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22号染色体特异性低拷贝重复序列与22q11.2缺失综合征:基因组组织与缺失端点分析

Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis.

作者信息

Shaikh T H, Kurahashi H, Saitta S C, O'Hare A M, Hu P, Roe B A, Driscoll D A, McDonald-McGinn D M, Zackai E H, Budarf M L, Emanuel B S

机构信息

Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

出版信息

Hum Mol Genet. 2000 Mar 1;9(4):489-501. doi: 10.1093/hmg/9.4.489.

Abstract

The 22q11.2 deletion syndrome, which includes DiGeorge and velocardiofacial syndromes (DGS/VCFS), is the most common microdeletion syndrome. The majority of deleted patients share a common 3 Mb hemizygous deletion of 22q11.2. The remaining patients include those who have smaller deletions that are nested within the 3 Mb typically deleted region (TDR) and a few with rare deletions that have no overlap with the TDR. The identification of chromosome 22-specific duplicated sequences or low copy repeats (LCRs) near the end-points of the 3 Mb TDR has led to the hypothesis that they mediate deletions of 22q11.2. The entire 3 Mb TDR has been sequenced, permitting detailed investigation of the LCRs and their involvement in the 22q11.2 deletions. Sequence analysis has identified four LCRs within the 3 Mb TDR. Although the LCRs differ in content and organization of shared modules, those modules that are common between them share 97-98% sequence identity with one another. By fluorescence in situ hybridization (FISH) analysis, the end-points of four variant 22q11.2 deletions appear to localize to the LCRs. Pulsed-field gel electrophoresis and Southern hybridization have been used to identify rearranged junction fragments from three variant deletions. Analysis of junction fragments by PCR and sequencing of the PCR products implicate the LCRs directly in the formation of 22q11.2 deletions. The evolutionary origin of the duplications on chromosome 22 has been assessed by FISH analysis of non-human primates. Multiple signals in Old World monkeys suggest that the duplication events may have occurred at least 20-25 million years ago.

摘要

22q11.2缺失综合征,包括迪乔治综合征和腭心面综合征(DGS/VCFS),是最常见的微缺失综合征。大多数缺失患者在22q11.2区域存在一个共同的3 Mb半合子缺失。其余患者包括那些有较小缺失的个体,这些较小缺失嵌套在通常缺失的3 Mb区域(TDR)内,还有少数患者有罕见的与TDR无重叠的缺失。在3 Mb TDR端点附近发现的22号染色体特异性重复序列或低拷贝重复序列(LCR),引发了它们介导22q11.2缺失的假说。整个3 Mb TDR已被测序,这使得对LCR及其在22q11.2缺失中的作用进行详细研究成为可能。序列分析在3 Mb TDR内鉴定出了四个LCR。尽管这些LCR在共享模块的内容和组织上有所不同,但它们之间共有的那些模块彼此之间具有97 - 98%的序列同一性。通过荧光原位杂交(FISH)分析,四个变异的22q11.2缺失的端点似乎定位于LCR。脉冲场凝胶电泳和Southern杂交已被用于鉴定来自三个变异缺失的重排连接片段。通过PCR对连接片段进行分析以及对PCR产物进行测序,直接表明LCR参与了22q11.用于评估22号染色体上重复序列的进化起源。在旧世界猴中的FISH分析显示多个信号,这表明重复事件可能至少在2000万至2500万年前就已发生。

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