Department of Molecular, Baylor College of Medicine, Houston, Texas 77030, USA.
Annu Rev Med. 2010;61:437-55. doi: 10.1146/annurev-med-100708-204735.
During the last quarter of the twentieth century, our knowledge about human genetic variation was limited mainly to the heterochromatin polymorphisms, large enough to be visible in the light microscope, and the single nucleotide polymorphisms (SNPs) identified by traditional PCR-based DNA sequencing. In the past five years, the rapid development and expanded use of microarray technologies, including oligonucleotide array comparative genomic hybridization and SNP genotyping arrays, as well as next-generation sequencing with "paired-end" methods, has enabled a whole-genome analysis with essentially unlimited resolution. The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. It is now thought that CNVs encompass more total nucleotides and arise more frequently than SNPs. CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals, and a rapidly increasing number of traits or susceptibility to traits; such conditions have been referred to as genomic disorders. In addition to well-known sporadic chromosomal microdeletion syndromes and Mendelian diseases, many common complex traits including autism and schizophrenia can result from CNVs. Both recombination- and replication-based mechanisms for CNV formation have been described.
在二十世纪的最后四分之一时间里，我们对人类遗传变异的了解主要局限于在光镜下可见的大小足够大的异染色质多态性，以及通过传统基于 PCR 的 DNA 测序鉴定的单核苷酸多态性 (SNP)。在过去五年中，微阵列技术的快速发展和广泛应用，包括寡核苷酸微阵列比较基因组杂交和 SNP 基因分型微阵列，以及“末端配对”方法的下一代测序，使我们能够进行具有基本无限分辨率的全基因组分析。在我们的基因组中发现的亚微观拷贝数变异 (CNV) 极大地改变了我们对 DNA 结构变异和疾病的看法。现在认为，CNV 包含的总核苷酸数量更多，出现的频率也高于 SNP。与 SNP 相比，CNV 已被证明在更大程度上与人类进化、个体间遗传多样性以及越来越多的特征或对特征的易感性有关；这些情况被称为基因组疾病。除了众所周知的散发性染色体微缺失综合征和孟德尔疾病外，许多常见的复杂特征，包括自闭症和精神分裂症，都可能由 CNV 引起。已经描述了基于重组和复制的 CNV 形成机制。
