Positive Selection Analysis Of DHSs In The Regulatory Regions Of Brain Development-related Genes

A large number of genes in the modern population are selected by positive Darwinian selection,analysis of the evolutionary characteristics of these gene regulatory regions will provide important clues for the study of human evolution and various disease mechanisms.Positive selection has long been thought to be the driving force behind phenotypic distinctions between humans and the chimpanzees.Accelerated evolution of regulatory sequence can alter the expression pattern of targetgenes,and cause phenotypic changes,but regulatory DNA has been much more difficult to study compared to protein-coding regions.DNaseI hypersensitive sites(DHSs)is just the mark of regulation DN A and all known cis-acting elements(enhancer,promoter,insulator,silencer and locus control region)coupled with DHSs.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 DHSs data are generated and the DHSs map has been incorporated into the ENCODE project and Roadmap Epigenomics Project.In this study,based on the DHSs database and functional genomics database,we use bioinformatics methods to analyze the distribution of DHSs in the regulatory region of Human brain development-related genes,then we find the evidences of selection and analyze their function.The results of our study are as follows:(1)A total of 243 genes related to brain development were obtained from GO term,184,113 DHSs were identified in the regulatory regions of brain development-related genes,After several filtering steps,we selected a total number of 3,538 DHSs for investigation.Working under the assumption that local ancient repeat elements(AREs)of DHSs are under neutral evolution,we discovered that 6.197%(2,425)of DHSs are under accelerated evolution(ace DHSs).Our results suggest that the regulatory region of brain development-related genes is more strongly selected than the other regions of the genome.(2)Compared with background DHSs,we found that ace DHSs are significantly enriched in non-coding regions(intergenic and intron regions),and the numbers of ace DHS in the coding region(exon region)are significantly less than the background DHS s.Our results suggest that the gene coding region is relatively conserved in evolution while the regulation of aceDHSs in noncoding regions(intron regions)is more likely to played an important role in the brain development and species evolution.(3)Most of the target genes regulated by ace DHSs have a higher expression level in brain tissue,and 38 target genes are enriched in the GO process related to brain development in brain function.Indicating that ace DHSs played a certain role in the regulating of brain development.(4)We identified 48 instances of transcription factor binding motif gains within theses DHSs,including many transcription factors such as USF1,USF2,SP1,MNX1,FOXQ1,RREB1,KLF5,and found these transcription factors play an important role in the development of the brain and nervous system and are associated with a variety of brain diseases.(5)In the study,108 GWAS SNPs associated with disease or other traits were observed in the DHSs of the the regulatory regions of brain development-related genes,providing evidence for a potentially causal role for these SNPs.