Figure 3: Missense regional constraint captured by MTR.

A. Odds ratios of ClinVar pathogenic versus benign variants in MTR ranking regions across the whole exome. The pink points represent MTR calculated with a 31 amino-acid sliding window using 824K unrelated samples from RGC-ME and the yellow points represent a random subset of 225K samples.

B. MTR ranking distribution of different protein functional regions. From left, each category’s distribution of MTR exome-wide ranks was centered at a significantly different location compared to the next category to its right with Wilcoxon rank-sum test (largest p-value =5×10–10).

C. MTR scores of 6.5 million amino acid sites containing missense variants observed from 824K samples against their GERP++ score average on the amino acid site. Cyan dots are overlaid to show sites that are predicted to be deleterious by five missense effect prediction tools. The dotted box highlights sites that are human missense constrained but not cross-species conserved and includes missense variants that have MTR<=0.52 (MTR 1% exome-wide rank) and GERP++ score < 2.

D. Distribution of the gene proportion located in exome-wide top 1% MTR regions against the heterozygous selection coefficient, shet. Genes with significant proportion in most constrained 1% MTR region are colored in orange and red (FDR < 0.1, binomial tests), stratified by LOF constraint (shet=0.075). Red dots label genes with missense-specific constrained regions that are LOF-tolerant

E. MTR track of a cancer oncogene, KRAS, a missense-specific constrained gene, along with the domain structure of the protein. Blue MTR constraint region is defined by top 1% exome-wide MTR rank.