e9a2b5a28cb4e3970977c76d84649bdd339a8423
lrnassar
  Thu Jul 30 17:00:51 2026 -0700
Address popEVE code-review feedback (v502). refs #37950 refs #37791

- popEve.ra dataVersion now names the score source (March per-transcript release) and the
July VCF as the coordinate/strand source, rather than only the VCF date.
- vcfToPopEveHeatmap.py: when the CSV wildtype disagrees with the genomic wildtype, skip the
position and keep the correct sparse data instead of attaching CSV scores computed for a
different residue; skip CSV rows with a nan/empty popEVE; add a posSparse counter for
positions with genomic coordinates but no CSV row. All three are 0 on the current data, so
the bigBed output is unchanged (verified byte-identical), but they make the converter fail
safe for future per-transcript releases.
- Add the build drivers runBuild.sh and runBuildDense.sh to the tree (the anchor computation
previously lived only in the hive build directory), and add a makedoc forward-pointer so
the intermediate sparse section is not mistaken for the final dense build.

diff --git src/hg/makeDb/doc/hg38/popEve.txt src/hg/makeDb/doc/hg38/popEve.txt
index 94c34e3c581..8fdcd8b45aa 100644
--- src/hg/makeDb/doc/hg38/popEve.txt
+++ src/hg/makeDb/doc/hg38/popEve.txt
@@ -1,118 +1,128 @@
 # [Claude/lrnassar] popEVE - proteome-wide missense deleteriousness scores (2026-06-30)
 
 # popEVE places missense variants on a single proteome-wide, human-specific spectrum of
 # deleteriousness by calibrating EVE + ESM-1v evolutionary scores against UK Biobank
 # population variation with a Gaussian process.
 # Reference: Orenbuch et al. (2025) Nat Genet 57:3165-3174, PMID 41286104.
 # https://doi.org/10.1038/s41588-025-02400-1
 
 # Data: the complete UKBB-trained GRCh38 VCF (popEVE v1.1, dated 2025-07-15) from the
 # pop.evemodel.org bulk downloads. The VCF carries, per missense substitution, genomic
 # coordinates plus INFO fields protein (RefSeq NP_), gene, mutant (e.g. E773D),
 # gap_frequency, popEVE, pop-adjusted_EVE, pop-adjusted_ESM1v, EVE, ESM1v.
 # Source size 1476124568 bytes, Last-Modified 2025-10-29.
 
 mkdir -p /hive/data/outside/popEve
 mkdir -p /hive/data/genomes/hg38/bed/popEve/sorttmp
 cd /hive/data/genomes/hg38/bed/popEve
 ln -s /hive/data/outside/popEve input
 
 cd /hive/data/outside/popEve
 wget -nv https://data.evemodel.org/popeve/v1.1/downloads/grch38_popEVE_ukbb_20250715.vcf.gz
 
+# NOTE: the steps in this section produce the intermediate SPARSE heatmap. The final track is
+# DENSE (all 19 substitutions per position); see the DENSE REBUILD section below. These steps
+# still run because they produce popEve_sorted.tsv, the codon-coordinate and strand source
+# reused by the dense build.
+#
 # The combined VCF is one position-sorted file with all proteins interleaved (overlapping
 # genes share positions), so records are grouped by protein on disk before conversion.
 # Each protein becomes one heatmap BED12+ entry: columns = amino acid positions at codon
 # genomic coordinates, rows = 20 standard amino acids ordered by class (A V L I M F Y W R H
 # K D E S T N Q G C P), matching the MaveDB heatmap track. Multiple codon changes encoding
 # the same amino acid substitution carry identical popEVE scores and are deduplicated.
 # Wildtype cells are empty. popEVE lists only positions carrying a missense alt, so a codon
 # may have only 2 of its 3 genomic positions; block sizes are clamped (min(3, gap-to-next))
 # so adjacent codon blocks cannot overlap, which keeps the file valid for bedToBigBed.
 # Strand is taken from NCBI RefSeq (the VCF has no strand field), cross-checked against the
 # strand inferred from genomic-vs-protein-position direction.
 # Color: global cross-gene gradient keyed to raw popEVE; interior anchors at the published
 # severe (-5.056) and moderate (-4.617) cutoffs and the proteome median (~-3.5); outer
 # saturation anchors at the 0.5th / 99.5th percentiles of the proteome-wide distribution.
 # Records with popEVE=nan (e.g. start-codon M1 variants) are skipped.
 
 cd /hive/data/genomes/hg38/bed/popEve
 # Full build (download already done): strand map, extract, color anchors, sort, convert,
 # filter to chrom.sizes, bigBed. See runBuild.sh in this directory.
 bash runBuild.sh
 
 # runBuild.sh steps, in order:
 #   1. NP_->strand map:
 #        hgsql hg38 -N -e "select distinct l.protAcc, g.chrom, g.strand from ncbiRefSeqLink l
 #          join ncbiRefSeq g on g.name=l.mrnaAcc where l.protAcc like 'NP\_%'"
 #        -> np_strand.tsv (prefer the strand on a primary chromosome)
 #   2. extract: zcat ...vcf.gz | extractPopEve.py > popEve_records.tsv
 #   3. color anchors: p0.5 / p99.5 of popEVE over all records -> anchors.txt
 #   4. sort -t$'\t' -k1,1 -k4,4n -S 4G -T sorttmp popEve_records.tsv > popEve_sorted.tsv
 #   5. vcfToPopEveHeatmap.py popEve_sorted.tsv np_strand.tsv popEve_raw.bed $LO $HI
 #   6. bedSort + awk filter to chrom.sizes -> popEve_filtered.bed
 #   7. bedToBigBed -type=bed12+ -tab -as=popEve_heatmap.as popEve_filtered.bed chrom.sizes popEve.bb
-# Scripts: ~/kent/src/hg/makeDb/scripts/popEve/{extractPopEve.py,vcfToPopEveHeatmap.py,popEve_heatmap.as}
+# Scripts (all in ~/kent/src/hg/makeDb/scripts/popEve/): extractPopEve.py,
+#   vcfToPopEveHeatmap.py, popEve_heatmap.as, and the build drivers runBuild.sh (sparse /
+#   coordinate foundation) and runBuildDense.sh (dense rebuild).
 
 # Notes:
 #  - The genomic VCF contains only single-nucleotide-reachable substitutions (~6-9 of 19 per
 #    codon). The DENSE REBUILD below supersedes this with the full per-amino-acid matrix; the
 #    VCF-derived popEve_sorted.tsv remains the source of genomic codon coordinates and strand.
 #  - The heatmap renderer parses the score array (chopCommas, keeps trailing empty) and the
 #    label array (chopByCharRespectDoubleQuotesKeepEmpty, drops one trailing empty)
 #    differently. When the last cell (last row, last column) is empty the counts disagree and
 #    the track aborts; the converter sets a non-empty placeholder label on that one trailing
 #    cell (its score stays empty so the cell is uncolored). trailingFix count below.
 
 # Build results:
 #   records extracted: 66,400,085 (nan skipped: 15,156)
 #   color anchors: loAnchor=-5.742 hiAnchor=-2.287 (popEVE p0.5 / p99.5; median -3.358)
 #   proteins: 18,968 (18,343 distinct gene symbols; remainder are RefSeq isoforms)
 #   amino-acid positions: 10,114,809;  bases covered: 886,638,890
 #   strand: 0 inferred-vs-RefSeq mismatches; 25 proteins not in the RefSeq map (strand from
 #     coordinate inference); 0 with no strand signal; 0 dropped by chrom.sizes filter
 #   trailingFix (trailing empty cell relabeled): 15,555 proteins
 #   mouseover: HTML multi-line labels (<br>/<b>); component scores rounded to 3 dp;
 #     missing/nan components shown as NA
 #   popEve.bb size: 1,592,586,266 bytes
 
 # ============================================================================
 # DENSE REBUILD (2026-07-23) - full per-amino-acid matrix, per collaborator request
 # ============================================================================
 # The popEVE authors confirmed the per-transcript CSV download carries the COMPLETE
 # per-amino-acid matrix (all 19 substitutions per position), unlike the genomic VCF above
 # (single-nucleotide-reachable only, ~6 of 19 per codon). This rebuild takes the SCORES from
 # the per-transcript CSVs and REUSES the genomic codon coordinates, strand, and blocks
 # already derived from the VCF (popEve_sorted.tsv), producing dense heatmaps. Proteins present
 # in the VCF but absent from the (older, March 2025) CSV release fall back to sparse VCF scores.
 
 cd /hive/data/outside/popEve
 wget -nv https://data.evemodel.org/popeve/v1.1/downloads/popEVE_ukbb_20250312.zip
 #   2915714283 bytes, Last-Modified 2025-10-29
 mkdir -p popeve_csv
 unzip -q popEVE_ukbb_20250312.zip -d popeve_csv/
 #   18,332 per-transcript CSVs at popeve_csv/popEVE_ukbb_20250312/<NP_acc>.csv
 #   columns: mutant,gap frequency,popEVE,popped EVE,popped ESM-1v,EVE,ESM-1v
 
 cd /hive/data/genomes/hg38/bed/popEve
 bash runBuildDense.sh
 # runBuildDense.sh steps:
 #   1. proteins not in the CSV (sparse fallback): 637
 #   2. color anchors: p0.5 / p99.5 of popEVE over the full matrix (all CSV popEVE values plus
 #      VCF popEVE for the 637 non-CSV proteins) -> anchorsDense.txt
 #   3. vcfToPopEveHeatmap.py popEve_sorted.tsv np_strand.tsv popEve_dense_raw.bed $LO $HI <csvDir>
 #        the optional <csvDir> arg enables dense mode; loadCsv() fills all 19 substitutions
 #        per position from the CSV, keeping the VCF codon coordinates and wildtype residue
 #   4. bedSort + filter to chrom.sizes + bedToBigBed -> popEve.bb
 
 # Dense build results:
 #   full-matrix popEVE values: 187,547,662
 #   color anchors: loAnchor=-6.035 hiAnchor=-2.407 (popEVE p0.5 / p99.5; median -3.489)
 #   proteins: 18,968 (dense 18,331 from CSV; sparse 637 VCF fallback)
 #   NP_065910.3 (SHROOM3) is in the CSV but not the VCF coordinate set (all its VCF records
 #     were nan-skipped start codons), so its dense matrix is unused -> 18,331 dense, not 18,332
-#   wtMismatch 0 (CSV and VCF wildtype residues agree); trailingFix 1043
+#   wtMismatch 0 (CSV and VCF wildtype residues agree); posSparse 0 (every dense position
+#     also had CSV coverage); trailingFix 1043. The converter skips CSV rows with a nan/empty
+#     popEVE and skips positions where the CSV wildtype disagrees with the genomic one; both
+#     are 0 in this build (empty-popEVE rows already render as empty cells).
 #   popEve.bb size: 4,726,263,622 bytes
 
 mkdir -p /gbdb/hg38/popEve
 ln -sf /hive/data/genomes/hg38/bed/popEve/popEve.bb /gbdb/hg38/popEve/popEve.bb