Research Article

Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes

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Science  17 May 2012:
DOI: 10.1126/science.1219240

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As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111x in 2,440 individuals of European (n = 1,351) and African (n = 1,088) ancestry. We identified >500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency < 0.5%), novel (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carries were predicted to impact protein function of ~313 genes per genome, and ~95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits.

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