Integration target site selection by a resurrected human endogenous retrovirus
Integration target site selection by a resurrected human endogenous retrovirus
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DOI：
10.1101/gad.1762309
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发表时间：
2009-03-01
影响因子：
10.5
通讯作者：
Bushman, Frederic D.
中科院分区：
文献类型：
--
作者：
Brady, Troy;Lee, Young Nam;Bushman, Frederic D.
至少 8% 的人类基因组是由逆转录病毒 DNA 序列整合而成。在这里，我们通过比较从头 HERV 整合靶向与人类基因组中固定 HERV 元件的分布，分析了引导人内源性逆转录病毒 (HERV) 积累的力量。所有已知的基因组 HERV 均因突变而失活，但我们能够使用重建的共有 HERV-K（指定为 HERV-K-Con）来研究整合靶向。我们发现 HERV-KCon 优先整合在转录单元、基因丰富的区域以及与活性转录单元和相关调控区域相关的特征附近。相比之下，基因组 HERV-K 原病毒优先出现在转录单位之外。转录单元内存在的少数基因组 HERVK 相对于宿主基因处于相反的转录方向，预计该方向对宿主 mRNA 合成的干扰最小，但转录单元内的从头 HERV-K-Con 整合显示没有方向偏差。我们还发现，人类基因组中最年轻的 HERV-K 元件表现出介于从头 HERV-K-Con 整合位点和较旧的固定 HERV-K 之间的分布。这些发现表明，HERV 在人类种系中的积累是一个两步过程：整合靶向偏差直接导致初始积累，然后纯化选择导致原病毒丢失，破坏基因功能。
At least 8% of the human genome was formed by integration of retroviral DNA sequences. Here we analyze the forces directing the accumulation of human endogenous retroviruses (HERVs) by comparing de novo HERV integration targeting with the distribution of fixed HERV elements in the human genome. All known genomic HERVs are inactive due to mutation, but we were able to study integration targeting using a reconstituted consensus HERV-K (designated HERV-K-Con). We found that HERV-KCon integrated preferentially in transcription units, in gene-rich regions, and near features associated with active transcription units and associated regulatory regions. In contrast, genomic HERV-K proviruses are found preferentially outside transcription units. The minority of genomic HERVKs present inside transcription units are in opposite transcriptional orientation relative to the host gene, the orientation predicted to be minimally disruptive to host mRNA synthesis, but de novo HERV-K-Con integration within transcription units showed no orientation bias. We also found that the youngest HERV-K elements in the human genome showed a distribution intermediate between de novo HERV-K-Con integration sites and older fixed HERV-Ks. These findings indicate that accumulation of HERVs in the human germline is a two-step process: integration targeting biases direct initial accumulation, then purifying selection leads to loss of proviruses disrupting gene function.