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related mtDNA haplotypes known as a haplogroup. Because the number of possible adaptive mtDNA mutations is finite, the same adaptive mutations have been observed repeatedly on different mtDNA backgrounds around the world. This convergent evolution confirms that these mtDNA mutations are adaptive.

Each regional indigenous human population has its own distinctive mtDNAs. African mtDNAs belong to macrohaplogroup L, which encompasses the greatest mtDNA sequence diversity, implying an African origin for the mtDNA tree (Johnson et al., 1983; Cann et al., 1987; Merriwether et al., 1991). Of all of the African mtDNA variants, only two mtDNAs successfully left Africa and colonized Eurasia, founding macrohaplogroups M and N. Only macrohaplogroup N radiated into Europe, generating the European-specific lineages H, I, J, Uk, T, U, V, W, and X. Both macrohaplogroups M and N radiated into Asia, generating a plethora of mtDNA lineages. Of these, only A, C, and D became enriched in northeastern Siberia and were in a position to cross the Bering land bridge to colonize the Americas (Wallace, 2007; Wallace et al., 2007).

The regional specificity of mtDNA lineages suggests that mtDNA variation permitted humans to live in different climatic zones, perhaps through regulation of OXPHOS coupling efficiency and thus thermal regulation (Wallace, 2007). Accordingly, mtDNA variation but not nDNA variation correlates with regional temperature extremes (Balloux et al., 2009). In mtDNAs harboring the two founder macrohaplogroup N missense mutations, ND3 nucleotide 10398 (amino acid change A114T) and ATP6 nucleotide 8701 (amino acid change A59T), several mitochondrial physiological parameters have been shown to be altered (Kazuno et al., 2006). Furthermore, a mtDNA control region variant has been found to change mitochondrial transcription and copy number (Suissa et al., 2009).

Although mild mtDNA mutations may be adaptive in one local energy environment, the same mutation might be maladaptive in another energy environment. Consistent with this conjecture, mtDNA haplogroups have been found to be important risk factors for a wide range of common metabolic and degenerative diseases and to influence various cancers and longevity (Wallace, 2005; Wallace and Fan, 2009).

Once a subpopulation has become established in a region through adaptive mtDNA mutations, additional mutations can arise in nDNA bioenergetic genes to further enhance physiological adaptation and contribute to speciation (Mishmar et al., 2006). Examples of such variants in human populations include polymorphisms in the nDNA-encoded mitochondrial uncoupling protein genes (Bulotta et al., 2005; Cha et al., 2006; Nakano et al., 2006; Villarroya et al., 2006) and in the bioenergetic transcription factor genes for the peroxisome-proliferator-activated receptor γ (PPARγ) (Altshuler et al., 2000) and PPARγ-coactivator 1α (PCG-1α)



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