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MBE Advance Access published online on February 12, 2009
Molecular Biology and Evolution, doi:10.1093/molbev/msp025
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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

Microsatellites are molecular clocks that support accurate inferences about history

James X. Sun1,2,4,5, James C. Mullikin3, Nick Patterson1 and David E. Reich1,2

1 Broad Institute of Harvard and MIT, Cambridge, MA
2 Harvard Medical School Department of Genetics, Boston, MA
3 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
4 Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA
5 MIT Department of Electrical Engineering and Computer Science, Cambridge, MA

Correspondences to either: James X. Sun (xinsun{at}mit.edu, Tel: 617-432-5348), David E. Reich (reich{at}genetics.med.harvard.edu, Tel: 617-432-6548), Both have the same address and fax: 77 Ave Louis Pasteur, #336, Boston, MA 02115, Fax: 617-432-6306

Received for publication December 5, 2008. Revision received January 16, 2009. Accepted for publication January 16, 2009.

Microsatellite length mutations are often modeled using the generalized stepwise mutation process, which is a type of random walk. If this model is sufficiently accurate, one can estimate the coalescence time between alleles of a locus after a mathematical transformation of the allele lengths. When large-scale microsatellite genotyping first became possible, there was substantial interest in using this approach to make inferences about time and demography, but that interest has waned because it has not been possible to empirically validate the clock by comparing it to data in which the mutation process is well understood. We analyzed data from 783 microsatellite loci in human populations and 292 loci in chimpanzee populations, and compared them to up to one gigabase of aligned sequence data, where the molecular clock based upon nucleotide substitutions is believed to be reliable. We empirically demonstrate a remarkable linearity (r2 > 0.95) between the microsatellite average squared distance (ASD) statistic and sequence divergence. We demonstrate that microsatellites are accurate molecular clocks for coalescent times of at least two million years. We apply this insight to confirm that the African populations San, Biaka Pygmy, and Mbuti Pygmy have the deepest coalescent times among populations in the Human Genome Diversity Project. Furthermore, we show that microsatellites support unbiased estimates of population differentiation (FST) that are less subject to ascertainment bias than single nucleotide polymorphism (SNP) FST. These results raise the prospect of using microsatellite data sets to determine parameters of population history. When genotyped along with SNPs, microsatellite data can also be used to correct for SNP ascertainment bias.

Key Words: Microsatellite evolution • molecular clocks • coalescent time • average square distance • FST • SNP ascertainment bias


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