Originally published as Genetics Published Articles Ahead of Print on September 14, 2008.

Genetics, Vol. 180, 1511-1524, November 2008, Copyright © 2008
doi:10.1534/genetics.108.091116

Maximum-Likelihood Estimation of Site-Specific Mutation Rates in Human Mitochondrial DNA From Partial Phylogenetic Classification

Saharon Rosset^*,,1, R. Spencer Wells, David F. Soria-Hernanz, Chris Tyler-Smith, Ajay K. Royyuru, Doron M. Behar^** and The Genographic Consortium²

^* Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, 69978 Israel, IBM T. J. Watson Research Center, Yorktown Heights, New York 10598, Missions Program, National Geographic Society, Washington, DC 20036, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom, ^** Molecular Medicine Laboratory, Rambam Health Care Campus, Haifa 31096, Israel

¹ Corresponding author: Department of Statistics, Tel Aviv University, Tel Aviv, 69978 Israel.
E-mail: saharon{at}post.tau.ac.il

The mitochondrial DNA hypervariable segment I (HVS-I) is widely used in studies of human evolutionary genetics, and therefore accurate estimates of mutation rates among nucleotide sites in this region are essential. We have developed a novel maximum-likelihood methodology for estimating site-specific mutation rates from partial phylogenetic information, such as haplogroup association. The resulting estimation problem is a generalized linear model, with a nonstandard link function. We develop inference and bias correction tools for our estimates and a hypothesis-testing approach for site independence. We demonstrate our methodology using 16,609 HVS-I samples from the Genographic Project. Our results suggest that mutation rates among nucleotide sites in HVS-I are highly variable. The 16,400–16,500 region exhibits significantly lower rates compared to other regions, suggesting potential functional constraints. Several loci identified in the literature as possible termination-associated sequences (TAS) do not yield statistically slower rates than the rest of HVS-I, casting doubt on their functional importance. Our tests do not reject the null hypothesis of independent mutation rates among nucleotide sites, supporting the use of site-independence assumption for analyzing HVS-I. Potential extensions of our methodology include its application to estimation of mutation rates in other genetic regions, like Y chromosome short tandem repeats.

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