Germline Chromothripsis Driven by L1‐Mediated Retrotransposition and Alu/Alu Homologous Recombination
Germline Chromothripsis Driven by L1‐Mediated Retrotransposition and Alu/Alu Homologous Recombination
复制标题
L1 介导的逆转录转座和 Alu/Alu 同源重组驱动的种系染色体碎裂
作者：
Lusine Nazaryan;B. Bertelsen;M. Bak;L. Jønson;N. Tommerup;Dustin C. Hancks;Z. Tümer
染色体断裂（CTH）是一种多个局部双链DNA断裂导致复杂基因组重排的现象。虽然CTH中涉及的DNA修复机制已经被描述，但驱动局部“破碎”过程的机制仍不清楚。对家族性种系CTH的高通量序列分析显示，插入的SVAE逆转录转座子与110 kb缺失相关，显示L1介导的逆转录转座的标志。我们的分析表明，SVAE插入不是发生在CTH事件之前或之后，而是与CTH事件同时发生。我们还在其他断点中观察到L1内切核酸酶的潜在靶位点。此外，我们发现了4个Alu元件位于110 kb缺失的侧翼，并与倒位相关。我们认为，由同源Alu元件介导的染色质成环可能使远端DNA区域非常接近，从而促进催化活性L1内切核酸酶对DNA的切割。我们的数据提供了第一个证据表明，活跃和不活跃的人类反转录转座子可以作为内源性诱变剂驱动CTH的生殖系。
Chromothripsis (CTH) is a phenomenon where multiple localized double‐stranded DNA breaks result in complex genomic rearrangements. Although the DNA‐repair mechanisms involved in CTH have been described, the mechanisms driving the localized “shattering” process remain unclear. High‐throughput sequence analysis of a familial germline CTH revealed an inserted SVAE retrotransposon associated with a 110‐kb deletion displaying hallmarks of L1‐mediated retrotransposition. Our analysis suggests that the SVAE insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1‐endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110‐kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1‐endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline.
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DOI：
10.1016/j.tig.2008.08.007
发表时间：
2008-11
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
McVey M;Lee SE
通讯作者：
Lee SE
影响因子：
3.5
作者：
Deepa Srikanta;S. Sen;Erin M. Conlin;M. Batzer
通讯作者：
Deepa Srikanta;S. Sen;Erin M. Conlin;M. Batzer
影响因子：
4
作者：
Hancks, Dustin C.;Kazazian, Haig H., Jr.
通讯作者：
Kazazian, Haig H., Jr.
对人类 LINE-1 和 Alu 逆转录转座子 5 连接的分析表明，需要微同源介导的末端连接的 5 末端附着的替代模型。
影响因子：
7
作者：
Zingler,Nora;Willhoeft,Ute;Brose,Hans-Peter;Schoder,Volker;Jahns,Thomas;Hanschmann,Kay-MartinO;Morrish,TammyA;Lower,Johannes;Schumann,GeraldG
通讯作者：
Schumann,GeraldG
影响因子：
12.3
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
通讯作者：
Kehrer-Sawatzki H