Analysis Of Potential Function SNPs In The 1000 Genomes Project With CTCF Associated Chromatin Organization

As development of new technology,our knowledge about chromatin architecture has been updated.The classical chromosome(chromatin in mitotic phase is called chromosome)structure can be described as follow,chromosome is basically formed by 10 nm fiber that consist of DNA and histone and it is further compressed to 30nm fiber,300nm fiber and 700nm fiber,which condense 2m DNA to a tiny nucleus.With application of 3C-based approaches in the last decade,another model has been proposed.Based on 10nm fiber,hierarchical structures of chromatin are enhancer-promoter loops,TADs,compartments and chromatin territory.These new aspects of chromatin structure play key roles in development and diseases,mediating by disrupt of enhancer-promoter loops and TADs.As one architectural factor that enriched in TAD and sub-TAD boundaries,CTCF can disrupt normal chromatin structure and regulate gene expression through DNA mutation within its binding motifs.This mechanism plays a key role in genetic diseases and cancers induced by rare mutations.Yet we still know little about its relationship with common mutations like population genetic diversity sites.In the meantime,fast development of sequencing technique accelerated accomplishment of the 1000 Genomes Project(1kG).These multiple populations'genome data promoted progress of human genetic diversity associated researches.For example,genes under selection are related to phenotypes like skin colors,lactose tolerance and malaria tolerance in different populations.But these researches focused on selection signals of mutations within coding region,leaving majority of mutations within non-coding region behind.Therefore,our research aims at exploring the contribution of non-coding mutation on human genetic diversity.Based on the new gene regulation mechanism conducted by CTCF and chromatin loops,our work aims at digging hidden genetic information in non-coding regions of human genome through 1kG data.First,3100 SNPs located in CTCF binding motif were filtered.Within them,54 population-specific SNPs co-locate with known chromatin loop boundaries,indicative of functional potential.And through 3-dimensinoal chromatin structure associated gene annotation,100 genes were annotated to these 54 SNPs.Especially,12 SNPs of them significantly change expression of its 20 annotated genes.Finally,4 SNP-gene pairs with known gene function are highlighted:rs876934-WDR66,rs12235009-EXTL3,rs9471058-KCNK17,rs897804-PRDX2.Their functions are associated with sperm flagellum,immune and skeleton development,sperm number and oxidation resistance of red cells respectively.Reproduction and immune development are known target for positive selection in human population differentiation,indicating that CTCF and chromatin structure may play a role in population differentiation and adaption after "out of Africa" event.Our work,for the first time,found that common SNPs can disrupt CTCF binding and chromatin structure,underlining the universality of CTCF and chromatin structure on gene regulation.Our research also provides clues for exploring role of chromatin structure on evolution.