Deep resequencing reveals excess rare recent variants consistent with explosive population growth.
Accurately determining the distribution of rare variants is an important goal of human genetics, but resequencing of a sample large enough for this purpose has been unfeasible until now. Here, we applied Sanger sequencing of genomic PCR amplicons to resequence the diabetes-associated genes KCNJ11 and HHEX in 13,715 people (10,422 European Americans and 3,293 African Americans) and validated amplicons potentially harbouring rare variants using 454 pyrosequencing. We observed far more variation (expected variant-site count ∼578) than would have been predicted on the basis of earlier surveys, which could only capture the distribution of common variants. By comparison with earlier estimates based on common variants, our model shows a clear genetic signal of accelerating population growth, suggesting that humanity harbours a myriad of rare, deleterious variants, and that disease risk and the burden of disease in contemporary populations may be heavily influenced by the distribution of rare variants.
1] Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA. [2].
Alex
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Coventry
Lara M
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Bull-Otterson
Xiaoming
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Liu
Andrew G
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Clark
Taylor J
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Maxwell
Jacy
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Crosby
James E
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Hixson
Thomas J
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Rea
Donna M
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Lora R
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Lewis
David A
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Wheeler
Aniko
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Sabo
Christine
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Lusk
Kenneth G
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Weiss
Humeira
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Akbar
Andrew
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Cree
Alicia C
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Hawes
Irene
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Newsham
Robin T
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Varghese
Donna
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Villasana
Shannon
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Gross
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Joshi
Jireh
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Santibanez
Margaret
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Morgan
Kyle
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Chang
Walker Hale
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Alan R
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Templeton
Eric
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Boerwinkle
Richard
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Gibbs
Charles F
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