Oct 30, 2015

Analysis of protein-coding genetic variation in 60,706 humans

BioRxiv : the Preprint Server for Biology
Daniel MacArthur

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) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). The resulting 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 show that this catalogue can be used to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; we identify 3,230 genes with near-complete depletion of truncating variants, 72% of which have 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.

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Mentioned in this Paper

Genes
Aggregation
Human Genetics
Recurrent Malignant Neoplasm
Gene Mutation
Genetic Markers
Whole Exome Sequencing
Ethnic Group
Protein Aggregation, Pathological
Recurrence (Disease Attribute)

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