Diverse ancestral representation improves genetic intolerance metrics.

ABSTRACT: The unprecedented scale of genomic databases has revolutionized our ability to identify regions in the human genome intolerant to variation-regions often implicated in disease. However, these datasets remain constrained by limited ancestral diversity. Here, we analyze whole-exome sequencing data from 460,551 UK Biobank and 125,748 Genome Aggregation Database (gnomAD) participants across multiple ancestries to test several key intolerance metrics, including the Residual Variance Intolerance Score (RVIS), Missense Tolerance Ratio (MTR), and Loss-of-Function Observed/Expected ratio (LOF O/E). We demonstrate that increasing ancestral representation, rather than sample size alone, critically drives their performance. Scores trained on variation observed in African and Admixed American ancestral

SUBMITTER: Han AL 

PROVIDER: S-EPMC11920395 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature