MTR-Viewer: identifying regions within genes under purifying selection

Abstract

Advances in genomic sequencing have enormous potential to revolutionize personalized medicine, however distinguishing disease-causing from benign variants remains a challenge. The increasing number of human genome and exome sequences available has revealed areas where unfavourable variation is removed through purifying selection. Here, we present the MTR-Viewer, a web-server enabling easy visualization at the gene or variant level of the Missense Tolerance Ratio (MTR), a measure of regional intolerance to missense variation calculated using variation from 240 000 exome and genome sequences. The MTR-Viewer enables exploration of MTR calculations, using different sliding windows, for over 18 000 human protein-coding genes and 85 000 alternative transcripts. Users can also view MTR scores calculated for specific ethnicities, to enable easy exploration of regions that may be under different selective pressure. The spatial distribution of population and known disease variants is also displayed on the protein's domain structure. Intolerant regions were found to be highly enriched for ClinVar pathogenic and COSMIC somatic missense variants (Mann-Whitney U test P < 2.2 × 10-16). As the MTR is not biased by known domains and protein features, it can highlight functionally important regions within genes overlooked or inaccessible by traditional methods. MTR-Viewer is freely available via a user friendly web-server at http://biosig.unimelb.edu.au/mtr-viewer/.

Figure 1.

MTR-Viewer gene query results page. (A) A line graph displays the MTR distribution for example gene BRAF with regions in red indicating observed variation differs significantly from neutrality. (B) Lollipop plots show the underlying gnomAD missense and synonymous variation and (C) ClinVar known pathogenic and known benign variants for the gene. (D) Alternate transcripts are displayed below with matching RefSeq transcript ID’s.

Figure 2.

Distribution of MTR scores for known disease variants compared to background. (A) Cumulative distribution of MTR scores for ClinVar pathogenic variants (red), ClinVar benign variants (blue) and DiscovEHR novel missense control variants (black). (B) Cumulative distribution of MTR scores for COSMIC somatic missense variants (red) compared with DiscovEHR novel missense control variants (black).