Evolution of DNAase I Hypersensitive Sites in MHC Regulatory Regions of Primates

文献类型： 外文期刊

第一作者： Lu, Yueer

作者： Lu, Yueer;Ling, Fei;Jin, Yabin;Gittelman, Rachel M.;Akey, Joshua M.;Liu, Xiaohui;Li, Ming D.

作者机构：

关键词： positive selection; purifying selection; DNase I hypersensitive sites; major histocompatibility complex; primate genome; regulatory variation; GenPred; Shared Data Resources; Genomic Selection

期刊名称：GENETICS （ 影响因子：4.562； 五年影响因子：4.845 ）

ISSN： 0016-6731

年卷期： 2018 年 209 卷 2 期

页码：

收录情况： SCI

摘要： It has been challenging to determine the disease-causing variant(s) for most major histocompatibility complex (MHC)-associated diseases. However, it is becoming increasingly clear that regulatory variation is pervasive and a fundamentally important mechanism governing phenotypic diversity and disease susceptibility. We gathered DNase I data from 136 human cells to characterize the regulatory landscape of the MHC region, including 4867 DNase I hypersensitive sites (DHSs). We identified thousands of regulatory elements that have been gained or lost in the human or chimpanzee genomes since their evolutionary divergence. We compared alignments of the DHS across six primates and found 149 DHSs with convincing evidence of positive and/or purifying selection. Of these DHSs, compared to neutral sequences, 24 evolved rapidly in the human lineage. We identified 15 instances of transcription-factor-binding motif gains, such as USF, MYC, MAX, MAFK, STAT1, PBX3, etc., and observed 16 GWAS (genome-wide association study) SNPs associated with diseases within these 24 DHSs using FIMO (Find Individual Motif Occurrences) and UCSC (University of California, Santa Cruz) ChIP-seq data. Combining eQTL and Hi-C data, our results indicated that there were five SNPs located in human gains motifs affecting the corresponding gene's expression, two of which closely matched DHS target genes. In addition, a significant SNP, rs7756521, at genome-wide significant level likely affects DDR expression and represents a causal genetic variant for HIV-1 control. These results indicated that species-specific motif gains or losses of rapidly evolving DHSs in the primate genomes might play a role during adaptation evolution and provided some new evidence for a potentially causal role for these GWAS SNPs.

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