人类基因组中常见变异与罕见变异分布模式差异研究

Distribution patterns of common and rare variants in human genomes

目的探讨人类遗传变异中常见变异与罕见变异在基因组功能区域和基因区域分布模式的差异。方法根据国际千人基因组计划(1000 Genomes Project,1 KG)计算得到的次要等位基因频率把基因组变异位点分为常见变异和罕见变异;分析这两类变异在染色体、种族及基因组功能区域中的整体分布特征;分析致病性、性状相关和表达调控型3类功能性变异位点中这两类变异在基因组功能区域的分布差异;分析常见变异和罕见变异在基因区域分布密度的差异,并对密度分布排名前500位和后500位的基因进行本体(GO)的功能富集分析。结果这两类变异在基因组功能区域的分布特点基本一致,在基因组非编码区(内含子区和基因间区)分布最多。与基因组功能变异整体分布不同,致病性变异中这两类变异在基因组功能区域的分布模式差异具有显著性意义(χ~2=2503.74,P<0.001),罕见变异在外显子区和剪接位点处频率较高,常见变异在非编码区频率较高。性状相关和表达调控型变异中这两类变异在基因组功能区域上的分布比较类似,其中常见变异在编码区和非编码区的比例均高于罕见变异。此外,这两类变异在基因区域的密度分布模式也不相同。结论在致病性、性状相关和表达调控型3类功能性变异位点中,这两类变异在基因组功能区域和基因区域的分布模式均不相同。

Objective To investigate the difference in distribution patterns between common and rare variants in hu-man genomes across functional genomic regions and gene regions.Methods On the basis of the minor allele frequency generated by the 1000 Genomes Project(1 KG),the genomic variants were classified into common and rare variants.The distribution of these variants across different chromosomes,races and functional genomic regions was assessed.The differ-ences in distribution patterns between common and rare variants among pathogenic variants,trait-associated variants and expression regulatory variants were analyzed respectively.The differences in the distribution density between common and rare variants across the gene bodies were also analyzed.Gene ontology(GO)enrichment analysis was carried out for the top(bottom)500 genes with the highest(lowest)variant densities,respectively.Results The common and rare variants showed similar distribution patterns across functional genomic regions,mostly in noncoding genomic regions(intron and intergenic regions).Unlike the distribution of the whole variants,the distribution of common and rare variants in pathogen-ic variants was significantly different across genomic regions(χ~2=2503.74,P<0.001).Among the pathogenic variants,rare ones often occurred in exon and splice sites,while common ones often occurred in the non-coding region.Trait-associ-ated variants and expression regulatory variants mainly occurred in intron and intergenic regions,with high frequency of common variants in all the genomic regions.In addition,it was found that the densities of common and rare variants werealso distributed differently across protein-coding genes.Conclusion Common and rare variants in pathogenic,traits-asso-ciated and expression regulatory variants exhibit significantly different distribution patterns across functional genomic re-gions and gene regions.