Patterns of genic intolerance of rare copy number variation in 59,898 human exomes

Abstract

Copy number variation (CNV) impacting protein-coding genes contributes significantly to human diversity and disease. Here we characterized the rates and properties of rare genic CNV (<0.5% frequency) in exome-sequencing data from nearly 60,000 individuals in the Exome Aggregation Consortium (ExAC). On average, individuals possessed 0.81 deleted and 1.75 duplicated genes, and most (70%) carried at least one rare genic CNV. For every gene, we empirically estimated an index of relative intolerance to CNVs that demonstrated moderate correlation with measures of genic constraint based on single-nucleotide variation (SNV) and was independently correlated with measures of evolutionary conservation. For individuals with schizophrenia, genes impacted by CNVs were more intolerant than in controls. ExAC CNV data constitutes a critical component of an integrated database spanning the spectrum of human genetic variation, aiding the interpretation of personal genomes as well as population-based disease studies. These data are freely available for download and visualization online.