Mechanism of Alu integration into the human genome.

IF 3.5 Q1 EDUCATION & EDUCATIONAL RESEARCH
Genomic medicine Pub Date : 2007-01-01 Epub Date: 2007-03-28 DOI:10.1007/s11568-007-9002-9
Jian-Min Chen, Claude Férec, David N Cooper
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引用次数: 18

Abstract

LINE-1 or L1 has driven the generation of at least 10% of the human genome by mobilising Alu sequences. Although there is no doubt that Alu insertion is initiated by L1-dependent target site-primed reverse transcription, the mechanism by which the newly synthesised 3' end of a given Alu cDNA attaches to the target genomic DNA is less well understood. Intrigued by observations made on 28 pathological simple Alu insertions, we have sought to ascertain whether microhomologies could have played a role in the integration of shorter Alu sequences into the human genome. A meta-analysis of the 1624 Alu insertion polymorphisms deposited in the Database of Retrotransposon Insertion Polymorphisms in Humans (dbRIP), when considered together with a re-evaluation of the mechanism underlying how the three previously annotated large deletion-associated short pathological Alu inserts were generated, enabled us to present a unifying model for Alu insertion into the human genome. Since Alu elements are comparatively short, L1 RT is usually able to complete nascent Alu cDNA strand synthesis leading to the generation of full-length Alu inserts. However, the synthesis of the nascent Alu cDNA strand may be terminated prematurely if its 3' end anneals to the 3' terminal of the top strand's 5' overhang by means of microhomology-mediated mispairing, an event which would often lead to the formation of significantly truncated Alu inserts. Furthermore, the nascent Alu cDNA strand may be 'hijacked' to patch existing double strand breaks located in the top-strand's upstream regions, leading to the generation of large genomic deletions.

Alu整合到人类基因组的机制。
通过调动Alu序列,LINE-1或L1驱动了至少10%的人类基因组的产生。尽管毫无疑问,Alu插入是由l1依赖的靶点引物逆转录启动的,但新合成的Alu cDNA的3'端附着到目标基因组DNA的机制尚不清楚。通过对28个病理性简单Alu插入的观察,我们试图确定微同源性是否可能在较短的Alu序列整合到人类基因组中发挥作用。对人类反转录转座子插入多态性数据库(dbRIP)中的1624个Alu插入多态性进行荟萃分析,并重新评估先前注释的三个与缺失相关的短病理性Alu插入的产生机制,使我们能够提出一个统一的Alu插入到人类基因组中的模型。由于Alu元件相对较短,因此L1 RT通常能够完成新生Alu cDNA链的合成,从而产生全长Alu插入物。然而,如果新生的Alu cDNA链的3'端由于微同源介导的错配对而向顶端链5'悬垂的3'端靠近,则其合成可能会过早终止,这一事件通常会导致Alu插入体明显截断。此外,新生的Alu cDNA链可能被“劫持”,以修补位于顶部链上游区域的现有双链断裂,导致大量基因组缺失的产生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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