An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People
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
Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. We conclude that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.
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Supplementary Material
Summary
Materials and Methods
Supplementary Text
Figs. S1 to S15
Tables S1 to S17
Databases S1 to S3
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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: 14 December 2011
Accepted: 3 May 2012
Published in print: 6 July 2012
Acknowledgments
We thank GSK colleagues who advised on the selection of genes and collections, especially W. Anderson, L. Condreay, P. Agarwal, A. Hughes, J. Rubio, C. Spraggs, and D. Waterworth; the sample preparation team, especially J. Charnecki, M. E. Volk, D. Duran, D. Briley, and K. King for data preparation; A. Slater for subject selection and preparation of genome-wide genotype data; E. Woldu for capillary sequencing; A. Nelsen, S. Buhta-Halburnt, L. Amos, and J. Forte for consent review; M. Lawson for assistance in running the association analyses; J. Brown for discussions about gene feature analyses; S. Ghosh for providing reviews of the manuscript; and G. Tian, H. Jiang, Z. Su, X. Sun, L. Yang, and X. Zhang at BGI for sequencing. We acknowledge the work of collaborating clinicians and researchers who contributed to recruiting and characterizing subjects (13). J.N. and D.W. were supported by a Searle Scholars Program award to J.N. D.K. is supported by a NIH Genome Analysis training grant. All variants described in this study have been submitted to dbSNP; accession nos. are included in database S2. Subject-level sequence data for CoLaus and LOLIPOP studies are available in dbGaP. Additional subject-level sequence data can be made available upon request from the authors under a Data Transfer Agreement for the purpose to understand, assess, or extend the conclusions of this paper.
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