A deep catalogue of protein-coding variation in 983,578 individuals

Area of Science:

• Genomics
• Human genetics
• Population genetics

Background:

• Rare coding variants offer insights into gene function.
• Identifying these variants requires large-scale sequencing data.
• Previous studies lacked the sample size to comprehensively catalog rare variants.

Purpose of the Study:

• To create a comprehensive catalog of human protein-coding variation.
• To identify genes with loss-of-function (LOF) variants and assess gene intolerance to LOF.
• To define regions of missense variant depletion and identify potentially deleterious variants.

Main Methods:

• Exome sequencing of 983,578 individuals from diverse populations.
• Analysis of over 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants.
• Quantitative estimation of selection against heterozygous LOF and missense variant depletion.

Main Results:

• A catalog of human protein-coding variation including over 11.5 million variants.
• Identification of 4,848 genes with rare biallelic pLOF variants, 1,751 previously unreported.
• Discovery of 3,988 LOF-intolerant genes and 1,482 genes with missense-depleted regions.
• Estimation that 3% of individuals harbor clinically actionable variants and identification of 11,773 likely deleterious variants in ClinVar.

Conclusions:

• The generated catalog provides a valuable resource for variant interpretation and precision medicine.
• The study refines our understanding of gene function, LOF intolerance, and missense variant constraints.
• Public accessibility of this data will accelerate genetic research and clinical applications.