title: The role of selection in the evolution of human mitochondrial genomes.
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 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.
authors.affiliation: Department of Human and Clinical Genetics, Leiden University Medical Center, 2333 AL Leiden, The Netherlands. tkivisil@ebc.ee
authors.forename: Toomas
authors.initials: T
authors.lastname: Kivisild
authors.forename: Peidong
authors.initials: P
authors.lastname: Shen
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Wall
authors.forename: Bao
authors.initials: B
authors.lastname: Do
authors.forename: Raphael
authors.initials: R
authors.lastname: Sung
authors.forename: Karen
authors.initials: K
authors.lastname: Davis
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Passarino
authors.forename: Peter A
authors.initials: PA
authors.lastname: Underhill
authors.forename: Curt
authors.initials: C
authors.lastname: Scharfe
authors.forename: Antonio
authors.initials: A
authors.lastname: Torroni
authors.forename: Rosaria
authors.initials: R
authors.lastname: Scozzari
authors.forename: David
authors.initials: D
authors.lastname: Modiano
authors.forename: Alfredo
authors.initials: A
authors.lastname: Coppa
authors.forename: Peter
authors.initials: P
authors.lastname: de Knijff
authors.forename: Marcus
authors.initials: M
authors.lastname: Feldman
authors.forename: Luca L
authors.initials: LL
authors.lastname: Cavalli-Sforza
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
mesh_terms: D019943:Amino Acid Substitution; D020029:Base Pairing; D001483:Base Sequence; D003062:Codon / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D019143:Evolution, Molecular; D015894:Genome, Human; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010802:Phylogeny; D012335:RNA, Ribosomal / Q000235:genetics; D012641:Selection, Genetic
chemical_list: D003062:Codon; D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal