SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints.
SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints.
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DOI：
10.1186/gb-2014-15-6-r80
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发表时间：
2014-06-02
期刊：
影响因子：
12.3
通讯作者：
Kehrer-Sawatzki H
中科院分区：
文献类型：
--
作者：
Vogt J;Bengesser K;Claes KB;Wimmer K;Mautner VF;van Minkelen R;Legius E;Brems H;Upadhyaya M;Högel J;Lazaro C;Rosenbaum T;Bammert S;Messiaen L;Cooper DN;Kehrer-Sawatzki H
基因组疾病是由拷贝数变化引起的，这些变化可能表现出由非等位基因同源重组处理的复发性断点。然而，也观察到区域特异性疾病相关的拷贝数变化，其表现出非复发性断点。这些非经常性拷贝数变化的机制尚未完全阐明。我们分析了具有非复发性断点的大NF 1缺失作为模型，以研究致病机制的全谱，并观察到它们由各种DNA双链断裂修复机制以及异常复制介导。此外，在无关患者中鉴定的17个具有非复发性断点的NF 1缺失中的两个与在缺失断点处伴随插入SINE/可变数目串联重复序列/Alu（SVA）逆转录转座子相关。相应的断点难以通过标准断点跨越PCR进行分析，并且仅通过设计用于扩增富含GC的序列的优化PCR方案来鉴定。在这两个患者的SUZ 12 P内含子8内整合的SVA元素，并介导的靶启动逆转录SVA mRNA中间体来自反转录活性源元件。这两个SVA插入发生在早期的合子后发育，是唯一相关的1 Mb和867 kb的大缺失，分别在插入位点。由于活性SVA元件在人类基因组中是丰富的，并且许多SVA源元件的逆转录转座活性是高的，因此包含数百个转座酶的SVA插入相关的大基因组缺失可能构成了人类基因组中大规模拷贝数变化的潜在的新的且尚未被充分认识的机制。
Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non-recurrent copy number changes have not yet been fully elucidated. We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites. Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome.
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影响因子：
14.9
作者：
Belancio VP;Roy-Engel AM;Pochampally RR;Deininger P
通讯作者：
Deininger P
影响因子：
3.9
作者：
Cooper, David N.;Bacolla, Albino;Ferec, Claude;Vasquez, Karen M.;Kehrer-Sawatzki, Hildegard;Chen, Jian-Min
通讯作者：
Chen, Jian-Min
影响因子：
4
作者：
Hancks, Dustin C.;Kazazian, Haig H., Jr.
通讯作者：
Kazazian, Haig H., Jr.
影响因子：
2.8
作者：
Bantysh, O. B.;Buzdin, A. A.
通讯作者：
Buzdin, A. A.
影响因子：
64.5
作者：
Gilbert, N;Lutz-Prigge, S;Moran, JV
通讯作者：
Moran, JV