library(tidyverse)
library(BSgenome.Scerevisiae.UCSC.sacCer3)
library(rtracklayer)

gff = rtracklayer::import("~/ref/sacCer3/S288C_reference_genome_R64-5-1_20240529/saccharomyces_cerevisiae_R64-5-1_20240529_chr_normalized.gtf")
 
gff_with_conditions = gff %>% 
  as_tibble() %>% 
  select(seqnames, start, end, strand, type, Name, conditions) %>% 
  filter(type %in% c("gene", "mRNA", "CDS")) %>% 
  mutate(locus_tag = str_remove(Name, "_.*")) %>% 
  replace_na(list(conditions = "none"))

gff_with_conditions_tss <- gff_with_conditions %>%
  filter(seqnames != "chrM") %>%
  mutate(fiveprime_loc = ifelse(strand == "+", start, end)) %>%
  group_by(locus_tag) %>%
  reframe(
    seqnames = unique(seqnames),
    strand = unique(strand),
    cds_start = ifelse(
      any(type == "CDS"),
      ifelse(
        unique(strand) == "+",
        min(start[type == "CDS"], na.rm = TRUE),
        max(end[type == "CDS"], na.rm = TRUE)
      ),
      NA_integer_
    ),
    tss_ypd = ifelse(
      any(type == "mRNA" & conditions == "YPD"),
      fiveprime_loc[type == "mRNA" & conditions == "YPD"][1],
      NA_integer_
    ),
    tss_gal = ifelse(
      any(type == "mRNA" & conditions == "GAL"),
      fiveprime_loc[type == "mRNA" & conditions == "GAL"][1],
      NA_integer_
    )
  ) %>%
  pivot_longer(-c(locus_tag, seqnames, strand, cds_start), names_to = "conditions", values_to = "tss") %>%
  mutate(inferred = is.na(tss),
         five_utr_width = abs(cds_start-tss)) %>%
  mutate(avg_5utr_width_across_conds = median(five_utr_width, na.rm=TRUE)) %>%
  group_by(conditions) %>%
  mutate(avg_5utr_width_in_conds = median(five_utr_width, na.rm=TRUE)) %>%
  mutate(tss = case_when(
    is.na(tss) & strand == "+" ~ cds_start - avg_5utr_width_in_conds,
    is.na(tss) & strand == "-" ~ cds_start + avg_5utr_width_in_conds,
    .default = tss
  )) %>%
  ungroup() %>%
  mutate(five_utr_width = abs(cds_start-tss)) %>%
  mutate(source = "sgd-5-1")

orf_classifications_tmp = gff %>% 
  as_tibble() %>% 
  filter(type == "gene", !is.na(orf_classification)) %>%
  select(Name, orf_classification) %>%
  dplyr::rename(locus_tag = Name)
  
orf_classifications_complete = orf_classifications_tmp %>%
  bind_rows(
    # the na orf_classifications
    gff_with_conditions_tss %>%
    select(locus_tag) %>%
    distinct() %>%
    filter(!locus_tag %in% orf_classifications_tmp$locus_tag) %>%
    select(locus_tag) %>%
    left_join(
        gff %>%
            as_tibble() %>%
            filter(type %in% c("transposable_element_gene", "blocked_reading_frame")) %>%
            select(ID, type, display), by = c("locus_tag" = "ID")) %>%
      select(locus_tag, type) %>% dplyr::rename(orf_classification = type)
  )

gff_with_conditions_tss_complete_orf_classification = gff_with_conditions_tss %>%
  left_join(orf_classifications_complete)
  

create_condition_specific_tss = function(df, sel_cond){
  gr = makeGRangesFromDataFrame(
    df %>%
      filter(conditions == sel_cond) %>%
      dplyr::rename(name = locus_tag),
      keep.extra.columns = TRUE,
      seqnames.field = "seqnames",
      start.field = "tss",
      end.field = "tss",
      strand.field = "strand")
  
  suppressWarnings(seqinfo(gr) <- seqinfo(BSgenome.Scerevisiae.UCSC.sacCer3))
  message("trimming in order to avoid out of bounds locations on inferred TSS")
  trim(gr)
}

median_across_conds_tss = gff_with_conditions_tss_complete_orf_classification %>%
  select(locus_tag, seqnames, orf_classification,
         strand, cds_start, avg_5utr_width_across_conds) %>%
  distinct() %>%
  mutate(tss = ifelse(strand == "+",
                      cds_start - avg_5utr_width_across_conds,
                      cds_start + avg_5utr_width_across_conds)) %>%
  mutate(conditions = "median_utr_across_conds")

tss_gr_list = list(
  ypd = create_condition_specific_tss(gff_with_conditions_tss_complete_orf_classification, "tss_ypd"),
  gal = create_condition_specific_tss(gff_with_conditions_tss_complete_orf_classification, "tss_gal"),
  median_across_conds_tss_gr = create_condition_specific_tss(median_across_conds_tss,
                                                           "median_utr_across_conds")
)

rtracklayer::export(tss_gr_list$ypd, "~/code/hf/yeast_genome_resources/ypd_tss_sgd-5-1.bed")
rtracklayer::export(tss_gr_list$gal, "~/code/hf/yeast_genome_resources/gal_tss_sgd-5-1.bed")
rtracklayer::export(tss_gr_list$median_across_conds_tss_gr, "~/code/hf/yeast_genome_resources/median_across_conds_tss_sgd-5-1.bed")

rtracklayer::export(tss_gr_list$ypd[tss_gr_list$ypd$orf_classification=="Verified"], "~/code/hf/yeast_genome_resources/ypd_tss_sgd-5-1_verified_orf.bed")

rtracklayer::export(tss_gr_list$gal[tss_gr_list$gal$orf_classification=="Verified"], "~/code/hf/yeast_genome_resources/gal_tss_sgd-5-1_verified_orf.bed")

rtracklayer::export(tss_gr_list$median_across_conds_tss_gr[tss_gr_list$median_across_conds_tss_gr$orf_classification=="Verified"], "~/code/hf/yeast_genome_resources/median_across_conds_tss_sgd-5-1_verified_orf.bed")