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Open Access Highly Accessed Research article

Heterozygosity increases microsatellite mutation rate, linking it to demographic history

William Amos1*, Jonathan Flint2 and Xin Xu3

Author Affiliations

1 Department of Zoology, Downing Street, Cambridge, CB4 3DB, UK

2 Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK

3 Program for Population Genetics, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA

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BMC Genetics 2008, 9:72  doi:10.1186/1471-2156-9-72

Published: 14 November 2008

Abstract

Background

Biochemical experiments in yeast suggest a possible mechanism that would cause heterozygous sites to mutate faster than equivalent homozygous sites. If such a process operates, it could undermine a key assumption at the core of population genetic theory, namely that mutation rate and population size are indpendent, because population expansion would increase heterozygosity that in turn would increase mutation rate. Here we test this hypothesis using both direct counting of microsatellite mutations in human pedigrees and an analysis of the relationship between microsatellite length and patterns of demographically-induced variation in heterozygosity.

Results

We find that microsatellite alleles of any given length are more likely to mutate when their homologue is unusually different in length. Furthermore, microsatellite lengths in human populations do not vary randomly, but instead exhibit highly predictable trends with both distance from Africa, a surrogate measure of genome-wide heterozygosity, and modern population size. This predictability remains even after statistically controlling for non-independence due to shared ancestry among populations.

Conclusion

Our results reveal patterns that are unexpected under classical population genetic theory, where no mechanism exists capable of linking allele length to extrinsic variables such as geography or population size. However, the predictability of microsatellite length is consistent with heterozygote instability and suggest that this has an important impact on microsatellite evolution. Whether similar processes impact on single nucleotide polymorphisms remains unclear.