McCarroll Steven A, Altshuler David M
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Nat Genet. 2007 Jul;39(7 Suppl):S37-42. doi: 10.1038/ng2080.
The central goal of human genetics is to understand the inherited basis of human variation in phenotypes, elucidating human physiology, evolution and disease. Rare mutations have been found underlying two thousand mendelian diseases; more recently, it has become possible to assess systematically the contribution of common SNPs to complex disease. The known role of copy-number alterations in sporadic genomic disorders, combined with emerging information about inherited copy-number variation, indicate the importance of systematically assessing copy-number variants (CNVs), including common copy-number polymorphisms (CNPs), in disease. Here we discuss evidence that CNVs affect phenotypes, directions for basic knowledge to support clinical study of CNVs, the challenge of genotyping CNPs in clinical cohorts, the use of SNPs as markers for CNPs and statistical challenges in testing CNVs for association with disease. Critical needs are high-resolution maps of common CNPs and techniques that accurately determine the allelic state of affected individuals.
人类遗传学的核心目标是了解人类表型变异的遗传基础，阐明人类生理学、进化和疾病。已发现罕见突变是两千种孟德尔疾病的潜在病因；最近，系统评估常见单核苷酸多态性（SNP）对复杂疾病的贡献已成为可能。拷贝数改变在散发性基因组疾病中的已知作用，再加上有关遗传性拷贝数变异的新信息，表明在疾病研究中系统评估拷贝数变异（CNV），包括常见拷贝数多态性（CNP）的重要性。在此，我们讨论CNV影响表型的证据、支持CNV临床研究的基础知识方向、临床队列中CNP基因分型的挑战、使用SNP作为CNP的标记以及检测CNV与疾病关联的统计挑战。关键需求是常见CNP的高分辨率图谱以及准确确定受影响个体等位基因状态的技术。
