted metabolomics and epigenetic modifications? Thank you very much for your help! </p>
Answer: <p>This is a fascinating question, and I spent a fair amount of time looking into it. From what I've been able to find regarding the relationship between metabolics and epigenetics, it seems that metabolites drive epigenetic changes, not the other way around.
This can be shown quite well by looking at cell differentiation and induced pluripotent stem cells. The epigenetic changes that happen in these processes happen due to the cell's environment. </p>
<p><em>However</em>, epigenetic changes cause changes in transcription rates, so it can indirectly influence metabolics. The circadian clock uses this system (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392647/" rel="nofollow noreferrer">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392647/</a>).
Cell signaling appears to be the most significant cause of metabolic change, though. The aforementioned paper also says this: </p>
<blockquote>
<p>As most metabolites are not diffusible between mitochondria and
cytosol/nucleus, accurate determination of the cytoplasmic pool size
is critical to understand their effects on epigenetic signaling.
Although attempts have been made, so far the technology to reliably
measure metabolite concentrations in different cellular compartments
is lacking.</p>
</blockquote>
<p>Which, I'm sorry to say, leads me to believe that there are very few metabolic pathways that have known effects on epigenetic factors.
That said, there are several references in that paper which may put you on a good path forward.</p>
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https://biology.stackexchange.com/questions/93075/can-untargeted-metabolomics-detect-epigenomic-changes-such-as-methylation
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Question: <p>Most adaptations are what I'd call first-order. Cats evolve better eyesight; redwoods evolve to grow taller; male cardinals evolve attractive bright feathers. All of these changes were selected for because they directly make the organisms and their offspring more likely to reproduce. But it seems like there is a fundamentally different minority of adaptations, which I'll call second-order. Second-order adaptations do not make organisms and their offspring more fit directly, but rather they make an organisms' lineage more quickly responsive to selective pressures. Sexual reproduction is certainly the best example. The primary evolutionary benefit of sex doesn't come from increasing immediate fitness. In fact, I'd argue that many organisms' fitness is <em>reduced</em> by the fact that they cannot reproduce without a partner. Sex evolved not because it confers fitness to individuals, but because it confers adaptability to lineages: sexually reproducing lineages are quicker to evolve to fill new niches and avoid new threats. This is why I'd call sex a second-order adaptation, because it seems to be a rare adaptation which improves the process of evolution itself rather than the evolving organisms.</p>
<p>Is my understanding correct here, that sex is a fundamentally different kind of adaptation from, say, prehensile tails? If so, are there any other documented examples of second-order adaptations? Is there more accepted terminology than "first-order" vs "second-order" for this distinction?</p>
<p>Also, can anyone think of a <em>third-order</em> adaptation or pressure? Does that even make sense?</p>
<p>Possibly related: <a href="https://biology.stackexchange.com/questions/100073/could-an-organism-evolve-to-adaptively-evolve">this post</a>. But to be clear, I'm not asking about epigenetics.</p>
Answer: <p>I think that you are talking about evolvability (as I see it).</p>
<p>Sex is indeed a sort of a meta-adaptation, see e.g. <a href="https://books.google.com/books/about/The_Evolution_of_Sex.html?id=SbI5AAAAIAAJ" rel="nofollow noreferrer">The Evolution of Sex by John Maynard Smith</a>. The math for this is rather well developed at this point.</p>
<p>In terms of higher order effects like e.g. sex, I think that you are really talking about ideas like <a href="https://www.pnas.org/content/95/15/8420#:%7E:text=Evolvability%20is%20an%20organism%27s%20capacity,developmental%20processes%20are%20largely%20conserved." rel="nofollow noreferrer">evolvability</a>, and questions about constraints on paths over high-dimensional fitness landscapes. Examples of this might include <a href="https://pubmed.ncbi.nlm.nih.gov/27388336/" rel="nofollow noreferrer">the evolution of genome structure</a>, and the idea that certain genome architectures are more conducive to generating novel variation. A specific example (though one could argue about it) would be <a href="https://en.wikipedia.org/wiki/V(D)J_recombination" rel="nofollow noreferrer">V(D)J recombination</a>'s role in the adaptive immune system.</p>
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https://biology.stackexchange.com/questions/101284/higher-order-evolutionary-adaptations
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Question: <p>I'm a medical student (who is halfway through med school) looking for a textbook that will <strong>consolidate</strong> some of the biology I already know. While I've read a lot of books that go into great detail about genetics, immunology and cell signaling, I've not found many books that focus on clear insights.</p>
<p>After recently having perused a very well-written nanotechnology book geared towards bionanotechnology ("Bionanotechnology: lessons from nature," by Goodsell), I found many cell biology topics very well explained. For example, it states simply that "<em>lipids are used for infrastructure [in the body]</em>", and that "<em>polysaccharides are used in specialized structural roles</em>". Such sentences I've personally never really come across in any of the "standard" molecular biology texts (Alberts, Cooper, etc); I found that they focus far too much on detailing exactly the components of the DNA polymerase, or the ribosome (which are very important, but also something I'd like to go "beyond".)</p>
<p>Clarification on what type of book I seek:</p>
<ul>
<li>A book within cell or molecular biology</li>
<li>Scope of book; a book that covers any of the following: biochemistry, genetics (replication, translation, transcription, gene expression and its regulation, epigenetics, heredity, genetic engineering), developmental biology, cell biology (cell structure, organelles, cellular processes, cell signaling) and molecular biology (techniques such as high-throughput biology; concepts such as enhancers, repressors) and molecular evolution.</li>
<li>Level of the book doesn't matter, although I have completed all the subjects above at an undergraduate (bachelor) level - the book could thus be directed towards graduate/masters students.</li>
</ul>
<p>Any books/texts that will hone one's knowledge on the subjects mentioned will be warmly received!</p>
Answer: <p>Campbell's Biology is, I quote my biology teacher, "the Bible of AP Biology". I know you're a medical student and therefore far past that introductory college level, but Campbell's does quite a good and thorough job of explaining a plethora of biology topics. It's a fairly reliable textbook, I think you might like it. It also gives a good deal of examples for the various concepts and avoids such abstract statements as those you quoted from your textbook. I would suggest skimming through the book at a local bookstore if you can and seeing if it fits your criteria.</p>
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https://biology.stackexchange.com/questions/43608/molecular-cellular-biology-textbook-to-consolidate-what-i-know-about-molecular-c
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Question: <p>This may sound like a broad question to ask, but I am working on interpreting a review article for my epigenetics course and I'm having trouble reconciling two seemingly contradictory things this review is saying.</p>
<p>Ehrlich, M., & Lacey, M. (2013). DNA methylation and differentiation: Silencing, upregulation and modulation of gene expression. Epigenomics, 5(5), 553-568. doi:10.2217/epi.13.43</p>
<p>On page 554,</p>
<blockquote>
<p>Constantinides
et al. found that treatment of an embryonic
fibroblast cell line with 5-azacytidine (5azaCR),
an inhibitor of DNA methylation, induces the
formation of [myotubes] [35].</p>
</blockquote>
<p>and</p>
<blockquote>
<p>Treatment with DNA demethylating agents
can not only convert non-myogenic progenitor cells to Mt, but also can induce other cell-
type interconversions in progenitor cells. For
example, with 5azaCR treatment, the C2C12
Mb cell line can be induced to express genes for
key osteogenic transcription factors as well as
adipocyte markers [40]. The outcome of DNA
demethylation treatment is dependent upon the
cell type as well as the treatment and growth
conditions [41].</p>
</blockquote>
<p>and</p>
<blockquote>
<p>The conversion of a multipotent adult stem
cell to dissimilar differentiation products by
treatment with DNA demethylating agents
can be explained by the hypothesis that some
genomic methylation restricts the differentiation
potential of progenitor cells [40].</p>
</blockquote>
<p>These three quotes, all on the same page, seem to indicate that at the very least, induction of differentiation is contingent on demethylation. More specifically, DNA methylation restricts the possible differentiation activity that a progenitor cell can undergo. However, just a little further down, </p>
<blockquote>
<p>Terminal
differentiation predominantly led to increases
in DNA methylation and both increases and
decreases in H3K27me3, depending on the
gene involved.</p>
</blockquote>
<p>and</p>
<blockquote>
<p>[...] to
hypothesize that changing the DNA methylation status of pluripotency genes in vivo is critical to their function [43]. DNA methylation is
considered a more stable repressive mark than
repression-associated histone modifications [42].
The association of differentiation and the loss of
pluripotency with DNA methylation at previously unmethylated sites (de novo methylation)is consistent with the inability of ESCs to differentiate when Dnmt1, the most abundantly
expressed DNA methyltransferase gene, is
homozygously knocked out [44].</p>
</blockquote>
<p>I'm working on a presentation on DNA methylation and gene silencing, and I want to make an accurate portrayal of the role of DNA methylation in cell differentiation, and this is only a portion of the whole presentation, so I am not including a lot of data on this topic. However, I want whatever I do present to be self-consistent and accurate. How do I reconcile these two phenomena? From what I can tell, there is no explanation in the intervening text between these passages about how these two phenomena are similar but distinct. Am I accurate in determining that this is a difference between induction of differentiation and terminal methylation status? If so, how is it that ESCs can be differentiated with demethylating agents, but also ESCs have trouble differentiating when <em>Dmnt1</em>, which promotes methylation, is knocked out?</p>
Answer: <p>This is a good question. I'm not as steeped in this literature as I'd like, but here is my understanding of the process:</p>
<p>Methylation is one of the key methods by which cell fate is restricted. The review you're reading is giving specific examples of cell lines that are at least partially restricted into cells that are of an entirely different type. Thus <em>de-methylation</em> is a method for <em>de-differentiation</em>, which then allows differentiation along a different line.</p>
<p>Your three examples that it sounds like you're interpreting as induction of differentiation, are actually examples of that effect -- de-differentiation that then allows for differentiation to a different fate. Constantinides work, for example, showed the conversion of a <strong>non</strong>-myoblast precursor into functional striated muscle cells. Not only can fibroblasts be turned into muscle cells, myoblast cell lines can be made to look like bone cells or fat cells. None of these things would happen without <em>re</em>-programming the cell fate by <em>de</em>-differentiating the cell lines to form <em>dis</em>-similar differentiation products.</p>
<p>This is consistent with other findings about de-methylation in vivo. An important example is the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051243/" rel="nofollow noreferrer">global de-methylation of primordial germ cells</a>, as demonstrated in this figure from the linked review, summarizing the methylation state of the germ line in mice. Pay particular attention to the blue line. The pronucleus of the highly differentiated spermatazoon (along with its highly methylated DNA and histones) undergoes global de-methylation. Its products include the primordial germ cells of the developing mouse, the most de-differentiated state, which, in the case that it is a male, then become methylated as they become primed to differentiate, and then differentiate.</p>
<p><a href="https://i.sstatic.net/oFDPe.png" rel="nofollow noreferrer"><img src="https://i.sstatic.net/oFDPe.png" alt="enter image description here"></a></p>
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https://biology.stackexchange.com/questions/74959/what-is-the-relationship-between-induction-of-cell-differentiation-and-dna-methy
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Question: <p>In September 2019 Fahy et al. <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028" rel="nofollow noreferrer">published</a> results from the TRIIM (Thymus Regeneration, Immunorestoration, and Insulin Mitigation) trial. Their stated goals were to investigate whether they could restore the immune systems in eight healthy older men (ages 51 - 65) using a combination of recombinant human growth hormone, dehydroepiandrosterone and metformin. While they achieved impressive on-paper results partially restoring the <a href="https://en.wikipedia.org/wiki/Thymus" rel="nofollow noreferrer">thymus</a>, the most impressive result came from their <a href="https://en.wikipedia.org/wiki/Epigenetic_clock" rel="nofollow noreferrer">epigenetic measurement of aging</a> of subjects in the trial.</p>
<p>Fahy et al. had successfully reversed aging in their subjects according to four epigenetic measures of aging. The effect size was large: each measure indicated an average gain of over 2 years after 1 year of treatment.</p>
<p>In other words, if hypothetically a subject was 60 years old at the beginning of the trial, both chronologically and epigenetically, then by the end of the year they would be 61 years old chronologically but less than 59 years old epigenetically.</p>
<p>Of the epigenetic measures of aging, GrimAge is thought to be the best available predictor of lifespan. From <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/" rel="nofollow noreferrer">the paper</a> introducing GrimAge,</p>
<blockquote>
<p>Using large scale validation data from thousands of individuals, we demonstrate that DNAm GrimAge stands out among existing epigenetic clocks in terms of its predictive ability for time-to-death, time-to-coronary heart disease, time-to-cancer, its strong relationship with computed tomography data for fatty liver/excess visceral fat, and age-at-menopause.</p>
</blockquote>
<p>Fahy et al. demonstrated a mean age reversal of 2.16 years after 1 year of treatment according to the GrimAge measurement (see Table 1 in <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028" rel="nofollow noreferrer">the paper</a>).</p>
<p>Fahy is reportedly spearheading a new trial, called TRIIM-X (see <a href="https://youtu.be/PFg-OMHvI2E?t=968" rel="nofollow noreferrer">this part of his recent TEDx talk</a>). He hopes to investigate the effects of a modified version of the same treatment with the benefits of a larger trial and a more diverse set of participants.</p>
<p>The skeptical side of me has a question:</p>
<ul>
<li>Is a reversal of the epigenetic clock good evidence that aging was reversed, or is there a good theoretical reason to think that you can reverse the epigenetic clock without reversing “true” aging and thus increasing lifespan?</li>
</ul>
Answer:
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https://biology.stackexchange.com/questions/92906/is-this-trial-that-reversed-aging-in-humans-worth-taking-seriously
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Question: <p>We know that exposure to many toxic chemicals during embryonic development may show toxic effects later in life. It is called Developmental Origins of Health and Disease (DOHAD). Most of the mechanisms reported behind these kind of toxic effects are epigenetic. I could not find any genetic mechanism in the literature. Is there any example of genetic mechanisms behind DOHAD?</p>
Answer:
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https://biology.stackexchange.com/questions/78447/is-there-any-example-of-genetic-mechanism-of-delayed-onset-toxic-effects
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Question: <p>I was once told that if a woman experiences a famine, her grandchildren will show epigenetic changes because the egg that the intervening mother came from also experienced the famine.</p>
<p>In other words, the grandchild would be more susceptible to obesity, due to the grandmother's nutritional environment, even though the famine might have been 40-50 years distant.</p>
<p>However, I can't remember where I heard this, and could not locate a reference.</p>
Answer: <p>Here's an article in Science about the phenomenon:</p>
<p><a href="https://www.science.org/content/article/moms-environment-during-pregnancy-can-affect-her-grandchildren" rel="nofollow noreferrer">https://www.science.org/content/article/moms-environment-during-pregnancy-can-affect-her-grandchildren</a></p>
<p>It references a variety of different studies, not sure which you are most familiar with, but they include a population study of Dutch children whose grandmothers were pregnant with their mothers in 1944 and some more mechanistic studies in mice.</p>
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https://biology.stackexchange.com/questions/113229/searching-for-reference-regarding-the-impact-of-famine-on-a-womans-grandchildre
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Question: <p>I have an inquiry regarding the exact function of height genes.</p>
<p>To my knowledge, although they are heavily regulated by epigenetic factors, height genes can have either an "on" or an "off" allele, and the probability of the person being "tall" shows positive correlation with the number of "on" height genes alleles he has.</p>
<p>However, I could not find any resources showing the exact function or mechanism of these genes' function. Do these genes code for a specific protein when they are "on"? And if there are any, how do these proteins increase the probability of the person being "tall"?</p>
<p>Thank you.</p>
Answer:
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https://biology.stackexchange.com/questions/37208/function-and-mechanism-of-height-genes
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Question: <p>Is there any relationship between DNA methylation as a level of stability to epigenetic states and genome size? For example, it is claimed that DNA methylation is not required for epigenetic stability in <em>Drosophila melanogaster</em> and yeast, both genomes much smaller than mammalian or plant genomes. Could it be that DNA methylation is needed to help activate/repress certain genomic regions on top of other epigenomic marks when the genome is so vast that there is a need for an extra level of marking? Is there any evidence along those lines?</p>
Answer: <blockquote>
<p>Is there any relationship between DNA methylation as a level of
stability to epigenetic states and genome size?</p>
</blockquote>
<p>I would say yes, because methylation is used to disable genes in differentiated cells. Disabled genes in differentiated cells generally need to stay disabled to maintain normal behavior for the cell type. Larger genomes usually encode more different types of cells.</p>
<blockquote>
<p>it is claimed that DNA methylation is not required for epigenetic
stability in Drosophila melanogaster and yeast, both genomes much
smaller than mammalian or plant genomes. </p>
</blockquote>
<p>According to my book (S377 molecular and cell biology, book 2, p140) Drosphila don't need methylation because they perform transcriptional regulation by persistent chromatin remodelling instead. Yeast being single celled would have less need for this type of control.</p>
<blockquote>
<p>Could it be that DNA methylation is needed to help activate/repress certain genomic regions on top of other epigenomic marks when the genome is so vast that there is a need for an extra level of marking?</p>
</blockquote>
<p>It is used as a repressor because it inhibits hydrogen bonding of transcription factors and the like. I have not heard of it functioning as an activator.</p>
<p>There are also other uses for methylation, for example newly synthesized DNA is hemimethylated - where the parent strand is methylated and the child one not. From this it can be determined which is the parent strand during DNA repair.</p>
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https://biology.stackexchange.com/questions/2680/dna-methylation-and-genome-size
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Question: <p>Till now I thought that embryonic stem cells have no epigenome as they are pluripotent. (I thought that since epigenome is what gives a cell its identity, no cellular identity means no epigenome) I saw something similar to this on this Wikipedia page. <a href="https://en.wikipedia.org/wiki/Reprogramming#Embryonic_development" rel="nofollow noreferrer">After fertilization, the paternal and maternal genomes are demethylated in order to erase their epigenetic signatures and acquire totipotency.</a>.
Other sources mention 'reset' in place of 'erase'.
This paper rather suggests that stem cells do have an epigenome. <a href="https://www.nature.com/articles/pr2006122.pdf" rel="nofollow noreferrer">Specifically, genes associated with self-renewal are silenced, while cell-type-specific genes undergo transcriptional activation during differentiation.</a>.
I am not very literate in biology, please excuse me if I made a mistake.</p>
Answer: <p>So there are a couple of things to bear in mind.</p>
<ol>
<li><p>pluripotent does not mean that all genes are active. It means that the stem cells have the ability to form different cell types. However, it still needs to keep the cellular programme of a neuron for example silent. So the epigenome is still present to keep other cell type programmes silent until there is a transition.</p>
</li>
<li><p>DNA methylation is not the only source of epigenetics. Active and inactive genes also correspond to particular post translational modifications on tails of histone proteins. In the cell, DNA is wrapped around histones to form what is known as chromatin.</p>
</li>
</ol>
<p>Hope that is a starting point to answer your question</p>
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https://biology.stackexchange.com/questions/98898/do-stem-cells-have-no-epigenome
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Question: <p><strong>Disclaimer</strong>: I'm neither a genetics professional nor an anti-vax fanatic, I just tried to compare COVID-19 vaccine types currently available on the market and got some questions that I'd like to answer rationally.</p>
<p>Some of the vaccines that are being actively used now are based on adenoviral vectors, such as ChAdOx1, Ad26, or Ad5. These vectors are replication-defective, usually due to removed E1/E3 regions.</p>
<p>I looked for existing information about adenoviral vectors and found some facts that may relate to safety, but I can't conclude if they are rational or not for vaccine applications, since most studies are made for gene therapy or animal models.</p>
<p><strong>Proteins activity</strong></p>
<p>Wild-type adenoviruses are considered to be able to lead to tumors in rodents (<a href="https://en.wikipedia.org/wiki/Oncovirus#DNA_oncoviruses" rel="noreferrer">Wiki: DNA oncoviruses</a>), mostly due to E1 region activity, but E4 also adds to its oncogenic effect
(<a href="https://pubmed.ncbi.nlm.nih.gov/31821536/" rel="noreferrer">Cell transformation by the adenovirus oncogenes E1 and E4</a>), and may affect DSB repair (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC419473/" rel="noreferrer">Expression of the adenovirus E4 34k oncoprotein inhibits repair of double-strand breaks</a>). That may be related to the “hit-and-run” mutagenesis theory.</p>
<p>For Ad9, E4 alone can show that effect, E1 is dispensable (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC236897/" rel="noreferrer">Adenovirus type 9 E4 open reading frame 1 encodes a transforming protein required for the production of mammary tumors in rats</a>)</p>
<p><strong>Genome integration</strong></p>
<p>It's thought that adenoviruses do not integrate into the host genome, since they don't have a tool for that, but occasionally it happens with low probability (10^-3 .. 10^-7 per cell), particularly in cells where the virus can't replicate and lysis doesn't happen, which is always the case for replication-defective vectors (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937808/" rel="noreferrer">Chromosomal Integration of Adenoviral Vector DNA In Vivo</a>, <a href="https://jvi.asm.org/content/73/7/6141" rel="noreferrer">Frequency and Stability of Chromosomal Integration of Adenovirus Vectors</a>, <a href="https://www.nature.com/articles/3301121" rel="noreferrer">Insertion vectors for gene therapy</a>, <a href="https://www.nature.com/articles/3302074" rel="noreferrer">Illegitimate DNA integration in mammalian cells</a>, <a href="https://academic.oup.com/toxsci/article/155/2/315/2681762" rel="noreferrer">Viral Vectors: The Road to Reducing Genotoxicity</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478594/" rel="noreferrer">Viral Epigenetics</a>).</p>
<p>That raises questions about the possibility of insertional mutagenesis. As I see, such questions are often discussed in the context of DNA vaccines, but extremely rarely for adenoviral vectors which also deliver DNA into cells.</p>
<p><strong>Finally, the question itself</strong>:</p>
<p>Should risks of insertional mutagenesis due to viral genome integration and E4 region's proteins activity be considered and discussed or they are not important / do not exists at all for adenoviral vector vaccines? Have I missed any studies about these topics?</p>
<p>Can these risks be estimated in numbers and compared with similar natural events?</p>
Answer: <p>This question envisages putative harmful changes arising in host tissue cells infected with the replication-defective virus of a 'vectored' vaccine.</p>
<p>The scenarios of the question leave out of account a significant factor that opposes such putative harms. That is, one of the main purposes and effects of such vectored virus vaccines, which is to produce an adaptive cytotoxic T-cell immune response, targeted on (cell-surface-displayable fragments of) the viral gene-products (i.e. proteins) foreign to the tissues of the vaccinated host.</p>
<p>The aim of stimulating cytotoxic T-cell responses from vaccination is especially important against pathogens such as viruses (or intracellular parasites such as malaria) that disappear into the interior of cells of the host, and thereby become 'invisible' to circulating antibodies of the host immune system. This makes the antibody part of the response less useful against such pathogens.</p>
<p>Once such cytotoxic T-cells have been developed, they circulate and can detect and kill host tissue cells displaying fragments of those 'foreign' proteins on which the T-cells are targeted.</p>
<p>All of the host tissue cells infected by the vaccine virus are in this targeted category, and the consequence is that those infected host tissue cells have only a short life. They also are generally somatic cells with little cell-division, e.g. where the vaccine is given intramuscularly. Also, the replication-defect of the vaccine virus means that the vaccine-virus-infected cells are number-limited by the number of infectious units in the vaccine dose, there is no production of fresh generations of virus particles.</p>
<p>These factors and the processes of the cytotoxic immune response altogether oppose any likelihood of the putative harms envisaged by the question. The cited prototypes of those harms appear not to be reported in respect of situations that arise after vaccination with vectored virus vaccines.</p>
<p>(Supporting background can be found described and explained in the various editions of Janeway's 'Immunobiology'. The original author died in 2003, but the later editions have been retitled "Janeway's Immunobiology", in memoriam, to mark his founding contributions, e.g. the 9th edition (2017) is from authors/editors K Murphy & C Weaver.)</p>
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https://biology.stackexchange.com/questions/98143/why-are-adenoviral-vector-vaccines-safe-in-terms-of-insertion-mutagenesis-due-to
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Question: <p>I am confused on a detail in a paper I am reading and am not sure whether I am misunderstanding the wording or misunderstanding the concept. I am including the whole abstract of this paper for background:</p>
<blockquote>
<p><strong>Epigenetic regulation of uterine biology by transcription factor KLF11 via posttranslational histone deacetylation of cytochrome p450 metabolic enzymes.</strong></p>
<p>Zheng Y, Tabbaa ZM, Khan Z, Schoolmeester JK, El-Nashar S, Famuyide A, Keeney GL, Daftary GS.</p>
<p><strong>Abstract:</strong></p>
<p>Endocrine regulation of uterine biology is critical for embryo
receptivity and human reproduction. Uterine endometrium depends on
extrinsic sex steroid input and hence likely has mechanisms that
enable adaptation to hormonal variation. Emerging evidence suggests
that sex steroid bioavailability in the endometrium is determined by
adjusting their metabolic rate and fate via regulation of cytochrome
(CYP) p450 enzymes. The CYP enzymes are targeted by ubiquitously
expressed Sp/Krüppel-like (Sp/KLF) transcription factors.
Specifically, KLF11 is highly expressed in reproductive tissues,
regulates an array of endocrine/metabolic pathways via epigenetic
histone-based mechanisms and, when aberrantly expressed, is associated
with diabetes and reproductive tract diseases, such as leiomyoma and
endometriosis. Using KLF11 as a model to investigate epigenetic
regulation of endometrial first-pass metabolism, we evaluated the
expression of a comprehensive array of metabolic enzymes in Ishikawa
cells. KLF11 repressed most endometrial CYP enzymes. To characterize
KLF11-recruited epigenetic regulatory mechanisms, we focused on the
estrogen-metabolizing enzyme CYP3A4. KLF11 expression declined in
secretory phase endometrial epithelium associated with increased
CYP3A4 expression. Additionally, KLF11 bound to CYP3A4 promoter GC
elements and thereby repressed promoter, message, protein as well as
enzymatic function. This repression was epigenetically mediated,
because KLF11 colocalized with and recruited the corepressor
SIN3A/histone deacetylase resulting in selective deacetylation of the
CYP3A4 promoter. Repression was reversed by a mutation in KLF11 that
abrogated cofactor recruitment and binding. This repression was also
pharmacologically reversible with an histone deacetylase inhibitor.
Pharmacological alteration of endometrial metabolism could have
long-term translational implications on human reproduction and uterine
disease.</p>
<p><strong>Citation:</strong></p>
<p>Zheng Y, Tabbaa ZM, Khan Z, Schoolmeester JK, El-Nashar S, Famuyide A, et al. Epigenetic regulation of uterine biology by transcription factor KLF11 via posttranslational histone deacetylation of cytochrome p450 metabolic enzymes. Endocrinology. 2014;155:4507–20.</p>
</blockquote>
<p>My question is on the fourth-to-last sentence of this abstract specifically:</p>
<p><em>"This repression was epigenetically mediated, because KLF11 colocalized with and recruited the corepressor SIN3A/histone deacetylase resulting in selective deacetylation of the CYP3A4 promoter."</em></p>
<p>This sentence seems to say that SIN3A/histone deacetylase is deacetylating the CYP3A4 promoter itself (i.e. it is deacetylating a region of DNA directly). However, shouldn't a histone deacetylase be deacetylating a histone, not a region of DNA? Am I misunderstanding the mechanism? Or is "deacetylation of the CYP3A4 promoter" really a short-hand way of saying "deacetylation of a histone that is associated with the CYP3A4 promoter"?</p>
<p>Thanks in advance for your help!</p>
Answer: <p>The authors obviously meant to write that the histones associated with the promoter become deacetylated. They cannot mean the promoter itself as that is DNA.</p>
<p>What they wrote is not shorthand or acceptable alternative usage, but just a mistake — published papers often contain typos and mistakes of this sort. Probably the authors meant to write the technically correct form of words but lost a phrase. Or perhaps they had exceeded the limit to the number of words allowed in the summary, and so they went through trimming, but trimmed too much.</p>
<p>Why didn’t the referees pick this up? Of course they should have, but they were probably more concerned with the contents of the paper and whether the experiments described by the authors justified their conclusions. They are busy scientists and probably doing the job voluntarily.</p>
<p>In conclusion, scientists are human, scientific writing is difficult, and everyone makes mistakes. But we should still try to convey our ideas as clearly as possible, and certainly not copy something that is technically incorrect or ambiguous, just because it has made it into print.</p>
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https://biology.stackexchange.com/questions/45268/can-one-talk-about-deacetylation-of-a-promoter-rather-than-associated-histone
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Question: <p>Heterochromatin is defined as tightly packed form of DNA. But some experiments show that the average spacing of nucleosomes associated with H3K9me3 and H3K27me3, both heterochromatin marks, are longer than those with euchromatin marks. why packed DNA has longer spacing?</p>
<p>e.g in article :Genome-Wide Nucleosome Positioning Is Orchestrated by Genomic Regions Associated with DNase I Hypersensitivity in Rice. it says:"The average spacing of nucleosomes associated with H3K4me1 and H3K27ac, both euchromatin marks, are 178 bp and 179 bp, respectively. In contrast, the average spacing of nucleosomes associated with H3K9me3 and H3K27me3, both heterochromatin marks, are 205 bp"</p>
Answer:
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https://biology.stackexchange.com/questions/80561/why-nucleosome-spacing-is-longer-in-heterochromatin-than-euchromatin
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Question: <p>I'm studying bivalent promoters and enhancers. I understand that the same region of genome can have both H3K4me3 and H3K27me3.
But can they occur on the same histone tail?
Please provide me with a reference to support your answer.</p>
Answer: <p><a href="https://www.nature.com/articles/s41467-018-04836-y" rel="nofollow noreferrer">This paper</a> suggests that people have tested if two proteins can bind on a histone tail that contains both epigenetic marks. This implies that indeed both markings can be on the same tail.</p>
<p>"Next, we investigated if a histone tail bearing both H3K4me3 and H3K27me3 marks can be combinatorially recognized by SHL."</p>
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https://biology.stackexchange.com/questions/104546/can-the-same-histone-tail-have-both-h3k4me3-and-h3k27me3
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Question: <p>I understand that prions have been implicated in the passing on of epigentic information<sup>[<a href="http://dx.doi.org/10.1016/j.cell.2009.02.044" rel="nofollow">1</a>]</sup>. Are prions thought to play a significant role in the evolution of organisms?</p>
<ol>
<li><a href="http://dx.doi.org/10.1016/j.cell.2009.02.044" rel="nofollow"> <strong>Alberti S, Halfmann R, King O, Kapila A, Lindquist S</strong>. 2009. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137: 146–58.</a></li>
</ol>
Answer: <p>It is proposed that prions are a good mechanism for "testing" phenotypic variation.</p>
<p>There are many identified proteins with prion-determining domains (PrD) in the yeast genome that can spontaneously switch between conformations with some low probability (eg: check <a href="http://www.yeastgenome.org/cgi-bin/locus.fpl?dbid=S000002579">SUP35</a> for one example, and [1] for a good overview of more). The theory is that:</p>
<ol>
<li>the low probability of switching from non-prion to prion state allows for many more mutations and variations to accumulate -- generating greater genetic diversity than in standard expressed gene variability where most mutations are silent or detrimental</li>
<li>the prions provide a ready form of non-permanent inheritability that can be "trialed" by offspring and others in a colony of organisms -- this can be especially beneficial during say temporary changes in environment</li>
<li>if the prion phenotype is widely successful, selective pressure can easily mutate it into a more permanent fixture in the genome.</li>
</ol>
<p>Check out the excellent paper published just last week in Nature exploring this this topic [2]. To give a sense of just how evolutionarily-advantageous prions can be, in the author's experiments and analysis they note that 40% of the prion traits they analyzed were beneficial to growth (eg: in the paper strain UCD939 gains additional resistance to acidic conditions from the prion [PSI+]).</p>
<p>Assuming these hypothesis, prions would thus play a significant role in the evolution and variability of organisms.</p>
<p>[1] <a href="http://www.sciencedirect.com/science/article/pii/S1084952111000413">Crow, et. al. 2011. doi:10.1016/j.semcdb.2011.03.003</a></p>
<p>[2] <a href="http://www.nature.com/nature/journal/v482/n7385/full/nature10875.html">Halfmann, et. al. 2012. doi:10.1038/nature10875</a></p>
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https://biology.stackexchange.com/questions/1130/are-prions-an-important-driver-in-evolution
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Question: <p>Each cell in our body contains identical dna. And, yet some cells become liver cells, some become brain cells etc. How this happens , when all of them has same dna? Is it because of epigenetic control of gene expression?</p>
Answer:
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https://biology.stackexchange.com/questions/85563/what-causes-cellular-differentiation
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Question: <p><strong>Disclaimer</strong>: I don't know how much restless the leg has to be, in order to be considered a syndrome. </p>
<p>RLS runs not only in my family but also several people in the locality. My hypothesis is that RLS is a genetic/epigenetic adaptation to prevent mosquitoes or other insects from sucking blood. I, indeed, live in a malaria zone. I don't know enough biology to device a scientific experiment to prove my hypothesis. </p>
<p>Is there any scientific research done in this field? Someone who is well versed in this field should try it.</p>
Answer:
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https://biology.stackexchange.com/questions/45295/can-the-restless-leg-syndrome-may-have-been-caused-due-to-natural-selection
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Question: <p>So I read a journal article entitled <a href="http://www.ncbi.nlm.nih.gov/pubmed/22612345" rel="nofollow">"Maternal hypoxia and caffeine exposure depress fetal CV function during primary organogenesis</a>" (Momoi, et al., 2012) and in essence the article speaks of the period of time in embryological development when the cardiovascular system is developing as being the time when the fetus is most susceptible to epigenetic events, and how adenosine and its A2 receptor have a role in dilating coronary arteries in hypoxic conditions. It later goes on to say that since caffeine is an adenosine A2 receptor antagonist, mothers who consume caffeine regularly create a suboptimal environment for the fetus - this is referred to in the article as IUGR (intrauterine growth restriction).</p>
<p>My question is: Are there any effects (or do you believe there could be effects) of this inhibition occurring during development that affect the fetus later in life? As in, do you think there would be adult phenotypic changes of any kind due to the regular inhibition of a receptor during development? </p>
<p>I thought about this for a while and all that was apparent to me is that if the mother was both consuming caffeine and hypoxic, then the fetus could experience myocardial damage because its coronary arteries wouldn't be receiving the signal to dilate and the heart might be "starved" of the proper oxygenation. But even so, the receptor would still be present in the adult. Do you think there could be a decrease in transcription of a receptor that is continuously blocked (you don't need to address this in your answer -- notice that I'm asking for an opinion, which you can choose to give or withhold)?</p>
<p>FYI: I'm writing a review on how maternal prenatal health contributes to the epigenetic profile of offspring and I'm actually focusing more on the epigenetic contributions to the adult hypertensive phenotype. I stumbled upon the CV/adenosine article and was curious about whether there could be any long-term changes, so I asked all you wise folk. It has been observed that mothers fed a low-protein diet give birth to children with reduced nephron count and glomerular hypertrophy -- my goal is to understand what the current state of knowledge of this mechanism is. So if you have any ideas about anything here, or you've got an awesome resource related to this material, I'd really appreciate hearing about it. </p>
Answer:
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https://biology.stackexchange.com/questions/7543/if-a-receptor-is-inhibited-throughout-embryogenesis-could-there-be-observable-p
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Question: <p>I am reading Albert et. al’s Molecular Biology of the Cell and at one point the authors discuss the idea of “position effect variegation.” They mention that through events of DNA relocation, it’s possible for portions of echromatic DNA to become heterochromatic by being positioned next to heterochromatic DNA. They stress that “remarkably,” this heterochromatic state of DNA often gets inherited by the cell progeny. This phenomenon of inheritance is what they call, or I guess is called, position effect variegation. I don’t quite see what’s so “remarkable” about this, which is making me wonder if there’s something I’m underappreciating or misunderstanding. In particular, if the underlying DNA structure is changing, then wouldn’t we expect the progeny to inherit these epigenetic changes? Why is it so remarkable?</p>
<p>Here's the actual quote from the book:</p>
<blockquote>
<p>In chromosome breakage-and-rejoining events of the sort just
described, the zone of silencing, where euchromatin is converted to a
heterochromatic state, spreads for different distances in
different cells in the fly embryo. Remarkably,
these differences then are perpetuated for the rest of the
animal’s life: in each cell, once the heterochromatic condition is
established on a piece of chromatin, it tends to be stably inherited
by all of that cell’s progeny (Figure 4–31). This remarkable
phenomenon, called position effect variegation, was first recognized
through a detailed genetic analysis of the mottled loss of red pigment
in the fly eye</p>
</blockquote>
<p>and later on:</p>
<blockquote>
<p>But in at least some cases, the covalent modifications on nucleosomes
can persist long after the transcription regulator proteins that
first induced them have disappeared, thereby providing the cell with a
memory of its developmental history. Most remarkably, as in the
related phenomenon of position effect variegation discussed above,
this memory can be transmitted from one cell generation to the next.</p>
</blockquote>
Answer: <p>Re:</p>
<blockquote>
<p>In particular, if the underlying DNA structure is changing, then
wouldn’t we expect the progeny to inherit these epigenetic changes?
Why is it so remarkable?</p>
</blockquote>
<p>Given the context of the quote, the "variegation" part of the phrase refers to gene expression sometimes being turned off by influence of newly-nearby heterochromatin. The extent to which this suppression of expression extends into the euchromatic region from the adjacent heterochromatin varies from cell to cell, but once established is stably inherited through further divisions of that cell. It is unknown what molecular mechanisms initiate and maintain the suppression of expression in the formerly euchromatic genes.</p>
<p>Since we do not fully understand the molecular nature of what is required to initiate and maintain heterochromatin, especially in a section of DNA that was formerly euchromatin and so presumably does not contain any global "make me heterochromatin" sequence signals, the "remarkable" likely means "we don't yet understand the details" -- it's like magic.</p>
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https://biology.stackexchange.com/questions/103005/what-s-so-remarkable-about-position-effect-variegation
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Question: <p>I'm interested in the timing of events during <em>human</em> spermatogenesis, ideally with some references I can build off of. Specifically, I am trying to pin down the number of days for:</p>
<ul>
<li>Spermatogenesis, beginning to end (I have come across 65, 75, and 100). </li>
<li>Leptotene stage</li>
<li>Zygotene stage</li>
<li>Pachytene stage</li>
<li>Spermatozoa maturation and histone-protamine transition</li>
<li>Time in epididymis (I have come across 12 days)</li>
</ul>
<p>Again, I want to know the timing of these events in <em>humans</em>, not mice or rats. Specifically, I am trying to pin down the major epigenetic reprogramming stages, with a focus on those occurring in mature males. </p>
Answer: <h2><strong>Spermatogenesis (Beginning to end):</strong></h2>
<pre><code>64 +- 8 days (range 42 to 76)
</code></pre>
<p>There is considerable individual variation. This includes time in epididymis.</p>
<p>Amann 2008 argue for 74 days based on early study by Clermont 1972.
Also argue that biopsies are still needed on top of radiolabelling. </p>
<h2><strong>Substages:</strong></h2>
<p><em>Calculated from Amann 2008, Figure 1 using percent time in 16 day cycles.</em></p>
<p><strong>Leptotene:</strong> </p>
<pre><code>26.5 days (~70 days total - 26.5 days = ~ 43.5 days pre-ejaculation/conception)
</code></pre>
<p><strong>Zygotene:</strong> </p>
<pre><code>31.2 days (~70 days total - 31.2 days = ~ 38.8 days pre-ejaculation/conception)
</code></pre>
<p><strong>Pachytene:</strong> </p>
<pre><code>32 days (~70 days total - 32.0 days = ~ 38 days pre-ejaculation/conception)
</code></pre>
<p><strong>Histone-Protamine transfer</strong>:</p>
<pre><code>68.8 days (~70 days total - 68.8 = ~2 days pre-ejaculation).
</code></pre>
<p>The resolution of the data doesn’t really let us get at Epididymis vs. histone-protamine transfer, though.</p>
<p><strong>Time in the Epidymis:</strong></p>
<pre><code>10-14 days.
</code></pre>
<p><em>References:</em></p>
<blockquote>
<p>Misell LM, Holochwost D, Boban D, Santi N, Shefi S, Hellerstein MK,
Turek PJ. 2006. A Stable Isotope-Mass Spectrometric Method for
Measuring Human Spermatogenesis Kinetics In Vivo. The Journal of
Urology 175:242–246.</p>
<p>Amann RP. 2008. The Cycle of the Seminiferous Epithelium in Humans: A
Need to Revisit? Journal of Andrology 29:469–487.</p>
<p>Durairajanayagam D, Rengan AK, Sharma RK, Agarwal A. 2015. Sperm
Biology from Production to Ejaculation. In: Schattman GL, Esteves SC,
Agarwal A, editors. Unexplained Infertility. New York, NY: Springer
New York. p. 29–42. Available from:
<a href="http://link.springer.com/10.1007/978-1-4939-2140-9_5" rel="nofollow noreferrer">http://link.springer.com/10.1007/978-1-4939-2140-9_5</a></p>
</blockquote>
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https://biology.stackexchange.com/questions/52184/spermatogenesis-in-humans-timing-of-phases-and-chromatin-modifications
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Question: <p>I recently asked a question about the cause of motor laterality: <a href="https://biology.stackexchange.com/questions/95291/what-causes-motor-laterality-side-dominance">What causes motor laterality/ side dominance?</a></p>
<p>I understand that there can be genetic factors, epigenetic factors, or environmental factors. <em>But in terms of continuous practice of motor skills, what type of factor will that be?</em> Physical factors? Thank you!</p>
Answer:
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https://biology.stackexchange.com/questions/95369/what-type-of-factor-is-practice-of-motor-skills
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Question: <p>I'm actually currently studying physics but this came up in my textbook (taken from Giancoli 7th edition section 16-10):</p>
<p>The random (thermal) velocities of molecules in a cell affect cloning. When a bacterial cell divides, the two new bacteria have nearly identical DNA. Even if the DNA were perfectly identical, the two new bacteria would not end up behaving in exactly the same way. Long protein, DNA, and RNA molecules get bumped into different shapes, and even the expression of genes can thus be different. Loosely held parts of large molecules such as a methyl group can also be knocked off by a strong collision with another molecule. Hence, cloned organisms are not identical, even if their DNA were identical. Indeed, there can not really be genetic determinism.</p>
<p>I'm aware of different biological processes that can affect gene expression but this is random kinetic motion! Would you call this one of the epigenetic mechanisms that can affect gene expression? If so it would underlie ALL epigenetic mechanisms because all molecules have random kinetic motion. </p>
Answer: <p><strong>The two terms of main interest to you</strong></p>
<p><a href="https://en.wikipedia.org/wiki/Cellular_noise" rel="nofollow noreferrer"><strong>Cellular noise</strong></a></p>
<blockquote>
<p>Cellular noise is random variability in quantities arising in cellular biology. For example, cells which are genetically identical, even within the same tissue, are often observed to have different expression levels of proteins, different sizes and structures. These apparently random differences can have important biological and medical consequences</p>
<p>Cellular noise was originally, and is still often, examined in the context of gene expression levels – either the concentration or copy number of the products of genes within and between cells. As gene expression levels are responsible for many fundamental properties in cellular biology, including cells' physical appearance, behaviour in response to stimuli, and ability to process information and control internal processes, the presence of noise in gene expression has profound implications for many processes in cellular biology.</p>
</blockquote>
<p>There is also the term <strong><a href="https://en.wikipedia.org/wiki/Developmental_noise" rel="nofollow noreferrer">developmental noise</a></strong>.</p>
<blockquote>
<p>Developmental noise is a concept within developmental biology in which the phenotype varies between individuals even though both the genotypes and the environmental factors are the same for all of them. Contributing factors include stochastic gene expression and other sources of cellular noise.</p>
</blockquote>
<p>Developmental noise is often sounds like a synonym of cellular noise, but it is supposed to include more processes that are causing phenotypic variation then cellular noise. For example, it is common to consider "micro-environmental variation" as being part of developmental noise and not of cellular noise.</p>
<p><strong>The way your phrased your question</strong></p>
<p>In your question you describe only sources of cellular noise. However, you end up saying <code>Hence, cloned organisms are not identical, even if their DNA were identical</code>. I just want to highlight that, there are other reasons than cellular noise for which two clones differ. These include micro-environmental variance, physiological noise, epigenetic variance and macro-environmental variance (often just called environmental variance). Note that I had never encountered the term "physiological noise" before, I just made it up but I wanted to highlight that noise also happen in among cells processes, not only within cells processes.</p>
<p><strong>Intro to quantitative genetics</strong></p>
<p>For a short introduction to quantitative genetics and the different sources of phenotypic variance (genetic variance, environmental variance, developmental noise, etc..) and how the concept of heritability fits into this discussion, please have a look at the post <a href="https://biology.stackexchange.com/questions/42273/why-is-a-heritability-coefficient-not-an-index-of-how-genetic-something-is">Why is a heritability coefficient not an index of how “genetic” something is?</a></p>
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https://biology.stackexchange.com/questions/71807/does-anyone-know-if-there-is-a-term-to-describe-the-following-process
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Question: <blockquote>
<p>First off, it's not "we don't know," it's "they don't know." Just because some sources are uncertain doesn't mean the answer isn't out there. Consensus doesn’t determine truth. Look at how many still believe in astrology, miracles, or gods. Answers emerge over time, usually in pockets among those who actually understand the subject.
We aren’t still arguing about how to define life. Only people locked into rigid biases are. Strip away the bias and the argument disappears. Life operates through observable principles, and while edge cases exist, they don’t invalidate the broader understanding of biological processes.
As for sexuality, you just proved the point yourself. Everything exists on a spectrum. Even the most heterosexual men fall somewhere within it, whether they acknowledge it or not. This is evident in dominance and submission traits, social bonding behaviors, and even the way attraction works under varying conditions.
Sexual orientation is largely a result of long-term hormonal influences. If you we're to alter key hormones like testosterone, estrogen, oxytocin, and progesterone etc, you would see behavioral and attraction shifts in ANYONE. It’s all biochemical. Nature operates this way to create adaptability, allowing different individuals to thrive in different niches.
Your being gay has evolutionary advantages, even if they aren't as obvious in today’s social structures. Societal norms fluctuate and when they reach a breaking point they tend to cycle back. What may seem like a disadvantage now could become an asset later, as history has shown time and time again.
And to answer your last question, yes, it's "true" in the sense that your attraction is dictated by your physiology. The same applies to me. I’m attracted to women because of the hormones present in my body. But as we age and those hormones decline, sexual drive fades for both of us. That’s why the elderly don’t go clubbing they become sexually benign overtime absent of all desire. Resorting back to a neutral state as the hormones decline the same way we all were in before puberty (before bias's and judgement)
One last thing, epigenetics can modulate hormones, meaning certain life experiences can create lasting physiological changes. For example, if a girl is traumatized by a male with a beard, the stress response could trigger epigenetic modifications to her RNA, influencing her attraction patterns, perhaps making her avoid men with beards or even shifting her sexual preferences. So yes, you’re gay, but only to the extent that your physiology permits, just as my heterosexuality is also shaped by biological and environmental factors. This is adjustable with focus and understanding to a degree. But most people arevlazy and accept it as natural even if its dynamic. Hope that helps.. I dont see sex as defining i see life as defining. Your alive and beneficial as an intellectual curious person so that overrules society limited norms in my eyes. But im apparently rare in that regard.</p>
</blockquote>
<p>The massive quote is from someone who told me that sexuality is largely determined by hormones and that you can change it with focus and understanding (though all literature says you can't and conversion therapy fails).
I know that hormones play a role in the determination of orientation but are they the final line or just one part of a greater whole?</p>
<p>When I looked up some of his claims they were largely wrong, which makes me wonder where the information is coming from. Nothing shows that you can just change it by adjusting hormone levels.</p>
<p>But I googled a few things, the claim about elderly people isn't true:</p>
<p><a href="https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00003-X/fulltext" rel="nofollow noreferrer">https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00003-X/fulltext</a></p>
<p>In fact it's a common misunderstanding.</p>
<p>As for orientation, all I really found is that hormones affect it in pregnancy:</p>
<p><a href="https://www.sciencedirect.com/science/article/abs/pii/S009082581731510X" rel="nofollow noreferrer">https://www.sciencedirect.com/science/article/abs/pii/S009082581731510X</a></p>
<p>There wasn't anything about turning gay guys straight and vice versa through key hormones as adults.</p>
<p><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3138231/#:%7E:text=Many%20studies%20have%20analyzed%20the,2" rel="nofollow noreferrer">https://pmc.ncbi.nlm.nih.gov/articles/PMC3138231/#:~:text=Many%20studies%20have%20analyzed%20the,2</a>).</p>
<p>There are some reports among trans individuals with hormone therapy, but the results are mixed at best and anecdotal, it could also just be something among trans individuals. It's also not certain if it's the hormones or psychological effects of transitioning.</p>
Answer: <h3>Possibly yes, but <em>not the way you think</em>!</h3>
<p>The use of hormones to influence sexual orientation has a terrible history, which illustrates that it is not very simple to change sexual behavior. <a href="https://en.wikipedia.org/wiki/Alan_turing" rel="nofollow noreferrer">Alan Turing</a> was involuntarily subjected to a snake-oil hormone treatment - but he was <a href="https://www.reddit.com/r/explainlikeimfive/comments/2ufiem/eli5why_did_estrogen_hormone_therapy_break_down/" rel="nofollow noreferrer">forced to receive estrogen</a> not to make him more gay, but to <em>decrease</em> his libido. The OSS had a similar harebrained scheme to introduce estrogen to Hitler's garden vegetables ... though in their defense I'd like to think 'estrogen' might have been a code word for some more effective form of malpractice.</p>
<p>In reality, testosterone combined with sildenfil (Viagra) is more likely to be considered as a treatment to <a href="https://pubmed.ncbi.nlm.nih.gov/29289554/" rel="nofollow noreferrer">increase the libido of heterosexual women</a>. (I haven't tracked down how that research is going, since our paths diverge here)</p>
<p>Nonetheless, hormones <em>are</em> involved ... sort of. Namely, sex hormones are secreted by apocrine sweat glands beginning at puberty. Mutualistic bacteria in the skin convert these into human sex pheromones. And the response to sex pheromones <a href="https://pubmed.ncbi.nlm.nih.gov/24794295/" rel="nofollow noreferrer">depends on sexual orientation</a> I've seen several studies on squares cut from sweaty T-shirts reported that give this result.</p>
<p>The mechanisms are not often spelled out, but I'll string some ideas together, noting that not all the logical steps are well proven. Specifically, humans have a <a href="https://pubmed.ncbi.nlm.nih.gov/34266599/" rel="nofollow noreferrer">vomeronasal organ</a> and receive pheromone signals via cranial nerves 0 and 1 (terminal and olfactory nerves). These stimulate GnRH-expressing neurons that run to the hypothalamus, secreting gonadotropin releasing hormone that triggers LH and FSH secretion in the anterior pituitary (this is basic A&P content). LH and FSH can do things like trigger ovulation and sperm production, and promote testosterone production (which is converted into estrogen in ovaries).</p>
<p>There are <a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3987372/" rel="nofollow noreferrer">some indications</a> that pheromones increase sexual mood in the short term. I would hypothesize that the effects of GnRH also condition sexual behavior in the Pavlovian sense. As a result, things that are correlated with the 'right' pheromone will be perceived as sexually desirable. Perhaps in monosexuals the 'wrong' pheromone has an aversive effect as well. This would explain the observation that average faces are perceived as most attractive, though there are <a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4053512/" rel="nofollow noreferrer">other explanations</a>.</p>
<p>There are caveats here. Notably, a human pheromone receptor has been dubbed a pseudogene as it contains an in-frame stop codon ... though the sequence is conserved (I suspect SECIS, RNA editing, or some other biology). There are valid <a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4375873/" rel="nofollow noreferrer">criticisms</a> to how key experiments have been done and whether the right chemicals are being examined. Given the complexity of steroid chemistry and the number of other putative pheromones in play, it is a field that could use more study. When we think of the potential applications for restoring pleasure to married couples, providing enlightenment on issues regarding sexual orientation, perhaps even finding a cure for pedophilia, the problem should be worth investing in - unfortunately it seems very unlikely to receive much public funding now for political reasons. Still, the return from an effective drug modulating this system could be enormous.</p>
<ul>
<li>This answer addresses only the headline question, "Are hormones the main factor for determining sexual orientation?"</li>
</ul>
<p>Update: I found a source (<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5863565/" rel="nofollow noreferrer">McCarthy, 2017</a>) which describes experiments suggesting that estrogen is necessary for ovariectomized, sexually naive female mice to develop a preference for male pheromones. There is a <a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC8347621/" rel="nofollow noreferrer">curious suggestion</a> that the precise plasma testosterone level could select <em>between</em> male and female preference</p>
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https://biology.stackexchange.com/questions/116198/are-hormones-the-main-factor-for-determining-sexual-orientation
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Question: <p>Are there scientifically valid methods (possibly in the developmental stage) that can be used for aesthetic medicine. Usually surgical of physical therapies are used for aesthetic medicine, but actually all the problems of aesthetic appearance should be traceable to the genetic/epigenetic causes and that is why the molecular treatment at that level should be possible and optimal.</p>
<p>My question is can be considered also as a veterinary medicine question (aesthetics of pets) and that is why it is really a biology question.</p>
<p><a href="https://journals.sagepub.com/doi/full/10.1177/2470289718787086" rel="nofollow noreferrer">https://journals.sagepub.com/doi/full/10.1177/2470289718787086</a> is the only more or less relevant article that I have managed to find.</p>
<p>Also CRISPR can be quite promising tool, but I have not managed to find scientific studies for aesthetic medicine of it.</p>
Answer:
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https://biology.stackexchange.com/questions/82869/techniques-of-molecular-medicine-biology-for-aesthetic-medicine
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Question: <p>Usually the protocol for preparing electrocompetent E. coli cells calls for growing the cells at 37deg and 225rpms until they reach OD of 0.3. I was wondering, is there any reason they should grow at optimal conditions for growth, instead of at suboptimal, for example at 30 degrees? Also, what is the physiological/epigenetic difference between a culture of OD 0.2 vs 03. vs 0.3? </p>
Answer: <p>I'm new so I can't make this a comment, and I don't think the other commenter addressed your questions so here it goes: I don't think there will be much difference, if any, between 0.2 and 0.3 OD. Once you get higher and the cells start transitioning into a stationary phase is a different story. Did you mean to ask about 0.03 OD as well (you wrote 03.)? I'm not an expert in E. Coli, but they would probably be less likely to produce proteins that are contact inhibited. Sub-optimal temperatures may have a minor effect on growth, but I don't believe this will initiate much change or induce production of large amounts of cold shock proteins.</p>
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https://biology.stackexchange.com/questions/5295/cell-growth-conditions-for-preparing-electrocompetent-cells
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Question: <p><strong>Background</strong></p>
<p>In all <a href="http://en.wikipedia.org/wiki/Eutheria" rel="nofollow">eutherian</a> (mammals excluding the marsupials), the female (who is $XX$ for the pair of sexual chromosomes) inactivates one of her $X$. This is called <a href="http://en.wikipedia.org/wiki/Dosage_compensation" rel="nofollow">dosage compensation</a>. This inactivation occurs at a given time during the development when randomly one $X$ is silenced. The daughters of this cell inherit the $X$-inactivation pattern epigenetically, which results in some part of a tissue having the maternal $X$ inactivated while others having the paternal $X$ inactivated (daughters of some other cell which silenced the paternal $X$). This process yield to the famous <a href="http://en.wikipedia.org/wiki/Tortoiseshell_cat" rel="nofollow">turtoiseshell</a> coat in female cats.</p>
<p><strong>Question</strong></p>
<p><em>In short</em></p>
<p>Assuming X-inactivation occurred in the lineage of the oogonia/oocytes, when does the X-inactivation and X-reactivation occur in the lineage of the oocytes?</p>
<p><em>A bit developed</em></p>
<p>Are the X inactivated as well in primary oocytes? If not, is the $X$ inactivated in the secondary oocytes in a primary follicle? If not, did the diploid mother cells of the secondary oocytes have one $X$-inactivated? If yes, did all diploid mother cells of oocytes have the same $X$ inactivated (inactivation occurred relatively early in the development or is there an imprinting) or did the mother cells of oocytes differ in the $X$ they have inactivated (inactivation occurred relatively late in the development)</p>
Answer: <p>See these two papers:</p>
<ul>
<li><a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0000860#abstract0" rel="nofollow">Early Loss of Xist RNA Expression and Inactive X Chromosome Associated Chromatin Modification in Developing Primordial Germ Cells</a></li>
<li><a href="http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.0030116" rel="nofollow">X Chromosome Reactivation Initiates in Nascent Primordial Germ Cells in Mice</a></li>
</ul>
<p>Basically it happens just before the meiosis. </p>
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https://biology.stackexchange.com/questions/20277/x-inactivation-in-ovaries
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Question: <p>On the website <a href="http://www.whatisepigenetics.com/fundamentals/2/" rel="nofollow">http://www.whatisepigenetics.com/fundamentals/2/</a> it states that </p>
<blockquote>
<p>the imprint disorders Prader-Willi syndrome and Angelman syndrome, display an abnormal phenotype as a result of the absence of the paternal or maternal copy of a gene, respectively. In these imprint disorders, there is a genetic deletion in chromosome 15 in a majority of patients. The same gene on the corresponding chromosome cannot compensate for the deletion because it has been turned off by methylation, an epigenetic modification. Genetic deletions inherited from the father result in Prader-Willi syndrome, and those inherited from the mother, Angelman syndrome.</p>
</blockquote>
<p>To me it seems like this is suggesting the same problem in both Prader-Willi and Angelman sydrome- lack of expression of a particular gene. However in Prader-Willi syndrome it is the paternal chromosome that is missing and the maternal copy of this gene is silenced by methylation and the reverse applies for Angelman syndrome. Therefore it seems that in boh cases the problem is the lack of expression of this gene. Why, then, if both are caused by lack of expression of this gene, do these two illnesses have such different symptoms (constant hunger in Prader-Willi syndrome and mental disability and jerky movements in Angelman syndrome)? </p>
Answer: <p>In a wild-type human, you will inherit one paternal chromosome and one maternal chromosome, in this case, chromosome 15.</p>
<p>The paternal chromosome which is packaged into the sperm will be methylated in such a way that the <a href="http://omim.org/entry/601623" rel="nofollow">Ubiqitin-Protein Ligase E3A</a> (<em>UBE3A</em>) gene is silenced.</p>
<p>The maternal chromosome which is packaged into the oocyte will be methylated in such a way that the <a href="http://omim.org/entry/182279" rel="nofollow">Small Nuclear Ribonucleoprotein Polypeptide N</a> (<em>SNRPN</em>) and <a href="http://omim.org/entry/602117" rel="nofollow">NECDIN</a> (<em>NDN</em>) genes are silenced.</p>
<p>When the egg is fertilized, it has the paternal chromosome and the maternal chromosome, which <strong>complement</strong> each other (The same as a genetic complementation test would). </p>
<p>In a wild-time embryo, <em>UBE3A</em> is expressed off of the maternal chromosome, and <em>SNRPN</em> and <em>NDN</em> will be expressed from the paternal chromosome, and the wild-type phenotype will be rescued.</p>
<p>So in <a href="http://omim.org/entry/176270" rel="nofollow"><strong>Prader-Willi Syndrome</strong></a>, at some point in time, the DNA that went into the male gamete sustained a deletion at 15q11, so the entire locus, with those three genes was lost. If that sperm then fertilizes an egg, the paternal chromosome no longer has <em>SNRPN</em> and <em>NDN</em> to rescue the wild-type phenotype. Because those genes are silenced on the maternal chromosome and deleted on the paternal chromosome, there is no allele available to express the relevant gene product. In effect, this embryo will be the equivalent of <em>null/null</em> for <em>SNRPN</em> and <em>NDN</em>.</p>
<p>Then in <a href="http://omim.org/entry/105830" rel="nofollow"><strong>Angelman Syndrome</strong></a>, the opposite situation is in effect. The DNA that went into the female gamete sustained a deletion at 15q11, so the entire locus, with those three genes was lost. If that egg is fertilized, then the maternal chromosome will not be available to rescue the wild-type phenotype because the <em>UBE3A</em> is silenced on the paternal chromosome. In effect, this embryo will be the equivalent of <em>null/null</em> for <em>UBE3A</em></p>
<p>So in effect Prader-Willi Syndrome is the phenotype for the <em>SNRPN</em> and <em>NDN</em> <em>null/null</em> mutant and Angelman Syndrome is the phenotype for the <em>UBE3A</em> <em>null/null</em> mutant.</p>
<p>Even though the genes are present on one of the alleles, the sex determined imprinting causes different genes to be silence, so that is why the same deletion is able to produce two different phenotypes, depending on which gamete that forms the embryo sustains the deletion.</p>
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https://biology.stackexchange.com/questions/40963/prader-willi-syndrome-and-angelman-syndrome
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Question: <p>I know that when RNA is transcribed from the original strand of DNA it contains introns and exons, and that the introns are spliced out of the strand to provide genetic diversity. However, what I don't understand is, how does whatever is doing this splicing know whether the section it is reading is an intron or an exon? Are there start and stop codes like there are for polypeptides, or is it determined by epigenetic factors like methyl markers? Or is it neither?</p>
Answer: <p>Quick answer: we don't really know.</p>
<p>As WYSIWYG said, splice sites <em>do</em> have a sequence signature. The image below (taken from <a href="http://dx.doi.org/10.1016/j.sbi.2004.05.007" rel="nofollow noreferrer">[1]</a>) shows the consensus for human acceptor and donor sites:</p>
<p><img src="https://i.sstatic.net/mIy84.jpg" alt="enter image description here" /></p>
<p>In the images above, the size of a nucleotide represents its frequency at that location. As you can see, there is a clear signal around the splice sites and this signal is used by various programs that do splice site prediction. What is not quite clear yet is how the cell recognizes these signals. Sometimes a "perfect" (identical to the consensus) splice site is ignored by the cell in preference to one that we would consider "worse". This is further complicated by the presence of various downstream and upstream signals such as splicing <a href="http://en.wikipedia.org/wiki/Exonic_splicing_enhancer" rel="nofollow noreferrer">enhancers</a>, <a href="http://en.wikipedia.org/wiki/Exonic_splicing_silencer" rel="nofollow noreferrer">silencers</a> and structural elements (loops, hairpins etc) in the mRNA molecule.</p>
<p>So, to answer your question yes there are start/end markers for introns/exons but they are far more complex than the simple START and STOP codons of transcription. We know know a lot about it but we still don't fully understand the details of splicing.</p>
<hr />
<p>References</p>
<p><a href="http://dx.doi.org/10.1016/j.sbi.2004.05.007" rel="nofollow noreferrer">Brent MR, Guigó R., Recent advances in gene structure prediction, Curr Opin Struct Biol. 2004 Jun;14(3):264-72.</a></p>
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https://biology.stackexchange.com/questions/8204/detecting-introns-and-exons
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Question: <p>Is it possible to do Chip-Seq on specific region of the genome. The idea is to enrich before the sequencing step to have more sensitivity.</p>
Answer: <p>If the question here is to perform an assay that only sequences from a specific set of segments of the genome, you probably could, but it would be a lot of work and you'd need a good reason to want to go through that trouble.</p>
<p>Not sure how you would limit the nucleotides you get back to a specific region of the genome say. The entire point of a CHP-Seq experiment is to get as unbiased a set of nucleotides read and so using specific primers designed against only a specific set of the genome would be hard. </p>
<p>Usually CHP experiments focus the readout they are getting by only focusing on a specific transcription factor for instance. The number of variants of short binding sequences that usually come out will easily be read by a sequencing lane. You'd have to have a strong reason not to take all the data genome wide. Generally the results for many such pulldown sequences are pretty short and frequently can't be found uniquely on the genome, esp if there are lots of binding sites for the protein to be found. </p>
<p>I could speculate that you might synthesize labelled primers from random segments of a cut up library coming from a chromosomal segment you cloned somehow. That again that seems like a lot of work to cut back on the data you get from the experiment without a big reason for doing this. </p>
<p>Using a CHP-CHP experiment that only has specific regions tiled can make do something like this - this makes the chip itself more economical, making the experiment more accessible. </p>
<p>Hope this helps...</p>
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https://biology.stackexchange.com/questions/7424/is-it-possible-to-do-chip-seq-on-a-specfic-region
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Question: <p>I have not spoken to my mother in 15 years but recently connected with her and her side of the family. I was primarily raised in a different sub-culture after the age of 4. As it turns out I "accidentally" have a lot in common with my maternal relatives. We like and dislike many of the same things. Is there some dominate trait in our nature which affects our psychology to cause us to agree on everything from TV, food and lifestyle?</p>
Answer: <p>In this answer I mainly repeat the comments!</p>
<p>There are several reasons why you might share some traits with your mother.</p>
<ul>
<li>genetic (see below)</li>
<li>epigenetic</li>
<li>environmental influence while being in the womb</li>
<li>environmental influence up to the time you were 4 years old</li>
<li>the two environment were not so different (maybe because your adoptive parents wanted to follow the will of your mother or just because by chance your adoptive parents have similar behaviour that your mother)</li>
<li>multiple testing issue (see below)</li>
</ul>
<p>These reasons can be classified into three categories:</p>
<ul>
<li>environmental variance</li>
<li>genetic variance</li>
<li>poor observation (statistic mistake)</li>
</ul>
<p>The phenotypic variance in a population is influenced by the environmental variance + the genetic variance + the variance due to the interactions between the environmental and genetic variances. The heritability can be calculated as the part of the phenotypic variance which are genetically determined. Such calculations make sense only for populations not for a given parent-offpsring pair.</p>
<p><strong>genetic</strong>: It does not make sense to ask whether the variance of a trait is dominant or recessive. It makes sense to say that "liking pink" is dominant over "liking blue". Therefore, you should tell us what is the variant of a given trait that you share with your mother. In such case we might tell you if this variant is dominant or not over the other variants. But of course, this works only for traits that are at least slightly genetically determined. liking a color will certainly not have a strong genetic variance for example. And even if a trait is 100% genetically determined, complex genetic architecture might make it hard to answer. For example a given variant might be dominant in a given genetic background but recessive in another. Finally, I should say that it costs to perform the necessary study (Genome Wide Association Studies) to know exactly the part of the variance of a given trait that is genetically determined. And of course, such studies depend on the population we look at.</p>
<p><strong>Multiple testing issue</strong>: Without realizing, you actually looked at many different traits. You might have looked at your favorite color, your favorite beer, the way you wash your teeth, the sport you practice, the color of room, whether you are calm or impulsive, etc... You might not have paid attention only to things that match but you would have found as many similarities (not the same ones though) with any other human on earth.</p>
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https://biology.stackexchange.com/questions/10880/why-do-i-have-a-lot-in-common-with-my-mother
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Question: <p>What does a genomic code for nucleosome positioning in eukaryotes actually mean? By the code is it right to think that specific DNA sequences favour nucleosomes and others don't? I see that there for and against arguments on this topic. What is the current view on this topic? </p>
Answer: <p>The genome is the complete set of DNA in an organism, including genes and non-gene sequences of base pairs (bp).1 Each codon of three base pairs in a DNA sequence specifies one of twenty different amino acids. There are four available bases in DNA; Adenine (A), Thymine (T), Guanine (G), and Cytosine (C). Four letters taken three at a time (where order matters and repetition of a letter is permitted) gives 64 possible codes. There are only 20 amino acids necessary in most life on earth, so only 20 codes are needed from the 64 possible. One codon is also used as a start codon (start translation) and three codons are used as stop codons (stop translation). So there are 41 extra codons available. As it turns out, for most of the 20 amino acids several different codons can specify the same amino acid, but each codon only specifies a single, unique amino acid, so there is no ambiguity. The code is therefore said to be redundant or degenerate. This degeneracy allows the same protein (composed of amino acids) to be coded with different base pair sequences, which is important if one base pair sequence is better than another in its mechanical properties of bending DNA around a histone octamer to form a nucleosome.</p>
<p>If the DNA molecules in a typical human cell were lined up head to tail, they would form a string about 2 meters long. The diameter of a cell nucleus is only 5 μm (0.000005 meter), so the DNA really must be packaged or organized to fit. The packing solution eukaryotes developed is to coil DNA around histone proteins to form beadlike units called nucleosomes (packing the DNA also has implications for gene expression, but we will ignore that here).</p>
<p>Each nucleosome constains a 147 bp (base pair) stretch of DNA, which is sharply bent and tightly wrapped in a 1 and 3/4 turn (a left-handed superhelical turn to be exact) around the histone protein octamer. There are many of these nucleosome beads on each strand of DNA. Human chromosome 19, for example, has 58.6 million base pairs, so that makes for a lot of 147 base pair beads, even with streches of unwrapped linker DNA between the beads--about 75 – 90% of the base pairs end up wrapped in nucleosomes. </p>
<p>The bending of the DNA around the histone is made easier or more difficult depending on the geometrical and mechanical properties of the specific two base pairs or dinucleotides at the bend. This is not a trivial mechanical property: Some sequences may have a more than 1000 fold capacity to bend around the histone octamer compared with other sequences; we will say these sequences have an affinity for nucleosome positioning since they make it easy for the DNA to wrap. Conversely, some sequences are very "stiff" and are much more difficult to bend, e.g. poly dA:dT sequences. On average, high affinity sequences have more AA, TT and TA steps at positions where the minor groove faces inward towards the histone octamer, i.e., when more bendable di-nucleotides like AT and TA occur on the face of the helical repeat where it can directly interact with the histones (the helical repeat is about every 10 bp; see below). </p>
<p>What do we mean by "grooves?" Remember that DNA is a double stranded helix (as if you were twisting a flexible ladder) coiling two chains of sugar-phosphate "backbones" around the outside of the helix with the nitrogenous base pairs that connect the strands (with hydrogen bonds between base pairs) pointing toward the center of the helix (if you were twisting a flexible ladder into a helix the rungs would be the connected base pairs beween the two backbones). If you held up a screw you would see the threads as "grooves" in this similar helical structure. The backbones of the two strands are closer together on one side ("minor groove") of the double helix than the other ("major groove"). In undeformed β-DNA, the complementary base pairs of the "rungs" rise about 0.34 nm and twist ~36 degrees around the center axis of the "ladder" from each base pair rung to the next. A "helical repeat" will therefore occur every 10 bp's (10 x 36 = 360 degrees) as the helix completes a full turn around its axis. Don't confuse this helix with the wrapping of the DNA around a histone core; the DNA is a double stranded helix and that is in turn wound around the histone in a nucleosome.</p>
<p>But do nucleosomes in actual living organisms ("in vivo") actually tend to position themselves on sequences of DNA that wrap more easily around the histone core of the nucleosome, i.e., do nucleosomes in vivo actually show an affinity for specific DNA sequences? If they do, then that could be considered to be a "genomic code for nucleosome positioning." There are other factors (e.g., remodelling complexes which can move nucleosome positions) and related questions, e.g., do stiff sequences like poly dA:dT inhibit the formation of nucleosomes (and are nucleosome inhibitory sequences more common in DNA sequences like transcription start sites that should be exposed to facilitate interaction with trans proteins), but we will just consider simply the basic question.</p>
<p>By analogy, suppose I had a printer that could only print strips of paper a sentence high (vertical height of the strip sufficient to contain a 10 pitch character, say 0.1 inch high) but of arbitrary length. Imagine the printer is fed with a spool of this strip paper, like an old time printing calculator (or ATM receipt printer). If I printed this answer text page, out would come English sentences (at least I intend this to be recognizable English) on a long, thin strip. This sounds rather like a phylactery (tefillin) printer, now that I think of it, but that is a topic for comparative religion. If there are 66 lines of 7 inch long sentences on my page, then that is 38 feet of 0.1 inch paper strip to carry around for every page of text. I might find it more convenient to wind up portions of that long strip on little wooden dowels (like empty sewing thread spools for example) and then unwind them only when I wanted to read my article again (which I can never do enough). If DNA is kind of like this analogy (it is far more complex actually), then the spools are "histones" and when wrapped with paper strip become "nucleosomes." Does it makes sense that the letters I chose to construct the words in the sentences of my article were chosen to some extent based on some hypothetical capacity for some sequences of alphabetic characters to bend and coil around a spool (say some sequences had less cumulative stiff ink drying on the paper strip)? That gives you one angle on the controversy involving the idea of nucleosome positioning by genomic code. However, consider that, as in the case with degenerate DNA codons, I can choose different sequences of characters, i.e., words, to mean the same thing, so possibly I could still choose my words for meaning, but select synonyms that hypothetically bend easier, making it easier on average to coil my sentence strip up on spools.</p>
<p>A recent study, <a href="http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0156905" rel="nofollow">Multiplexing Genetic and Nucleosome Positioning Codes: A Computational Approach</a>, demonstrated that the local minima (the easy bending sequences) of a real gene could be repositioned (in computer simulation), that is, the nucleosome moved to another place in a real DNA gene sequence, by substituting equivalent base pairs (remember that a single amino acid can typically be defined by several different codons) to preserve the same protein encoding (a protein being a specific sequence of amino acids). This suggests that nucleosomes can at least theoretically be positioned anywhere on top of a gene, multiplexing the genetic information with the mechanical information as it were.</p>
<p>But do real genomes show any evidence of multiplexing genetic and mechanical information as described above? Experimentally mapped nucleosomes on top of genes do show strong signals in the probability for occurrence of mechanically favorable dinucleotides, but that does not prove the case (since shifting nucleosomes on random sequences may also demonstrate similar signals). The researchers in the study just cited then reasoned that if multiplexing is actually occuring, that is, if actual genomes have to balance the energy benefit of placing nucleosomes on DNA sequences where it is easier to bend the DNA into a coil around the histone, then it must be easier (and a more frequent occurrence therefore) to do that in non-coding sequences of DNA where only the "mechanical preference of the amino acids" need be considered (and not the necessity to maintain a specific sequence of amino acids to encode a particular protein).</p>
<p>Accordingly, they looked at the probability distribution for the amino acid threonine codons along nucleosomes on top of coding and non-coding regions of the S. cerevisiae and S. pombe genomes (high resolution nucleosome maps exist for both organisms). Both spectra showed a peak at the 10 bp (remember our earlier discussion of helical repeat), indicating that the codons for threonine display an overall rotational preference with respect to DNA bending within nucleosomes, but the non-coding peak was significantly higher for both organisms. When the 10 bp periodicity was plotted for all 20 amino acids for coding vs non-coding regions in both organisms the majority of points exhibited higher amplitude outside of genes, i.e., in non-coding regions where only the position preferences were a factor. </p>
<p>These findings (that the local minima, the easy bending sequences, of a real gene could be repositioned using degeneracy; that strong signals in the probability for occurrence of mechanically favorable dinucleotides are found in real genomes; and that the amplitude of 10 bp periodicity is higher in non-coding regions of actual genomes) at least suggest the possibility that nucleosome positions are the product of a mechanical evolution of DNA molecules, i.e., that there is a genomic code for nucleosome positioning in eukaryotes.</p>
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https://biology.stackexchange.com/questions/30652/is-there-a-genomic-code-for-nucleosome-positioning
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Question: <p>When evaluating methylation status at various CpG sites after sequencing, how much consideration should one give to random single base pair insertions and deletions. Suppose there is a CA dinucleotide; can we assume that the CA is native to the sequence or results from a G deletion especially when the latter is suspect once comparing to other sequences. Is there really a set standard sequence to compare it? </p>
Answer: <p>I agree with Vance, we need a little more detail to better answer your question. From what I can tell, you are asking whether a single nucleotide polymorphism (SNP) that results in the addition of a cytosine base to your sequence is of concern when examining the methylation signature of that sequence. </p>
<p>I would first determine whether the polymorphism is common in the population using NCBI. The more common the polymorphism, the less likely it is to have a serious effect. However, that is not to say that it doesn't have any effect.</p>
<p>I would then examine how much the methylation of that one site varies compared to samples without the additional cytosine base.</p>
<p>Finally I would determine the importance of the location of the SNP. Is it located in a CpG island? Or is it located on the shores, shelves or 'open sea'? (see work by <a href="http://www.ncbi.nlm.nih.gov/pubmed/21593595" rel="nofollow">Sandoval et al.</a>)</p>
<p>Without knowing all the above it is hard to make a call on how important/unimportant the SNP is in your methylation analysis. </p>
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https://biology.stackexchange.com/questions/48641/allele-specific-bisulfite-sequencing
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