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An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People
31 auth. M. Nelson, Daniel Wegmann, M. Ehm, Darren Kessner, P. S. St Jean, Claudio J. Verzilli, Judong Shen, Zhengzheng Tang, S. Bacanu, D. Fraser, L. Warren, Jennifer L. Aponte, M. Zawistowski, Xiao Liu, Hao Zhang, ...
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), …
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. A pharmacogenomics analysis shows how challenging it will be to associate rare variants with phenotypes. 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.
Published in
Science
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372
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9 | 2012 |
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