The Genom of Homo sapiens.pdf

ANALYSIS OF ADAPTIVE SELECTION FORREGIONAL mtDNA LINEAGESDirect evidence for the regional accumulation of adaptivemutations was obtained by the analysis of amino acidreplacement mutation frequencies at the Nodes and theTips of the mtDNA macro-haplogroups. The replacementmutation frequency of the Nodes of the regional macrohaplogroupsincreased progressively from its lowest levelin African L to intermediate levels for the Eurasian M andN(R) to their highest level for N(nonR). N(nonR) encompassesthe arctic haplogroups A and X (Fig. 6). Thissouth-to-north increase in Nodal replacement mutationsis also reflected in the Node/Tip ratio, which was lowestin African L (0.7), intermediate in Eurasia M and N(R)(0.8), and highest in Northern N(nonR) (0.94) (Fig. 6).Thus, more northern latitudes are associated with moreNodal replacement mutations.The excess of Nodal mutations in the higher, colder latitudeswas further confirmed by analysis of the haplogroupsthat reside in the arctic and subarctic (Fig. 7).Using the African macro-haplogroup L nodal replacementmutation frequency (0.31) as the reference, thenortheastern Siberian–northern Native American haplogroupsA, C, D, and X all had higher nodal values rangmtDNAVARIATION 475The average replacement mutation Conservation Indexof the Global Phylogeny’s Nodes and Tips is considerablylower than the average of the pathogenic mutations(Fig. 5).The lower average Global Phylogeny Node and TipConservation Indices, relative to the pathogenic mutations,reflect in part the presence of the neutral mutationsscattered across the Global Phylogeny. These depress themean Conservation Index of the functionally importantreplacement mutations. To distinguish between the adaptiveversus the neutral mutations in the Nodes, we usedtwo standard deviations from the mean (the 95% confidencelimit) of the pathogenic mutations as an indicatorof replacement mutations that might have phenotypicconsequences. Mutations below this limit were presumedto be relatively neutral (Fig. 5). Using these criteria, wefound that 26% of the nodal replacement mutations werehighly conserved with an average amino acid conservationindex of 33.2 ± 3.6 (85 ± 9%), slightly below the averageof the pathogenic mutations (Ruiz-Pesini et al.2004). The remaining 74% of the nodal replacement mutationshad a much lower average Conservation Index of9.1 ± 5.8 (23 ± 15%). The Conservation Index of the Tipswas comparable, 34.4 (CI = 88%) (42%) versus 9.9 (CI =25%) (58%).The high Conservation Index of amino acid replacementsoccurring at the Tips represents primarily deleteriousmutations in the process of being eliminated by purifyingselection (Templeton 1996). The highly conservednodal replacement mutations have a Conservation Indexcomparable to that of pathogenic mutations, yet they havebeen retained in the human population for tens of thousandsof years in the face of purifying selection. Consequently,these mutations could not be deleterious. Therefore,they must have been advantageous in the newenvironments confronted by our ancestors.Figure 6. Global and regional replacement mutation frequencies at Nodes and Tips of the mitochondrial phylogeny. Global encompassesthe entire mtDNA tree. L, M, N(R), and N(nonR) are individual region-specific macro-haplogroups. Replacement mutationfrequencies, listed on the bars in the Nodes (first row) and Tips (second row) are calculated by the ratio of nonsynonymous (NS) tosynonymous (S) nucleotide substitutions. The ratio of the Node and Tip NS/S ratios is shown above the back row of bars.