Exploration Of Genetic Adaptation At High Altitude And Insights From Tibetan Placental Gene Expression Profile

Genome-wide analysis of selection can provide unprecedented insight into the biological mechanisms of recent human evolution. In addition to answering long-standing questions in the field of high altitude research, such studies will enhance our understanding of the human response to hypoxia, which has broad reaching implications in medical research. Overall goal of this dissertation are 1) to detect the shared and unique signals of high altitude adaptation and phenotype association in distinct Tibetan populations further validate selection signals from previous reports; 2) to profile the global gene expression differences between high altitude Tibetan placenta and high altitude non-native population placenta to initiate the understanding toward Tibetan reproductive success at their native high altitude environment. 3) to investigate the ancestral structure, recent genetic admixture and selection regions on high altitude neighboring populationDU Mongolian, to highlight the high altitude environment as a selective stress toward population adaptation further form advantageous phenotype among population.Part I Shared and unique signals of high altitude adaptation and phenotype association in distinct Tibetan populationsRecent studies have used several different analytical methods to identify genes targeted by natural selection in high altitude populations located throughout the Tibetan Plateau. Despite differences in analytic strategies and populations’ samples, several hypoxia-related genes, including EPAS1 and EGLN1, were identified in multiple studies. By employing the same analytic strategies(i HS and XP-EHH statistics) used in our previous study of Tibetan high-altitude adaptation and through further comparison with a neighboring Mongolian population, we have identified common targets of natural selection in a second distinct Tibetan population from a different region of Tibetan Plateau. Our selection analysis provides evidence for adaptation in two Tibetan populations at the p<0.01 significance level for EPAS1, EGLN1, HMOX2, and CYP17A1 and p<0.02 for PKLR, HFE, and HBB and HBG2, which have been identified in other studies. By excluding the possibility of differences attributed to analytical methods and highlighting the relevance of admixture in studies of Tibetan populations, we suggest that sample location should be considered in replication studies of adaptation and phenotype association in Tibet. Part II Global gene expression profiling on high altitude TibetanHigh altitude hypoxia poses one of the greatest environmental threats to human survival. It has been well studied that such chronic hypoxic environment during pregnancy causes reduced birth weight, and an increased incidence of pregnancy complication, particularly in preeclampsia. Compared to lowland visitors Tibetan living at high altitude exhibit advanced phenotype such as greater birth weights, higher baby survival rate, lower Hb concentration at high altitude, which implicate the greater adaptation towards high altitude chronic hypoxia. Here we highlight the adaptations that serve to protect oxygenation and fetal growth under conditions of chronic hypoxia. So we hypothesized that in terms of reproductive success and protect the confounding effects of existing hypoxia related disease, Tibetans are adapted to have unique beneficial responses to chronic hypoxia during pregnancy. From the aspect of global gene expression profile, we performed gene expression microarray analysis to total 15 number of high altitude Tibetan placenta and 15 high altitude non-Tibetan placenta, out of 40183 target genes, we found 1382 genes were differentially expressed between two groups, in addition, we conducted GO enrichment analysis, classified the differentially expressed genes into different categories based on their biological functions. We observed that many hypoxia responsive genes are down regulated in Tibetan placenta, meanwhile ER Stress related genes and mitochondria stress related genes were down regulated in Tibetan placenta. Which indicate that High altitude Tibetan placentas do not appear hypoxically stressed compared with high altitude Caucasian placentas. It has been well studied that laboring can cause the ischemic/hypoxic stress to placenta, which can causes global gene expression differences and protein expression differences in placenta tissue. Interestingly, we did not find any gene expression differences between laboring and non-laboring placenta in high altitude Tibetan. Which implicate that Tibetan placentas appear to be protected from the ischemic/hypoxic stress induced by labor. Therefore from the global gene expression profile, high altitude Tibetan placenta appears to be protected from the impaired pregnancy at high altitude. Furthermore, more protein level study is necessary, as well as association study with selective genomic variants will be critical to understand the Tibetan high altitude adaptive traits and the underlying mechanisms which govern the beneficial effects. Part III Genomic Analysis of Natural Selection and Phenotypic Variation in High-Altitude MongoliansDeedu(DU) Mongolians, who migrated from the Mongolian steppes to the Qinghai-Tibetan Plateau approximately 500 years ago, are challenged by environmental conditions similar to native Tibetan highlanders. Identification of adaptive genetic factors in this population could provide insight into coordinated physiological responses to this environment. Here we examine genomic and phenotypic variation in this unique population and present the first complete analysis of a Mongolian whole-genome sequence. High-density SNP array data demonstrate that DU Mongolians share genetic ancestry with other Mongolian as well as Tibetan populations, specifically in genomic regions related with adaptation to high altitude. Several selection candidate genes identified in DU Mongolians are shared with other Asian groups(e.g., EDAR), neighboring Tibetan populations(including high-altitude candidates EPAS1, PKLR, and CYP2E1), as well as genes previously hypothesized to be associated with metabolic adaptation(e.g., PPARG). Hemoglobin concentration, a trait associated with high-altitude adaptation in Tibetans, is at an intermediate level in DU Mongolians compared to Tibetans and Han Chinese at comparable altitude. Whole-genome sequence from a DU Mongolian(Tianjiao1) shows that about 2% of the genomic variants, including more than 300 protein-coding changes, are specific to this individual. Our analyses of DU Mongolians and the first Mongolian genome provide valuable insight into genetic adaptation to extreme environments.