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采用阵列比较基因组杂交技术分析拷贝数变异,在健康白人男性中鉴定出1284个新的基因变异:对复杂疾病关联研究的启示。

Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases.

作者信息

de Smith Adam J, Tsalenko Anya, Sampas Nick, Scheffer Alicia, Yamada N Alice, Tsang Peter, Ben-Dor Amir, Yakhini Zohar, Ellis Richard J, Bruhn Laurakay, Laderman Stephen, Froguel Philippe, Blakemore Alexandra I F

机构信息

Genomic Medicine, Imperial College, London, UK.

出版信息

Hum Mol Genet. 2007 Dec 1;16(23):2783-94. doi: 10.1093/hmg/ddm208. Epub 2007 Jul 31.

Abstract

The discovery of copy number variation in healthy individuals is far from complete, and owing to the resolution of detection systems used, the majority of loci reported so far are relatively large ( approximately 65%>10 kb). Applying a two-stage high-resolution array comparative genomic hybridization approach to analyse 50 healthy Caucasian males from northern France, we discovered 2208 copy number variants (CNVs) detected by more than one consecutive probe. These clustered into 1469 CNV regions (CNVRs), of which 721 are thought to be novel. The majority of these are small (median size 4.4 kb) and most have common boundaries, with a coefficient of variation less than 0.1 for 83% of endpoints in those observed in multiple samples. Only 6% of the CNVRs analysed showed evidence of both copy number losses and gains at the same site. A further 6089 variants were detected by single probes: 48% of these were observed in more than one individual. In total, 2570 genes were seen to intersect variants: 1284 in novel loci. Genes involved in differentiation and development were significantly over-represented and approximately half of the genes identified feature in the Online Mendelian Inheritance in Man database. The biological importance of many genes affected, along with the well-conserved nature of the majority of the CNVs, suggests that they could have important implications for phenotype and, thus, be useful for association studies of complex diseases.

摘要

在健康个体中对拷贝数变异的发现远未完成,并且由于所使用检测系统的分辨率,到目前为止报道的大多数基因座相对较大(约65%>10 kb)。应用两阶段高分辨率阵列比较基因组杂交方法分析来自法国北部的50名健康白种男性,我们发现了2208个由多个连续探针检测到的拷贝数变异(CNV)。这些变异聚集成1469个CNV区域(CNVR),其中721个被认为是新的。这些变异中的大多数都很小(中位大小为4.4 kb),并且大多数具有共同边界,在多个样本中观察到的那些变异的83%的端点变异系数小于0.1。在分析的CNVR中,只有6%在同一位置显示出拷贝数丢失和增加的证据。通过单探针又检测到6089个变异:其中48%在不止一个个体中观察到。总共发现2570个基因与变异相交:1284个在新基因座中。参与分化和发育的基因明显过度富集,并且所鉴定的基因中约有一半在《人类孟德尔遗传在线》数据库中有记录。许多受影响基因的生物学重要性,以及大多数CNV的高度保守性质,表明它们可能对表型具有重要影响,因此可用于复杂疾病的关联研究。

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