Active Alu retrotransposons in the human genome
Active Alu retrotransposons in the human genome
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DOI：
10.1101/gr.081737.108
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发表时间：
2008-12-01
期刊：
影响因子：
7
通讯作者：
Devine, Scott E.
中科院分区：
文献类型：
--
作者：
Bennett, E. Andrew;Keller, Heiko;Devine, Scott E.
Alu逆转录转座子类似于6500万年前从7SL RNA进化而来，并在灵长类基因组中经历了几轮大规模扩增。因此，人类基因组目前拥有110万个Alu拷贝。这些拷贝中的一些保持活跃的移动的，并通过“跳跃”到新的基因组位置继续产生遗传变异和疾病。然而，目前还不清楚人类基因组中存在多少活跃的Alu拷贝，以及哪些Alu亚家族拥有这样的拷贝。在这里，我们提出了一个全面的功能分析Alu拷贝在整个人类基因组。我们从各种基因组位置克隆了Alu拷贝，并在基于质粒的动员测定中测试了这些拷贝。我们发现，功能完整的核心Alu元件是非常丰富的，远远超过所有其他活跃的转座子在人类。一系列的Alu血统被发现藏有这样的副本，包括所有现代的Alu Y亚科和大多数Alu S亚科。我们还确定了Alu活性的两个主要决定因素：（1）给定Alu拷贝的一级序列，以及（2）编码RNA与SRP 9/14相互作用形成RNA/蛋白质（RNP）复合物的能力。我们的结论是，Alu元件构成最大的转座子为基础的诱变威胁人类基因组。在我们的数据的基础上，我们已经开始识别可能在人类中产生遗传变异和疾病的Alu拷贝。
Alu retrotransposons evolved from 7SL RNA similar to 65 million years ago and underwent several rounds of massive expansion in primate genomes. Consequently, the human genome currently harbors 1.1 million Alu copies. Some of these copies remain actively mobile and continue to produce both genetic variation and diseases by "jumping" to new genomic locations. However, it is unclear how many active Alu copies exist in the human genome and which Alu subfamilies harbor such copies. Here, we present a comprehensive functional analysis of Alu copies across the human genome. We cloned Alu copies from a variety of genomic locations and tested these copies in a plasmid-based mobilization assay. We show that functionally intact core Alu elements are highly abundant and far outnumber all other active transposons in humans. A range of Alu lineages were found to harbor such copies, including all modern AluY subfamilies and most AluS subfamilies. We also identified two major determinants of Alu activity: ( 1) The primary sequence of a given Alu copy, and ( 2) the ability of the encoded RNA to interact with SRP9/14 to form RNA/protein ( RNP) complexes. We conclude that Alu elements pose the largest transposon-based mutagenic threat to the human genome. On the basis of our data, we have begun to identify Alu copies that are likely to produce genetic variation and diseases in humans.