Analysis of protein-coding genetic variation in 60,706 humans¶
Why this mattered¶
TBD
Abstract¶
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
Related¶
- cite → The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans — ExAC uses GTEx expression data to help interpret the functional impact of protein-coding variants across human tissues.
- cite → Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology — ExAC applies ACMG/AMP variant-interpretation principles when assessing which rare protein-coding variants are likely pathogenic.
- cite → A global reference for human genetic variation — ExAC complements the 1000 Genomes global variation map by providing deeper exome-scale catalogs of rare protein-coding variants.
- cite → A framework for variation discovery and genotyping using next-generation DNA sequencing data — ExAC variant calls rely on GATK-style next-generation sequencing discovery and genotyping methods.
- cite ← The UK Biobank resource with deep phenotyping and genomic data — UK Biobank cites ExAC as a large-scale catalog of protein-coding human genetic variation for comparison with its genotyping data.
- cite ← The mutational constraint spectrum quantified from variation in 141,456 humans — The 141,456-human constraint spectrum extends ExAC's protein-coding variation analysis to a larger gnomAD-scale dataset.
- enables ← A framework for variation discovery and genotyping using next-generation DNA sequencing data — GATK's variant discovery and genotyping framework enabled ExAC to call and aggregate protein-coding variants across tens of thousands of exomes.