An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people Public Deposited

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Creator
  • Wang, Jun
    • Other Affiliation: BGI, Shenzhen 518083, China; Department of Biology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 3393 9524, Denmark
  • Whittaker, John C.
    • Other Affiliation: Department of Quantitative Sciences, GSK, Stevenage SG1 2NY, UK
  • Wegmann, Daniel
    • Other Affiliation: Department of Ecology and Evolutionary Biology, University of California–Los Angeles, Los Angeles, CA 90095, USA
  • Chissoe, Stephanie L.
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Kessner, Darren
    • Other Affiliation: Department of Ecology and Evolutionary Biology, University of California–Los Angeles, Los Angeles, CA 90095, USA
  • Tang, Zhengzheng
    • Affiliation: School of Medicine, Department of Genetics, Gillings School of Global Public Health, Department of Biostatistics
  • Bacanu, Silviu-Alin
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • St. Jean, Pamela
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Cardon, Lon R.
    • Other Affiliation: Department of Quantitative Sciences, GSK, Upper Merion, PA 19406, USA
  • Nelson, Matthew R.
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Hall, Matthew D.
    • Other Affiliation: Department of Quantitative Sciences, GSK, Stevenage SG1 2NY, UK
  • Li , Jun
    • Other Affiliation: Department of Human Genetics, University of Michigan–Ann Arbor, Ann Arbor, MI 48109, USA
  • Li, Yun
    • Affiliation: School of Medicine, Department of Genetics, Gillings School of Global Public Health, Department of Biostatistics
  • Aponte, Jennifer
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Zöllner, Sebastian
    • Other Affiliation: Department of Biostatistics, University of Michigan–Ann Arbor, Ann Arbor, MI 48109, USA; Department of Psychiatry, University of Michigan–Ann Arbor, Ann Arbor, MI 48109, USA
  • Zhang, Yong
    • Other Affiliation: BGI, Shenzhen 518083, China
  • Abecasis, Gonçalo
    • Other Affiliation: Department of Biostatistics, University of Michigan–Ann Arbor, Ann Arbor, MI 48109, USA
  • Warren, Liling
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Shen, Judong
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Novembre, John
    • Other Affiliation: Department of Ecology and Evolutionary Biology, University of California–Los Angeles, Los Angeles, CA 90095, USA
  • Liu, Xiao
    • Other Affiliation: BGI, Shenzhen 518083, China
  • Ehm, Margaret G.
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Nangle, Keith
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Li, Li
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Fraser, Dana
    • Other Affiliation: Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA
  • Verzilli, Claudio
    • Other Affiliation: Department of Quantitative Sciences, GSK, Stevenage SG1 2NY, UK
  • Woollard, Peter
    • Other Affiliation: Department of Quantitative Sciences, GSK, Stevenage SG1 2NY, UK
  • Zawistowski, Matthew
    • Other Affiliation: Department of Biostatistics, University of Michigan–Ann Arbor, Ann Arbor, MI 48109, USA
  • Topp, Simon
    • Other Affiliation: Department of Quantitative Sciences, GSK, Stevenage SG1 2NY, UK
  • Mooser, Vincent
    • Other Affiliation: Department of Quantitative Sciences, GSK, Upper Merion, PA 19406, USA
  • Zhang, Hao
    • Other Affiliation: BGI, Shenzhen 518083, China
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.
Date of publication
Identifier
  • doi:10.1126/science.1217876
  • 2-s2.0-84863541347
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • Science
Journal volume
  • 337
Journal issue
  • 6090
Page start
  • 100
Page end
  • 104
Language
  • English
Version
  • Postprint
ISSN
  • 0036-8075
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