Somatic retrotransposition alters the genetic landscape of the human brain.
Somatic retrotransposition alters the genetic landscape of the human brain.
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DOI：
10.1038/nature10531
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发表时间：
2011-10-30
期刊：
影响因子：
64.8
通讯作者：
Faulkner, Geoffrey J.
中科院分区：
文献类型：
--
作者：
Baillie, J. Kenneth;Barnett, Mark W.;Upton, Kyle R.;Gerhardt, Daniel J.;Richmond, Todd A.;De Sapio, Fioravante;Brennan, Paul;Rizzu, Patrizia;Smith, Sarah;Fell, Mark;Talbot, Richard T.;Gustincich, Stefano;Freeman, Thomas C.;Mattick, John S.;Hume, David A.;Heutink, Peter;Carninci, Piero;Jeddeloh, Jeffrey A.;Faulkner, Geoffrey J.
反转录转座子是移动的遗传元件，其采用生殖系“复制和粘贴”机制在后生动物基因组中传播。至少50%的人类基因组来源于反转录转座子，其中三个活跃的家族（L1，Alu和SVA）与插入突变和疾病有关。表观遗传和转录后抑制阻断体细胞的逆转录转座，不包括早期胚胎发育和某些恶性肿瘤。最近的报告L1的表达和拷贝数变异（CNV）在人脑中表明L1动员也可能发生在以后的发展。然而，尚未绘制相应的整合地点。在这里，我们应用高通量的方法，以确定众多的L1，Alu和SVA种系突变，以及7,743推定的体细胞L1插入在海马和尾状核的三个人。令人惊讶的是，我们还分别发现了13，692和1，350个体细胞Alu和SVA插入。我们的研究结果表明，反转录转座子动员蛋白质编码基因的差异表达和活跃在大脑中。因此，由反转录转座驱动的体细胞基因组镶嵌可能重塑支持正常和异常神经生物学过程的遗传电路。
Retrotransposons are mobile genetic elements that employ a germ line “copy-and-paste” mechanism to spread throughout metazoan genomes. At least 50% of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells, excluding early embryo development and some malignancies. Recent reports of L1 expression and copy number variation (CNV) in the human brain suggest L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germ line mutations, as well as 7,743 putative somatic L1 insertions in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 and 1,350 somatic Alu and SVA insertions, respectively. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes.
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