Positive Selection Of DHSs In TRIM Family Regulatory Region

Viral selection pressure has acted on restriction factors that play an important role in the innate immune system by inhibiting the replication of viruses during primate evolution.Tripartite motif-containing(TRIM)family members are some of these restriction factors.It is well known that the TRIM superfamily is emerging as a central component of the innate antiviral immunity of primates.Previous studies have shown that evolutionary signatures of positive selective of TRIM multigene family often detected in gene coding region,especially at the interaction interface of host-virus.However,it is becoming increasingly clear that gene expression differences,rather than protein-coding regions changes,could play an important role in anti-retroviral immune mechanism.For instance,some viruses employ strategies to downregulate TRIM gene expression to escape immune surveillance.The best example of this is increasing the level of TRIM15 expression can enhance HIV(Human Immunodeficiency Virus)release.Genome-wide DNase I hypersensitive sites(DHS)mark different kinds of active regulatory elements,such as promoter,enhancer,silencer,insulator,in addition,according to data of GWAS,SNP and DNase I hypersensitive sites,it is shown that those DNA mutations which are relative to diseases,gather at non-coding regulatory region within human genome.Therefore DHS is one of the best objects to study non-coding regions within genome.To improve our understanding of the molecular evolution mechanism of antiviral differences between human and other relative primates species,in this study,according to the DHS data published by Duke University,ENCONDE(Encyclopedia of DNA Elements)and Human Epigenome Project(HEP),we obtained DHS data from 145 cell types,and then gained the EPO 6 primates(human,chimp,macaque,orangutan,gorilla,marmoset)corresponding alignment from Ensembl.As a result,we filter out 14130 DHS that located at regulatory region of TRIM family and we performed a comprehensively analysis on these DHSs to figure out their evolution characteristic and function.The analysis results are shown below:(1)On the basis of neutral evolution model,we performed a positive selection and/or purifying selection analysis on 14130 DHS.225 DHSs were significantly accelerated across all 6 primates;3109 DHSs were conserved across all 6 primates;826 DHSs were evolved rapidly in the human lineage and 4401 DHSs were conserved across all 5 primates except human.375 DHS are significantly accelerated in human lineage and conversed in other nonhuman primates,which defined as haDHS(human accelerated DHS).These could be the molecular evidence of "selection pressure drives the evolution of primates' TRIM region".(2)According to DHS-target gene data from University of Washington,we identified the target genes of these haDHS including TRIM6?TRIM8?TRIM11?TRIM13?TRIM14?TRIM23?TRIM55?TRIM68.These host limited factors of TRIM family play an important role in process of virus infection and interact with virus.(3)At the same time,we detected 31 potential and human-specific transcription factor binding sites within haDHS,including 18 transcription factors(MAZR,TBR2,OCT1,E2F1,AP2,TGIF,MZF1,CREB,NFAT,E47,Ets1,ELF1,FLI1,IRF,Oct4,FOXJ2)that interact with virus.These results demonstrate that haDHS located in regulatory region of TRIM family may contribute to the antiviral response difference between human and nonhuman primates.(4)We founda haDHS that located in chromosome 5(64919033-649214136).This haDHS's target gene was TRIM23,and it contained KROX,SP1,MAZR human-specific transcription factor binding sites,these transcription factors can both interact with virus.This suggested that these transcription factors may be relative to antiviral gene TRIM23 during the antiviral process,therefore leaded to the virus resistance differences between human and non-human primates.These results suggested that some viruses may contribute,through regulatory DNA differences,to organismal evolution by mediating TRIM gene expression to escape immune surveillance.These results provided us with some clues to the molecular level of cross-species phenotypic differences,especially the antiviral differences among primates.