The Evolution of Human mtDNA

University Of Texas Medical Branch At Galveston, Galveston TX

Investigators

Abstract

The mitochondrial genome (mtDNA) has been used extensively as an evolutionary clock with which to study the origins and population genetics of modern human populations because of its strict maternal inheritance, lack of recombination, and high but relatively constant or clock-like rate of divergence. However, there are indications that human mtDNA may not behave as a simple molecular clock. In addition, there are recent - and controversial - reports that mtDNA recombination has confounded the evolutionary pattern. This project will determine the pedigree rate of mtDNA divergence, and it will test, comprehensively and systematically, whether a simple mtDNA clock is a valid tool for studies of human molecular evolution. The possible role of mtDNA recombination during human evolution will also be investigated. A basic tenet of the mtDNA clock hypothesis is that there is a single rate of mtDNA divergence that can be applied to any set of sequences. However, many different models of evolution have been developed to estimate the rate of mtDNA divergence, and they yield mtDNA divergence rates that differ by an order of magnitude, and each is associated with a high degree of statistical uncertainty. In this project, sequence divergence within the rapidly-evolving, non-coding mtDNA D-loop will be analyzed. As a complementary approach to previous phylogenetic analyses at the population level, we will use a unique empirical approach to estimate the divergence rate of the D-loop at the level of the pedigree (Aim 1). We will test the hypothesis that the rate of D-loop divergence is higher in pedigrees than that obtained with phylogenetic, or population-based, approaches. In addition, we will undertake extensive phylogenetic analysis of the D-loop in two large sets of European mtDNA sequences to ascertain if the rate of divergence and the spectrum of sequence changes are the same in both sequence sets, as predicted by the molecular clock hypothesis (Aim 2). Finally, we will analyze the evolution of mtDNA through the comprehensive analysis of mtDNAs from Europeans whose entire sequences have been determined (Aim 3). Particular emphasis will be placed upon testing the mtDNA molecular clock hypothesis, and upon the possible role of recombination in human mtDNA evolution. The long-term goal of our research is to elucidate the processes by which mutations arise and become fixed within the human mitochondrial genome, and so to improve our understanding of human evolution and population genetics.