Evolution and functional impact of rare coding variation from deep sequencing of human exomes

Jacob A. Tennessen, Abigail W. Bigham, Timothy D. O'Connor, Wenqing Fu, Eimear E. Kenny, Simon Gravel, Sean McGee, Ron Do, Xiaoming Liu, Goo Jun, Hyun Min Kang, Daniel Jordan, Suzanne M. Leal, Stacey Gabriel, Mark J. Rieder, Goncalo Abecasis, David Altshuler, Deborah A. Nickerson, Eric Boerwinkle, Shamil SunyaevCarlos D. Bustamante, Michael J. Bamshad, Joshua M. Akey

Research output: Contribution to journalArticlepeer-review

1260 Scopus citations


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 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carried were predicted to affect 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.

Original languageEnglish (US)
Pages (from-to)64-69
Number of pages6
Issue number6090
StatePublished - Jul 6 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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