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

By D. Ruderfer, T. Hamamsy, M. Lek, Konrad J. Karczewski, D. Kavanagh, Kaitlin E. Samocha, Mark J. Daly, Daniel G. MacArthur, Menachem Fromer, Shaun Purcell. 2016

182 citations recorded by the source corpus.

Copy number variation (CNV) affecting protein-coding genes contributes substantially to human diversity and disease. Here we characterized the rates and properties of rare genic CNVs (<0.5% frequency) in exome sequencing data from nearly 60,000 individuals in the Exome Aggregation Consortium (ExAC) database. 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 affected by CNVs were more intolerant than in controls. The ExAC CNV data constitute a critical component of an integrated database spanning the spectrum of human genetic variation, aiding in the interpretation of personal genomes as well as population-based disease studies. These data are freely available for download and visualization online.

Subfields: Genetics, Plant Science

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Citations in the corpus

The ExAC browser: displaying reference data information from over 60 000 exomes (2016, methodology): “Gene summary CNV counts and related constraint scores are presented based on likelihoods of the CNV occurring within the genomic range of the gene, as described (16).”
Pathogenic germline variants in 10,389 adult cancers (2018, methodology): “XHMMwas run as previously described (Ruderfer et al., 2016).”
Pharmacogenomics of GPCR Drug Targets (2018, unknown): “Copy number variations (CNVs) were analyzed from 59,898 human exomes for all GPCR drug targets (Ruderfer et al., 2016).”