Analysis Of DHSs In MHC Regulatory Region In Primate Genomes

Major histocompatibility complex(MHC)is a gene cluster which encode major histocompatibility antigens.The protein molecules encode bt the genes of MHC family(MHC-?,MHC-?,MHC-?)express on the surface of cells and mainly involved in the antigen presented,immune response and recognition between cells.Due to the biological characteristics of MHC,this region is correlated with more diseases and traits than other region.Based on the genetics,it has been difficult to clearly determine the disease-causing variant(s)for most major histocompatibility complex(MHC)associated diseases and what drives MHC polymorphism.However,it is becoming increasingly clear that structural variation alone cannot fully account for disease associations in the MHC region and there is increasing interest in the regulation DNA which affect the phenotypic diversity and disease susceptibility.DNaseI hypersensitive site(DHS)is just the mark of regulation DNA and all known cis-acting elements(enhancer,promoter,insulator,silencer and locus control region)coupled with DHS.At present,the DNase I assay has proven to be a highly successful and extensively validated methodology for discovery of in vivo regulatory sequences in complex genomes and has been widely used in research.So a lot of DHS data are generated and the DHS map has been incorporated into the ENCODE project and Roadmap Epigenomics Project.In this study,based on the DHS database and functional genomics database,we use bioinformatics methods to analyze the distribution of DHS in primates' MHC region,then we find the evidences of selection and analyze their function.The results of our study are as follows:(1)We leveraged DNaseI data from 136 human cell lines in ENCODE project to characterize the regulatory landscape of human's MHC region,4867 DHSs are found,revealing the distribution of DHSs in human's MHC region.(2)We found 1885,2507,and 1736 DHSs in human,chimpanzee,and macaque fibroblasts,respectively.We identify thousands of regulatory elements that have been gained or lost in the human or chimpanzee genomes since their evolutionary divergence.Our results show that the distances of common DHSs to the nearest gene were closer than the species-specific DHSs,which suggest that the common DHSs maight be relatively conserved and modulate the shared traits among species.(3)We compared alignments of the DHS across six primates and found the DHSs with clear evidence of positive and/or purifying selection.Of these DHSs,compared to neutral sequence,1 was accelerated across all 6 primates,127 were conserved across all 6 primates,139 were conserved across all 5 primates except human,and 24 evolved rapidly in the human lineage.These could be the molecular evidence of "selection pressure drives the evolution of primates' MHC region".(4)We identified nine instances of transcription factor binding motif gains within theses 24 DHSs,including factors involved in reproductive fitness(SOX9,OLF1,ER,and SP3),cancer(HICI,GATA1,and TP53),and brain development(GLI3 and BEN).These results suggest that in addition to host-pathogen interactions and reproductive fitness,processes such as brain development and cognitive abilities may underlie the exceptional selection pressure on the MHC region,enabling novel insight into MHC function.(5)In the study,141 GWAS SNPs associated with disease or other traits were observed in the DHSs of the MHC region,providing evidence for a potentially causal role for these SNPs.