Natural selection may have shaped regional mtDNA variation in humans. 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, the researchers 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) (ka/ks) 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 ka/ks 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, the researchers concluded that selection may have played a role in shaping human regional mtDNA variation and that one of the selective influences was climate. The study found that mtDNA variation deviates from neutrality in European, Central Asian, and Siberian plus Native American mtDNA lineages but not African lineages. The ATP6 gene is the most variable gene among human mtDNAs. ATP6, cytochrome b, and COI are specifically variable in the arctic, temperate, and tropical zones, respectively. The researchers suggest that natural selection may have influenced the regional differences between mtDNA lineages. The study also found that mtDNA mutations may permit adaptation to changes in diet and climate. The high mutation rate of mtDNA and the central role of mitochondrial proteins in cellular energetics make the mtDNA an ideal system for permitting rapid human and animal adaptation to new climate and dietary conditions. The uniparental inheritance of the mtDNA favors the rapid segregation, expression, and adaptive selection of new advantageous mtDNA alleles. The lack of recombination would mean that selection of beneficial mutants would increase the frequency of the entire mtDNA haplotype through hitchhiking. Hence, climatic selection would lead to the regional-specific haplogroups that are observed. The study also found thatNatural selection may have shaped regional mtDNA variation in humans. 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, the researchers 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) (ka/ks) 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 ka/ks 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, the researchers concluded that selection may have played a role in shaping human regional mtDNA variation and that one of the selective influences was climate. The study found that mtDNA variation deviates from neutrality in European, Central Asian, and Siberian plus Native American mtDNA lineages but not African lineages. The ATP6 gene is the most variable gene among human mtDNAs. ATP6, cytochrome b, and COI are specifically variable in the arctic, temperate, and tropical zones, respectively. The researchers suggest that natural selection may have influenced the regional differences between mtDNA lineages. The study also found that mtDNA mutations may permit adaptation to changes in diet and climate. The high mutation rate of mtDNA and the central role of mitochondrial proteins in cellular energetics make the mtDNA an ideal system for permitting rapid human and animal adaptation to new climate and dietary conditions. The uniparental inheritance of the mtDNA favors the rapid segregation, expression, and adaptive selection of new advantageous mtDNA alleles. The lack of recombination would mean that selection of beneficial mutants would increase the frequency of the entire mtDNA haplotype through hitchhiking. Hence, climatic selection would lead to the regional-specific haplogroups that are observed. The study also found that