The Genom of Homo sapiens.pdf

476 WALLACE, RUIZ-PESINI, AND MISHMARFigure 7. Arctic zone replacement mutation frequencies. L equals African-specific macro-haplogroup L. A, B, C, D, and X representAsian or Eurasia mtDNA haplogroups that crossed from Eurasia into the Americas. ACDX equals the average of these haplogroups.nonACDX equals the average of all mtDNA haplogroups but A, C, D, and X. (First row) Nodal NS/S ratios. (Second row) Node/Tipratios.ing from 0.46 to 1.25. In contrast, haplogroup B, whichreached America without going through Siberia, had anodal replacement frequency similar to that of Africa(0.38). These same trends are seen in the Node/Tip replacementfrequency ratios. For African L, the ratio is0.70. For haplogroups A, C, D, and X the range of ratiosis 0.91–2.91. Haplogroup B is 0.75. Combining the datafrom haplogroups A, C, D, and X (ACDX) gives an averagenodal value of 0.61 and a Node/Tip ratio of 1.09,whereas all nonACDX haplogroups give an averagenodal ratio of 0.39 and a Node/Tip ratio of 0.74.This striking increase in the replacement mutation frequencyin the arctic and subarctic haplogroups is also reflectedin the average Conservation Index of the nodal replacementmutations. The nodal Conservation Indices ofhaplogroups A, C, and D were 20.8 (53%), 28.3 (73%),and 16.3 (42%), respectively, whereas those for AfricanL and haplogroup B were 14.1 (36%) and 12.0 (31%).Thus, the nodal replacement mutations of the arctic haplogroupshave both a higher frequency of replacementmutations and a higher Conservation Index of the alteredamino acid.A comparable result was obtained for the European(temperate zone) haplogroups (Fig. 8). Relative to theNode/Tip ratio of African L (0.70), the ratios of the Europeanhaplogroups H, V(HV*), J, T, and IWX weremarkedly higher (0.79–2.89). Likewise, compared to theAfrican 14.1 (36%), the nodal Conservation Indices ofhaplogroups H, J, T, and IWX were increased to therange of 16.5–20.3 (42–52%).Clearly, adaptive replacement mutations have accumulatedin human populations of both the arctic and temperatezones. Therefore, these mutations must have been selectedin the human mtDNAs as people moved out ofAfrica into colder climates.THE NATURE OF ADAPTIVE mtDNAMUTATIONSFrom this analysis we can conclude that highly conservednodal replacement mutations from the temperateand arctic haplogroups were important in adaptation tohigher, colder latitudes. The specific adaptive mutationswould be expected to occur close to the base of the region-specificmtDNA haplogroup and to change a highlyconserved amino acid. Using this logic, arctic haplogroupA was found to encompass two adaptive replacement mutations:ND2 np 4824G (T119A) and ATP6 np 8794T(H90Y). Similarly, the Siberian haplogroup C lineagewas found to be associated with two adaptive variants:ND4 np 11969A (A404T) and cytb np 15204C (I153T).The cytb np 15204C mutation is two amino acids awayfrom a pathogenic mutation S151P that alters the outerCoQ-binding site (Qo). Haplogroup D has only one likelyadaptive variant: ND2 np 5178A (L237M), and a majorsubbranch of haplogroup X harbored another likely adaptivemutation: ND5 np 13708A (A458T), one of the samevariants that occurs at the base of European haplogroup J.Similar functional mutations were found at the base ofEuropean haplogroups. For example, the sister hap-