2b1f91e141939f73201a8acd041de4c572baef99 lrnassar Wed May 25 18:01:30 2022 -0700 Expanding MTR scores description, and touching up HMC and JARVIS. Refs #29152 diff --git src/hg/makeDb/trackDb/human/constraintSuper.html src/hg/makeDb/trackDb/human/constraintSuper.html index 26ce924..7c40d0a 100644 --- src/hg/makeDb/trackDb/human/constraintSuper.html +++ src/hg/makeDb/trackDb/human/constraintSuper.html @@ -38,79 +38,83 @@ disrupting the amino-acid positions with HMC<0.8 are predicted to be likely deleterious <li><b><a href="http://biosig.unimelb.edu.au/mtr-viewer/" target="_blank"> MTR - Missense Tolerance Ratio</a> (hg19 only)</b>: Missense Tolerance Ratio (MTR) scores aim to quantify the amount of purifying selection acting specifically on missense variants in a given window of protein-coding sequence. It is estimated across sliding windows of 31 codons (default) and uses observed standing variation data from the WES component of gnomAD / the Exome Aggregation Consortium Database (ExAC), version 2.0. Scores were computed using Ensembl v95 release </ol> <h2>Display Conventions and Configuration</h2> +<h3>JARVIS</h3> <p> -Shown are the scores as a signal ("wiggle") track, with one score per genome position. -Mouse over the bars to see the exact values. -</p> +JARVIS scores are the scores as a signal ("wiggle") track, with one score per genome position. +Mousing over the bars displays the exact values. The scores were downloaded and converted to a single bigWig file. +See <a href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg19.txt" target=_blank>hg19 makeDoc</a> and +<a href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg38/jarvis.txt" target=_blank>hg38 makeDoc</a>.</p> +<h3>HMC</h3> <p> -For HMC, the highly-constrained cutoff 0.8 is indicated with a line. -</p> +HMC scores are displayed as a signal ("wiggle") track, with one score per genome position. +Mousing over the bars displays the exact values. The highly-constrained cutoff +of 0.8 is indicated with a line.</p> +<p> +The HMC scores were downloaded and converted to .bedGraph files with a +custom Python script. The bedGraph files were then converted to bigWig files, +as documented in our <a +href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg19.txt" +target=_blank>makeDoc</a> hg19 build log.</p> <h3>MTR</h3> <p> MTR data can be found on two tracks, <b>MTR All data</b> and <b>MTR Scores</b>. In the <b>MTR Scores</b> track the data has been converted into 4 separate signal tracks -representing each base pair mutation, with the highest possible score represented when +representing each base pair mutation, with the lowest possible score represented when multiple transcripts overlap. It is recommended that the data be explored using this version of the track, as it condenses the information substatially while retaining the magnitude of the data.</p> <p>Any specific point mutations of interest can then be researched in the <b> MTR All data</b> track. This track contains all of the information from <a href="http://biosig.unimelb.edu.au/mtr-viewer/downloads" target="_blank"> MTRV2</a> including more than 3 possible scores per base when transcripts overlap. A mouse-over on this track shows the ref and alt allele, as well as the MTR score and the MTR score percentile. Filters are available for MTR score, False Discovery Rate -(FDR), MTR percentile, and variant consequence. Items in the track are colored according +(FDR), MTR percentile, and variant consequence. By default, only items in the bottom +25 percentile are shown. Items in the track are colored according to their MTR percentile:</p> <ul> -<li><b><font color=red>Red items</font></b> MTR percentiles over 75 -<li><b><font color=black>Black items</font></b> MTR percentiles between 50 and 75 -<li><b><font color=green>Green items</font></b> MTR percentiles below 25 +<li><b><font color=green>Green items</font></b> MTR percentiles over 75 +<li><b><font color=black>Black items</font></b> MTR percentiles between 25 and 75 +<li><b><font color=red>Red items</font></b> MTR percentiles below 25 <li><b><font color=blue>Blue items</font></b> No MTR score </ul> - - -<p> -<b>Jarvis:</b> Scores were downloaded and converted to a single bigWig file. -See <a href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg19.txt" target=_blank>hg19 makeDoc</a> and -<a href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg38/jarvis.txt" target=_blank>hg38 makeDoc</a>. -<br> - -<b>HMC:</b> Scores were downloaded and converted to .bedGraph files with a -custom Python script. The bedGraph files were then converted to bigWig files, -as documented in our <a -href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg19.txt" -target=_blank>makeDoc</a> hg19 build log. </p> -By default, only scores with an MTR percentile over 75 are shown.</p> - <p> -By default, only scores with an MTR percentile over 75 are shown.</p> +<b>Interpretation:</b> Regions with low MTR scores were seen to be enriched with +pathogenic variants. For example, ClinVar pathogenic variants were seen to +have an average score of 0.77 whereas ClinVar benign variants had an average score +of 0.92. Further validation using the FATHMM cancer-associated training dataset saw +that scores less than 0.5 contained 8.6% of the pathogenic variants while only containing +0.9% of neutral variants. In summary, lower scores are more likely to represent +pathogenic variants whereas higher scores could be pathogenic, but have a higher chance +to be a false positive. For more information see the <a target="_blank" +href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602522/">MTR-Viewer publication</a>.</p> <h2>Methods</h2> <h3>HMC</h3> <p> Scores were downloaded and converted to .bedGraph files with a custom Python script. The bedGraph files were then converted to bigWig files, as documented in our <a href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg19.txt" target=_blank>makeDoc</a> hg19 build log.</p> <h3>Jarvis</h3> <p> Scores were downloaded and converted to a single bigWig file. See <a href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg19.txt" target=_blank>hg19 makeDoc</a> and <a href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg38/jarvis.txt"