BACKGROUND Human endogenous retroviruses (HERVs) occupy a substantial fraction of the genome and impact cellular function with both beneficial and deleterious consequences. The vast majority of HERV sequences descend from ancient retroviral families no longer capable of infection or genomic propagation. In fact, most are no longer represented by full-length proviruses but by solitary long terminal repeats (solo LTRs) that arose via non-allelic recombination events between the two LTRs of a proviral insertion. Because LTR-LTR recombination events may occur long after proviral insertion but are challenging to detect in resequencing data, we hypothesize that this mechanism is a source of genomic variation in the human population that remains vastly underestimated. RESULTS We developed a computational pipeline specifically designed to capture dimorphic proviral/solo HERV allelic variants from short-read genome sequencing data. When applied to 279 individuals sequenced as part of the Simons Genome Diversity Project, the pipeline retrieves most of the dimorphic loci previously reported for the HERV-K(HML2) subfamily as well as dozens of additional candidates, including members of the HERV-H and HERV-W families previously involved in human development and disease. We experimentally validate several of these newly discovered dimorphisms, including the first reported instance of an unfixed HERV-W provirus and an HERV-H locus driving a transcript (ESRG) implicated in the maintenance of embryonic stem cell pluripotency. CONCLUSIONS Our findings indicate that human proviral content exhibit more extensive interindividual variation than previously recognized, which has important bearings for deciphering the contribution of HERVs to human physiology and disease. Because LTR retroelements and LTR recombination are ubiquitous in eukaryotes, our computational pipeline should facilitate the mapping of this type of genomic variation for a wide range of organisms.

中文翻译：

---

LTR重组介导的人类基因组中前病毒含量的变化。

背景技术人类内源性逆转录病毒(HERV)占据了基因组的大部分并且影响细胞功能，具有有益和有害的后果。绝大多数 HERV 序列来自古老的逆转录病毒家族，不再能够感染或基因组繁殖。事实上，大多数不再由全长前病毒代表，而是由通过前病毒插入的两个 LTR 之间的非等位基因重组事件产生的孤立的长末端重复序列 (solo LTR) 代表。因为 LTR-LTR 重组事件可能在前病毒插入后很长时间发生，但在重新测序数据中检测起来具有挑战性，我们假设这种机制是人群中基因组变异的来源，但仍被大大低估。结果 我们开发了一个计算管道，专门设计用于从短读长基因组测序数据中捕获二态前病毒/单独 HERV 等位基因变体。当应用于作为 Simons 基因组多样性项目的一部分测序的 279 个人时，该管道检索了以前报告的 HERV-K(HML2) 亚家族的大部分二态基因座以及数十个其他候选者，包括 HERV-H 和HERV-W 家族以前参与人类发育和疾病。我们通过实验验证了其中一些新发现的二态性，包括第一个报告的未固定 HERV-W 原病毒和 HERV-H 基因座驱动与胚胎干细胞多能性维持有关的转录本 (ESRG)。结论 我们的研究结果表明，人类前病毒含量表现出比以前认识的更广泛的个体间变异，这对于破译 HERV 对人类生理和疾病的贡献具有重要意义。因为 LTR 逆转录元件和 LTR 重组在真核生物中普遍存在，我们的计算管道应该有助于为广泛的生物体绘制此类基因组变异的图谱。