基因组拷贝数变异及其突变机理与人类疾病

HEREDITAS (Beijing) 2011年8月, 33(8): 857―869 ISSN 0253-9772

综 述

收稿日期: 2011−04−07; 修回日期: 2011−06−03

基金项目:国家自然科学基金项目(编号: 30890034, 31000552), 教育部新世纪优秀人才支持计划项目(编号: NCET-09-0322)和上海市浦江人才

计划项目(编号: 10PJ1400300)资助

作者简介:杜仁骞, 在读博士研究生, 研究方向: 基因组拷贝数变异。E-mail: renqian.du@

通讯作者:张锋, 博士, 副教授, 博士生导师, 研究方向: 人类遗传学和医学遗传学。E-mail: feng.fudan@

DOI: 10.3724/SP.J.1005.2011.00857

基因组拷贝数变异及其突变机理与人类疾病

杜仁骞1,2, 金力1,2,3, 张锋1,2

1. 复旦大学生命科学学院现代人类学教育部重点实验室, 上海200433;

2. 复旦大学生命科学学院遗传工程国家重点实验室, 上海200433;

3. 复旦大学生物医学研究院, 上海200032

摘要: 拷贝数变异(Copy number variation, CNV)是由基因组发生重排而导致的, 一般指长度为1 kb 以上的基因

组大片段的拷贝数增加或者减少, 主要表现为亚显微水平的缺失和重复。CNV 是基因组结构变异(Structural variation, SV)的重要组成部分。CNV 位点的突变率远高于SNP(Single nucleotide polymorphism), 是人类疾病的重要致病因素之一。目前, 用来进行全基因组范围的CNV 研究的方法有: 基于芯片的比较基因组杂交技术(array-based comparative genomic hybridization, aCGH)、SNP 分型芯片技术和新一代测序技术。CNV 的形成机制有多种, 并可分为DNA 重组和DNA 错误复制两大类。CNV 可以导致呈孟德尔遗传的单基因病与罕见疾病, 同时与复杂疾病也相关。其致病的可能机制有基因剂量效应、基因断裂、基因融合和位置效应等。对CNV 的深入研究, 可以使我们对人类基因组的构成、个体间的遗传差异、以及遗传致病因素有新的认识。

关键词: 拷贝数变异; 突变机理; 疾病; 人类基因组

Copy number variations in the human genome: their mutational mechanisms and roles in diseases

DU Ren-Qian 1,2, JIN Li 1,2,3, ZHANG Feng 1,2

1. MOE Key Laboratory of Contemporary Anthropology , School of Life Sciences , Fudan University , Shanghai 200433, China ;

2. State Key Laboratory of Genetic Engineering , School of Life Sciences , Fudan University , Shanghai 200433, China ;

3. Institutes of Biomedical Sciences , Fudan University , Shanghai 200032, China

Abstract: Copy number variation (CNV) is the main type of structure variation (SV) caused by genomic rearrangement, which mainly includes deletion and duplication of sub-microscopic but large (>1 kb) genomic segments. CNV has been recognized as one of the main genetic factors underlying human diseases. The mutation rate (per locus) of CNV is much higher than that of single nucleotide polymorphism (SNP). The genome-wide assays for CNV study include array-based comparative genomic hybridization (aCGH), SNP genotyping microarrays, and next-generation sequencing techniques. Various molecular mechanisms are involved in CNV formation, which can be divided into two main categories, DNA re-combination-based and DNA replication-based mechanisms. CNVs can be associated with Mendelian diseases, sporadic diseases, and susceptibility to complex diseases. CNVs can convey clinical phenotypes by gene dosage, gene disruption, gene fusion, and position effects. Further studies on CNVs will shed new light on human genome structure, genetic varia-tions between individuals, and missing heritability of human diseases.

Keywords: copy number variation; mutational mechanism; diseases; human genome