Deep resequencing reveals excess rare recent variants consistent with explosive population growth

Alex Coventry (), Lara M. Bull-Otterson, Xiaoming Liu, Andrew G. Clark, Taylor J. Maxwell, Jacy Crosby, James E. Hixson, Thomas J. Rea, Donna M. Muzny, Lora R. Lewis, David A. Wheeler, Aniko Sabo, Christine Lusk, Kenneth G. Weiss, Humeira Akbar, Andrew Cree, Alicia C. Hawes, Irene Newsham, Robin T. Varghese, Donna Villasana, Shannon Gross, Vandita Joshi, Jireh Santibanez, Margaret Morgan, Kyle Chang, Walker Hale Iv, Alan R. Templeton, Eric Boerwinkle, Richard Gibbs and Charles F. Sing
Additional contact information
Alex Coventry: Cornell University
Lara M. Bull-Otterson: Human Genome Sequencing Center, Baylor College of Medicine
Xiaoming Liu: Human Genetics Center, UT Houston Health Science Center
Andrew G. Clark: Cornell University
Taylor J. Maxwell: Human Genetics Center, UT Houston Health Science Center
Jacy Crosby: Human Genetics Center, UT Houston Health Science Center
James E. Hixson: Human Genetics Center, UT Houston Health Science Center
Thomas J. Rea: University of Michigan School of Medicine
Donna M. Muzny: Human Genome Sequencing Center, Baylor College of Medicine
Lora R. Lewis: Human Genome Sequencing Center, Baylor College of Medicine
David A. Wheeler: Human Genome Sequencing Center, Baylor College of Medicine
Aniko Sabo: Human Genome Sequencing Center, Baylor College of Medicine
Christine Lusk: University of Michigan School of Medicine
Kenneth G. Weiss: University of Michigan School of Medicine
Humeira Akbar: Human Genome Sequencing Center, Baylor College of Medicine
Andrew Cree: Human Genome Sequencing Center, Baylor College of Medicine
Alicia C. Hawes: Human Genome Sequencing Center, Baylor College of Medicine
Irene Newsham: Human Genome Sequencing Center, Baylor College of Medicine
Robin T. Varghese: Human Genome Sequencing Center, Baylor College of Medicine
Donna Villasana: Human Genome Sequencing Center, Baylor College of Medicine
Shannon Gross: Human Genome Sequencing Center, Baylor College of Medicine
Vandita Joshi: Human Genome Sequencing Center, Baylor College of Medicine
Jireh Santibanez: Human Genome Sequencing Center, Baylor College of Medicine
Margaret Morgan: Human Genome Sequencing Center, Baylor College of Medicine
Kyle Chang: Human Genome Sequencing Center, Baylor College of Medicine
Walker Hale Iv: Human Genome Sequencing Center, Baylor College of Medicine
Alan R. Templeton: Washington University
Eric Boerwinkle: Human Genetics Center, UT Houston Health Science Center
Richard Gibbs: Human Genome Sequencing Center, Baylor College of Medicine
Charles F. Sing: University of Michigan School of Medicine

Nature Communications, 2010, vol. 1, issue 1, 1-6

Abstract: Abstract 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.

Date: 2010
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DOI: 10.1038/ncomms1130

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