Adaptive Selection Of Hypoxic Gene EP300 And It's Genetic Contribution To Adaptation To High Altitude Hypoxia In

The Qinghai-Tibet Plateau is one of the most extreme environments of human habitation,the Tibetans are well adapted to the extreme environment under long-term Darwinian selection,which is a process of multi-gene interaction involved several candidate genes.In this study,we conducted resequencing of a 108.83 kb region in 80 unrelated Tibetans,and then the allele-frequency and haplotype-based neutrality tests,Functional prediction,genetic association,with a group of variants showing allelic divergence between Tibetans and lowland reference populations including Han Chinese,Europeans and Africans.The SNPs of the EP300 gene were identified by reference to the 1000 genome,After the quality control,185 SNPs were obtained.The allele-frequency and haplotype-based neutrality tests detected signals of Darwinian positive selection on EP300(histone acetyltransferase p300)showed that there were 34 SNP loci FST greater than the whole genome mean divergence(0.03),XPEHH> 2,indicating that EP300 was selected by Darwin?Functional enrichment analysis of the candidate variants was performed using CADD database(Combined Annotation Dependent Depletion).We chose 149 candidate variants,and then performed functional prediction based on sequence conservation(GERP),transcription factor binding sites(TFBS),splicing motif,H3K4Me1/H3K4Me3 sites and DNAase-I hypersensitive sites.There were most of them are non-coding variants except for 2 synonymous variants,14 variants showing conserved sequences across species(GREP++ >5.0),an implication of functional constraint.In addition,multiple variants are located in the H3K4Me1/H3K4Me3 sites,suggesting their potential involvement in histone modification and chromosome remodeling as well as enhancer or promoter activities.Indicating that they promoter activity.we performed EP300 e QTL analysis,and we found that three of the six tag SNPs(rs2076578,rs5758251 and rs2143694)in our study showed significant association with the expression level of EP300 in blood(P value are 1.64×10-54,3.63×10-54 and 3.26×10-54,respectively).The results also prove that these variants in EP300 play a potential function in Tibetan hypoxia adaptation.The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of Collectively,we propose that EP300 harbors adaptive variants in Tibetans,which may contribute to high altitude adaptation through regulating blood NO production.