Phylogenetic Analysis Reveals That ERVs "Die Young" but HERV-H Is Unusually Conserved

About 8% of the human genome is made up of endogenous retroviruses (ERVs). Though most human endogenous retroviruses (HERVs) are thought to be irrelevant to our biology notable exceptions include members of the HERV-H family that are necessary for the correct functioning of stem cells. ERVs are commonly found in two forms, the full-length proviral form, and the more numerous solo-LTR form, thought to result from homologous recombination events. Here we introduce a phylogenetic framework to study ERV insertion and solo-LTR formation. We then apply the framework to site patterns sampled from a set of long alignments covering six primate genomes. Studying six categories of ERVs we quantitatively recapitulate patterns of insertional activity that are usually described in qualitative terms in the literature. A slowdown in most ERV groups is observed but we suggest that HERV-K activity may have increased in humans since they diverged from chimpanzees. We find that the rate of solo-LTR formation decreases rapidly as a function of ERV age and that an age dependent model of solo-LTR formation describes the history of ERVs more accurately than the commonly used exponential decay model. We also demonstrate that HERV-H loci are markedly less likely to form solo-LTRs than ERVs from other families. We conclude that the slower dynamics of HERV-H suggest a host role for the internal regions of these exapted elements and posit that in future it will be possible to use the relationship between full-length proviruses and solo-LTRs to help identify large scale co-options in distant vertebrate genomes.

人类基因组中约有8%的序列由内源性逆转录病毒（endogenous retroviruses, ERVs）构成。尽管多数人类内源性逆转录病毒（human endogenous retroviruses, HERVs）被认为与人体生理功能无关，但也存在显著例外：例如HERV-H家族的部分成员对干细胞的正常功能发挥不可或缺。ERV通常以两种形式存在：完整前病毒形式（full-length proviral form），以及数量更为丰富的单长末端重复序列形式（solo-LTR form），后者被认为是同源重组（homologous recombination）事件的产物。本研究构建了一套用于研究ERV插入事件与单LTR形成的系统发育框架（phylogenetic framework），随后将该框架应用于从覆盖6种灵长类基因组的长序列比对中采样得到的位点模式数据。通过对6类ERV的分析，我们定量重现了文献中通常以定性方式描述的ERV插入活性模式。研究观察到多数ERV类群的插入活性呈下降趋势，但我们提出，在人类与黑猩猩分化后，HERV-K的活性可能有所上升。我们发现，单LTR形成的速率随ERV的进化年龄增长而快速降低；相较于学界常用的指数衰减模型（exponential decay model），基于年龄依赖的单LTR形成模型能更准确地反映ERV的进化历史。此外我们证实，相较于其他家族的ERV，HERV-H位点形成单LTR的概率显著更低。本研究结论表明，HERV-H较慢的演化动态提示这类外适应元件（exapted elements）的内部区域可能具有宿主功能；我们还展望，未来可借助完整前病毒与单LTR之间的关联，帮助识别远缘脊椎动物基因组中的大规模共选择事件。