| Human mitochondrial DNA (mtDNA) has become one of the most popular markers in molecular anthropology and population genetics for its special properties of high coverage of copies, high rates of mutation, small genome, lack of recombination and maternal inheritance. Mitochondria are the cell energy plant and responsible for the90%of the total energy of metabolism in human body. The electron transport chain, whose subunits are partially encoded by mtDNA, generates most energy in the form of oxidative phosphorylation, which is also the major form of energy production in mitochondria. Thus, mitochondria are important for sustaining life activities, and mutations on mtDNA might result in maternal genetic disease, metabolism-related disease and ageing disease.Human mtDNA was shaped by purifying selection for the importance of its encoding proteins, and excess non-synonymous mutations accumulated on external lineages. Extensive previous studies have demonstrated that the mtDNA haplogroups were obviously regional specific. The excess of non-synonymous mutations was found in the lineages of arctic regions compared to those of tropic zones, which might be a signal of adaption in human mtDNA. In this study, previous reported complete mitochondrial DNA sequences were collected to construct a database. Maximum likelihood method was used to detect sites under positive selection in human mtDNA.3122random mtDNA sequences were employed to detect the sites correlating with latitudes and reflecting the difference among populations. Two potential mtDNA sites,10398and14053might undergo adaptive selections detected by the methods mentioned above. DNA Polymorphisms are converted between adenine (A) and guanine (G) at these two sites. With elevation in latitudes, frequency of adenine increases while that of guanine decreases in population. DNA Polymorphisms of A/G results in amino acid changes between threonine (T) and alanine (A)(ND3T114A and ND5T573A respectively). These two variants radically change the amino acid property of a-helical tendencies, making the secondary structural changes between an a-helix and a loop. Mammalian mtDNA phylogeny was reconstructed and there were excess radical missense changes in the two amino acid sites mentioned above, which means that these two sites were affected by positive selection in Mammalian evolutionary history and indicates that the polymorphisms in human beings were adaptive. To further investigate the effect of variant at10398on3D structure, molecular dynamics simulation on subunit ND3was constructed and results indicated that114T in ND3would form a loop structure, and further broaden the subunit functional area. Thus,114T in ND3would lead to more flexible protein surface compared with114A, and threonine, a hydrophilic amino acid, would also help to attract protons, which will elevate proton transfer rate. The enhancing proton pumping rate will promote the metabolism rate and help to generate more heat to maintain body temperature in arctic regions, where there is an enrichment of10398A. To further explore the effect of the two variants, every time mutation happened on site10398and14053were analyzed and the results showed that significant excess mutation from adenine to guanine (threonine to alanine in amino acid) happened in lower latitude region, which was also identical with the phenomenon that there were more10398G in lower-latitude region. The possible explanation is that low metabolism rate requires less food, which assists human being to adapt in early hunter-gatherer society with food restriction. In short, sites10398and14053might be shaped by positive selection, and deserve further functional analysis to confirm. Variations in East Islander mtDNA genomes were also analyzed and A3511G (ND1T69A) was identified. The fixation of3511G in East Islanders might be affected by the selection of voyage according to knowledge that alanine will inhibit the metabolic rate.Not only was the adaptive effect in human mitochondrial DNA studied, historical demographic variations could also be revealed by mtDNA. It is a major question in archaeology and anthropology whether human populations started to grow primarily after the advent of agriculture, i.e. the Neolithic time. To answer this question requires an accurate estimation of the time of lineage expansion as well as that of population expansion in a population sample without ascertainment bias and a comparison to the initiation of the Neolithic Time. The1000Genome Project provided a wonderful chance for investigating a large number of human complete mtDNA of random samples. At first, we analyzed all available mtDNA genomes of East Asians ascertained by random sampling, a total of367complete mtDNA sequences generated by the1000Genome Project, including249Chinese (CHB, CHD, and CHS) and118Japanese (JPT). The results showed that major mtDNA lineages underwent expansions, all of which, except for two JPT-specific lineages, including D4, D4b2b, D4a, D4j, D5a2a, A, N9a, Fla1’4, F2, B4, B4a, G2al and M7bl’2’4, occurred before 10thousand years ago (kya).Agriculture began about lOkya in some parts of the Middle East, and later originated independently in some other parts of the world, such as Africa, East Asia and America. In East Asia, Neolithic Time is symbolized by Dadiwan Culture at7.9kya. Thus, former estimation of major East Asian lineage expansion predates the advent of Neolithic Time. Consistent to this observation, the further analysis showed that the population expansion in East Asia started at13kya and lasted until4kya, which is also before the time of agriculture origin. In addition,736mtDNA genomes in11populations in Africa, Europe and America were also investigated to find similar demographic expansion patterns as East Asian, i.e. population expansion before Neolithic Time. The results suggest that the population growth in the world constituted a need for the introduction of agriculture, and might be one of the driving forces that led to the further development of agriculture. |
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