title: Natural selection shaped regional mtDNA variation in humans.
abstract: Human mtDNA shows striking regional variation, traditionally attributed to genetic drift. However, it is not easy to account for the fact that only two mtDNA lineages (M and N) left Africa to colonize Eurasia and that lineages A, C, D, and G show a 5-fold enrichment from central Asia to Siberia. As an alternative to drift, natural selection might have enriched for certain mtDNA lineages as people migrated north into colder climates. To test this hypothesis we analyzed 104 complete mtDNA sequences from all global regions and lineages. African mtDNA variation did not significantly deviate from the standard neutral model, but European, Asian, and Siberian plus Native American variations did. Analysis of amino acid substitution mutations (nonsynonymous, Ka) versus neutral mutations (synonymous, Ks) (kaks) for all 13 mtDNA protein-coding genes revealed that the ATP6 gene had the highest amino acid sequence variation of any human mtDNA gene, even though ATP6 is one of the more conserved mtDNA proteins. Comparison of the kaks ratios for each mtDNA gene from the tropical, temperate, and arctic zones revealed that ATP6 was highly variable in the mtDNAs from the arctic zone, cytochrome b was particularly variable in the temperate zone, and cytochrome oxidase I was notably more variable in the tropics. Moreover, multiple amino acid changes found in ATP6, cytochrome b, and cytochrome oxidase I appeared to be functionally significant. From these analyses we conclude that selection may have played a role in shaping human regional mtDNA variation and that one of the selective influences was climate.
authors.affiliation: Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, 92697-3940, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Mishmar
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ruiz-Pesini
authors.forename: Pawel
authors.initials: P
authors.lastname: Golik
authors.forename: Vincent
authors.initials: V
authors.lastname: Macaulay
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Clark
authors.forename: Seyed
authors.initials: S
authors.lastname: Hosseini
authors.forename: Martin
authors.initials: M
authors.lastname: Brandon
authors.forename: Kirk
authors.initials: K
authors.lastname: Easley
authors.forename: Estella
authors.initials: E
authors.lastname: Chen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brown
authors.forename: Rem I
authors.initials: RI
authors.lastname: Sukernik
authors.forename: Antonel
authors.initials: A
authors.lastname: Olckers
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
mesh_terms: D000349:Africa; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D019143:Evolution, Molecular; D014644:Genetic Variation; D015186:Hominidae / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D008969:Molecular Sequence Data; D010085:Oxidative Phosphorylation; D010802:Phylogeny; D012641:Selection, Genetic
chemical_list: D004272:DNA, Mitochondrial