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; Charles F. Sing

doi:10.1038/ncomms1130

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 VillasanaShannon Gross, Vandita Joshi, Jireh Santibanez, Margaret Morgan, Kyle Chang, Walker Hale IV, Alan R. Templeton, Eric Boerwinkle, Richard Gibbs, Charles F. Sing

Research output: Contribution to journal › Article › peer-review

181 Scopus citations

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.

Original language	English (US)
Article number	131
Journal	Nature communications
Volume	1
Issue number	8
DOIs	https://doi.org/10.1038/ncomms1130
State	Published - 2010
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Coventry, A., Bull-Otterson, L. M., Liu, X., Clark, A. G., Maxwell, T. J., Crosby, J., Hixson, J. E., Rea, T. J., Muzny, D. M., Lewis, L. R., Wheeler, D. A., Sabo, A., Lusk, C., Weiss, K. G., Akbar, H., Cree, A., Hawes, A. C., Newsham, I., Varghese, R. T., ... Sing, C. F. (2010). Deep resequencing reveals excess rare recent variants consistent with explosive population growth. Nature communications, 1(8), Article 131. https://doi.org/10.1038/ncomms1130

Coventry, A, Bull-Otterson, LM, Liu, X, Clark, AG, Maxwell, TJ, Crosby, J, Hixson, JE, Rea, TJ, Muzny, DM, Lewis, LR, Wheeler, DA, Sabo, A, Lusk, C, Weiss, KG, Akbar, H, Cree, A, Hawes, AC, Newsham, I, Varghese, RT, Villasana, D, Gross, S, Joshi, V, Santibanez, J, Morgan, M, Chang, K, Hale IV, W, Templeton, AR, Boerwinkle, E, Gibbs, R & Sing, CF 2010, 'Deep resequencing reveals excess rare recent variants consistent with explosive population growth', Nature communications, vol. 1, no. 8, 131. https://doi.org/10.1038/ncomms1130

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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.",

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AU - Crosby, Jacy

AU - Hixson, James E.

AU - Rea, Thomas J.

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AU - Gross, Shannon

AU - Joshi, Vandita

AU - Santibanez, Jireh

AU - Morgan, Margaret

AU - Chang, Kyle

AU - Hale IV, Walker

AU - Templeton, Alan R.

AU - Boerwinkle, Eric

AU - Gibbs, Richard

AU - Sing, Charles F.

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

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ASJC Scopus subject areas

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