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MBE Advance Access published online on March 11, 2009
Molecular Biology and Evolution, doi:10.1093/molbev/msp045
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© The Author 2009. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Article

Population genomics analysis of ALMS1 in humans reveals a surprisingly complex evolutionary history

Laura B. Scheinfeldt1, Shameek Biswas1, Jennifer Madeoy1, Caitlin F. Connelly1, Eric E. Schadt2 and Joshua M. Akey1,3

1 Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA
2 Rosetta Inpharmatics, LLC, a Wholly Owned Subsidiary of Merck and Co., Inc., Seattle, Washington 98109, USA

3 Corresponding Author: Joshua M. Akey, Department of Genome Sciences, University of Washington, Foege Building, S303, Seattle, WA. 98195-7730, Phone: (206) 543-7254, Fax: (206) 685-7301, akeyj{at}u.washington.edu

Received for publication November 21, 2008. Revision received March 5, 2009. Accepted for publication March 8, 2009.

Mutations in the human gene ALMS1 result in Alström Syndrome, which presents with early childhood obesity and insulin resistance leading to Type 2 diabetes. Previous genome-wide scans for selection in the HapMap data based on linkage disequilibrium and population structure suggest that ALMS1 was subject to recent positive selection. Through a detailed population genomics analysis of existing genome-wide data sets and new resequencing data obtained in geographically diverse populations, we find that the signature of selection at ALMS1 is considerably more complex than what would be expected for an idealized model of a selective sweep acting on a newly arisen advantageous mutation. Specifically, we observed three highly divergent and globally dispersed haplogroups, two of which carry a set of seven derived non-synonymous SNP alleles that are nearly fixed in Asian populations. Our data suggest that the interaction of human demographic history and positive selection on standing variation in Eurasian populations approximately 15 kya ago parsimoniously explains the spectrum of extant ALMS1 variation. These results provide new insights into the evolutionary history of ALMS1 in humans and suggest that selective events identified in genome-wide scans may be more complex than currently appreciated.

Key Words: ALMS1 • Positive Selection • Standing Variation


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