3D genome organization links non-coding disease-associated variants to genes.
3D genome organization links non-coding disease-associated variants to genes.
复制标题
DOI：
10.3389/fcell.2022.995388
复制
发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
基因组测序已经揭示了人类群体中超过3亿的遗传变异。超过90%的变异是单核苷酸多态性（SNP），其余的包括短缺失或插入，以及少量的结构变异。通过全基因组关联研究，成千上万的这些变体与特定的表型性状和疾病相关，该研究将变体频率的显著差异与大群体个体中的特定表型联系起来。只有5%的疾病相关SNP位于基因编码序列中，有可能破坏基因表达或改变编码蛋白质的功能。其余95%的疾病相关SNP位于非编码DNA序列中，占基因组的98%。非编码的、疾病相关的SNP的作用，其中许多位于与任何基因相当远的距离，起初是一个谜，直到发现基因启动子定期与远端调控元件相互作用以控制基因表达。疾病相关的SNP在分布于基因组的非编码序列中的数百万个基因调控元件中富集，表明它们作为基因调控变体发挥作用。它们控制的基因的特异性调控元件并不简单，因为它们可以相隔数百万个碱基对。在这篇综述中，我们描述了如何理解3D基因组组织可以识别基因启动子和远端调控元件之间的特定相互作用，以及3D基因组学如何将疾病相关的SNP与其靶基因联系起来。了解哪些基因或基因导致特定疾病是设计合理治疗干预措施的第一步。
Genome sequencing has revealed over 300 million genetic variations in human populations. Over 90% of variants are single nucleotide polymorphisms (SNPs), the remainder include short deletions or insertions, and small numbers of structural variants. Hundreds of thousands of these variants have been associated with specific phenotypic traits and diseases through genome wide association studies which link significant differences in variant frequencies with specific phenotypes among large groups of individuals. Only 5% of disease-associated SNPs are located in gene coding sequences, with the potential to disrupt gene expression or alter of the function of encoded proteins. The remaining 95% of disease-associated SNPs are located in non-coding DNA sequences which make up 98% of the genome. The role of non-coding, disease-associated SNPs, many of which are located at considerable distances from any gene, was at first a mystery until the discovery that gene promoters regularly interact with distal regulatory elements to control gene expression. Disease-associated SNPs are enriched at the millions of gene regulatory elements that are dispersed throughout the non-coding sequences of the genome, suggesting they function as gene regulation variants. Assigning specific regulatory elements to the genes they control is not straightforward since they can be millions of base pairs apart. In this review we describe how understanding 3D genome organization can identify specific interactions between gene promoters and distal regulatory elements and how 3D genomics can link disease-associated SNPs to their target genes. Understanding which gene or genes contribute to a specific disease is the first step in designing rational therapeutic interventions.
登录
查看更多内容
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
64.8
作者：
Boix CA;James BT;Park YP;Meuleman W;Kellis M
通讯作者：
Kellis M
影响因子：
12.3
作者：
Burren OS;Rubio García A;Javierre BM;Rainbow DB;Cairns J;Cooper NJ;Lambourne JJ;Schofield E;Castro Dopico X;Ferreira RC;Coulson R;Burden F;Rowlston SP;Downes K;Wingett SW;Frontini M;Ouwehand WH;Fraser P;Spivakov M;Todd JA;Wicker LS;Cutler AJ;Wallace C
通讯作者：
Wallace C
影响因子：
3.7
作者：
Aljogol D;Thompson IR;Osborne CS;Mifsud B
通讯作者：
Mifsud B
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen