title: Maximum-likelihood estimation of site-specific mutation rates in human mitochondrial DNA from partial phylogenetic classification.
abstract: 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.
authors.affiliation: Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel. saharon@post.tau.ac.il
authors.forename: Saharon
authors.initials: S
authors.lastname: Rosset
authors.forename: R Spencer
authors.initials: RS
authors.lastname: Wells
authors.forename: David F
authors.initials: DF
authors.lastname: Soria-Hernanz
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Royyuru
authors.forename: Doron M
authors.initials: DM
authors.lastname: Behar
mesh_terms: D003198:Computer Simulation; D004272:DNA, Mitochondrial / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016013:Likelihood Functions; D008957:Models, Genetic; D010802:Phylogeny; D017354:Point Mutation / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial
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