一项新的研究发现，单个基因拷贝数的不同对正常人之间的遗传不同有大的影响。科学家已经知道人类遗传的变异在很大程度上是与基因的复制和删节有关。但是，由于没有针对在整个基因组扫描这种拷贝数多态性(copy number polymorphisms，简称CNPs)的技术，人们对CNPs对人类遗传多样性程度的影响所知甚少。Jonathan Sebat和同事用代表性寡核苷酸微阵列分析(简称ROMA)产生了一个拷贝数差异的图谱。这个图显示出CNPs很常见，而且在人类基因组中广泛分布。作者观察到了70各不同基因的拷贝数变化，这些基因与神经功能、细胞生长的调节、以及心陈代谢有关，还有的基因与某些疾病有关。
Large-Scale Copy Number Polymorphism in the Human Genome
The extent to which large duplications and deletions contribute to human genetic variation and diversity is unknown. Here, we show that large-scale copy number polymorphisms (CNPs) (about 100 kilobases and greater) contribute substantially to genomic variation between normal humans. Representational oligonucleotide microarray analysis of 20 individuals revealed a total of 221 copy number differences representing 76 unique CNPs. On average, individuals differed by 11 CNPs, and the average length of a CNP interval was 465 kilobases. We observed copy number variation of 70 different genes within CNP intervals, including genes involved in neurological function, regulation of cell growth, regulation of metabolism, and several genes known to be associated with disease.
Fig. 1. Genome-wide map of CNPs identified by ROMA. The position of all CNPs (excluding somatic differences) is shown. CNPs identified in multiple individuals (by Bgl II–ROMA) are indicated in yellow, and CNPs observed in only one individual are indicated in red. Additional CNPs identified by one Hind III–ROMA experiment are indicated in blue. Symbols denoting CNPs are not drawn to scale. Genome assembly gaps in pericentromeric and satellite regions are indicated by gray boxes. Genomic regions where recurring de novo rearrangements cause the developmental disorders Prader-Willi and Angelman syndromes, cat eye syndrome, DiGeorge/velocardiofacial syndrome, and spinal muscular atrophy are labeled A, B, C, and D, respectively.
Fig. 2. Validation of ROMA results by FISH. (A), (C), (E), and (G) show CNPs identified by ROMA and include the CNP identification number, the name of one gene located entirely within the interval, and the experiment name. (B), (D), (F), (H), and (I) show cytogenetic analyses of one or both individuals with probes that target the same CNP intervals. In all panels, the polymorphic probe is labeled red. In interphase cells [(B), (D), and (F)], a control probe (labeled green) was also included to confirm that cells were diploid. (B) CNP15 probe in GM11322 cells; (D) CNP56 probe in GM10470 cells; (F) CNP21 probe in GM10470 cells; (H) CNP32 probe in GM10540 cells; (I) CNP32 probe in SKN1 cells. In (I), one parental copy of chromosome 16 in SKN1 lacks the duplication (arrow).
