Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes
A Deep Look Into Our Genes
Recent debates have focused on the degree of genetic variation and its impact upon health at the genomic level in humans (see the Perspective by Casals and Bertranpetit). Tennessen et al. (p. 64, published online 17 May), looking at all of the protein-coding genes in the human genome, and Nelson et al. (p. 100, published online 17 May), looking at genes that encode drug targets, address this question through deep sequencing efforts on samples from multiple individuals. The findings suggest that most human variation is rare, not shared between populations, and that rare variants are likely to play a role in human health.
Abstract
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 111× 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.
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References and Notes
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Science
Volume 337 | Issue 6090
6 July 2012
6 July 2012
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Copyright © 2012, American Association for the Advancement of Science.
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Received: 17 January 2012
Accepted: 3 May 2012
Published in print: 6 July 2012
Acknowledgments
We acknowledge the support of the NHLBI and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research; and the Population Genetics Project Team. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (Women’s Health Initiative Exome Sequencing Project, WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Filtered sets of annotated variants and their allele frequencies are available at http://evs.gs.washington.edu/EVS/ and have been deposited in dbSNP (www.ncbi.nlm.nih.gov/snp; local batch ID, ESP2500). Genotypes and phenotypes from a large subset of individuals are also available via dbGaP (www.ncbi.nlm.nih.gov/gap) using the following accession information: NHLBI GO-ESP: Women’s Health Initiative Exome Sequencing Project (WHI) – WHISP, WHISP_Subject_Phenotypes, pht002246.v2.p2, phs000281.v2.p2; NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (JHS), ESP_HeartGO_JHS_LDLandEOMI_Subject_Phenotypes, pht002539.v1.p1, phs000402.v1.p1; NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (FHS), HeartGO_FHS_LDLandEOMI_PhenotypeDataFile, pht002476.v1.p1, phs000401.v1.p1; NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (CHS), HeartGO_CHS_LDL_PhenotypeDataFile, pht002536.v1.p1, phs000400.v1.p1; NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (ARIC), ESP_ARIC_LDLandEOMI_Sample, pht002466.v1.p1, phs000398.v1.p1; NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Cystic Fibrosis), ESP_LungGO_CF_PA_Culture_Data, pht002227.v1.p1, phs000254.v1.p1; NHLBI GO-ESP: Early-Onset Myocardial Infarction (Broad EOMI), ESP_Broad_EOMI_Subject_Phenotypes, pht001437.v1.p1, phs000279.v1.p1; NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Pulmonary Arterial Hypertension), PAH_Subject_Phenotypes_Baseline_Measures, pht002277.v1.p1, phs000290.v1.p1; NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Lung Health Study of Chronic Obstructive Pulmonary Disease), LHS_COPD_Subject_Phenotypes_Baseline_Measures, pht002272.v1.p1, phs000291.v1.p1. C.D.B. is on the scientific advisory board for Personalis, Incorporated; Mubadala Medical Holding Company; 23andme “Roots into the future” project; and Ancestry.com. M.J.R. owns stock in Illumina.
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