Genetics. Published Articles Ahead of Print: September 19, 2005, Copyright © 2005
doi:10.1534/genetics.105.043901


A more recent version of this article appeared on January 1, 2006.

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The role of selection in the evolution of human mitochondrial genomes

Toomas Kivisild 1*, Peidong Shen 2, Dennis P. Wall 3, Bao Do 2, Raphael Sung 2, Karen K. Davis 2, Giuseppe Passarino 4, Peter A. Underhill 5, Curt Scharfe 2, Antonio Torroni 6, Rosaria Scozzari 7, David Modiano 7, Alfredo Coppa 6, Peter de Knjiff 8, Marcus W. Feldman 3, Luca L. Cavalli-Sforza 5 and Peter J. Oefner 2

1 Stanford University School of Medicine/Estonian Biocentre
2 Stanford Genome Technology Center
3 Stanford University
4 Università della Calabria
5 Stanford University School of Medicine
6 Università di Pavia
7 Università "La Sapienza"
8 Leiden University Medical Center

* To whom correspondence should be addressed. E-mail: tkivisil{at}ebc.ee.

Submitted on March 30, 2005
Revised on June 21, 2005
Accepted on 5 September 2005


Abstract

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 non-synonymous base substitutions among hotspots of recurrent mutation. Most hotspots involved transitions from guanine to adenine that, together 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 non-synonymous changes from and to threonine and valine differed significantly (P=0.003) between populations with neutral (22/58) and those with significantly negative Tajima's D values (70/76), independent of their geographic location. In contrast to a recent suggestion that the excess of non-silent mutations is characteristic to Arctic populations implying their role in cold adaptation, we demonstrate that the surplus of non-synonymous 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.

Key Words: evolution, human population genetics, mitochondrial genomes, molecular clock, natural selection




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