Originally published as Genetics Published Articles Ahead of Print on September 19, 2005.

Genetics, Vol. 172, 373-387, January 2006, Copyright © 2006
doi:10.1534/genetics.105.043901

The Role of Selection in the Evolution of Human Mitochondrial Genomes

Toomas Kivisild*,2,1, Peidong Shen{dagger},2, Dennis P. Wall{ddagger},3, Bao Do{dagger}, Raphael Sung{dagger}, Karen Davis{dagger}, Giuseppe Passarino§, Peter A. Underhill*, Curt Scharfe{dagger}, Antonio Torroni**, Rosaria Scozzari{dagger}{dagger}, David Modiano{ddagger}{ddagger}, Alfredo Coppa§§, Peter de Knijff***, Marcus Feldman{ddagger}, Luca L. Cavalli-Sforza* and Peter J. Oefner{dagger},2,4

* Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, {dagger} Stanford Genome Technology Center, Palo Alto, California 94304, {ddagger} Department of Biological Sciences, Stanford University, Stanford, California 94305, § Dipartimento di Biologia Cellulare, Università della Calabria, 87036 Rende, Italy, ** Dipartimento di Genetica e Microbiologia, Università di Pavia, 27100 Pavia, Italy, {dagger}{dagger} Dipartimento di Genetica e Biologia Molecolare, Università "La Sapienza," 00185 Rome, Italy, {ddagger}{ddagger} Dipartimento di Scienze di Sanità Pubblica, Sezione di Parassitologia, Università "La Sapienza," 00185 Rome, Italy, §§ Dipartimento di Biologia Animale e dell'Uomo, Università "La Sapienza," 00185 Rome, Italy and *** Department of Human and Clinical Genetics, Leiden University Medical Center, 2333 AL Leiden, The Netherlands

1 Corresponding author: Department of Evolutionary Biology, Tartu University and Estonian Biocenter, Riia 23, Tartu 51010, Estonia.
E-mail: tkivisil{at}ebc.ee

High mutation rate in mammalian mitochondrial DNA generates a highly divergent pool of alleles even within species that have dispersed and expanded in size recently. Phylogenetic analysis of 277 human mitochondrial genomes revealed a significant (P < 0.01) excess of rRNA and nonsynonymous base substitutions among hotspots of recurrent mutation. Most hotspots involved transitions from guanine to adenine that, with thymine-to-cytosine transitions, illustrate the asymmetric bias in codon usage at synonymous sites on the heavy-strand DNA. The mitochondrion-encoded tRNAThr varied significantly more than any other tRNA gene. Threonine and valine codons were involved in 259 of the 414 amino acid replacements observed. The ratio of nonsynonymous changes from and to threonine and valine differed significantly (P = 0.003) between populations with neutral (22/58) and populations with significantly negative Tajima's D values (70/76), independent of their geographic location. In contrast to a recent suggestion that the excess of nonsilent mutations is characteristic of Arctic populations, implying their role in cold adaptation, we demonstrate that the surplus of nonsynonymous mutations is a general feature of the young branches of the phylogenetic tree, affecting also those that are found only in Africa. We introduce a new calibration method of the mutation rate of synonymous transitions to estimate the coalescent times of mtDNA haplogroups.




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