The retrotransposon LINE-1 (L1) is central to the recent evolutionary history of the human genome and continues to drive genetic diversity and germline pathogenesis. However, the spatiotemporal extent and biological significance of somatic L1 activity are poorly defined and are virtually unexplored in other primates. From a single L1 lineage active at the divergence of apes and Old World monkeys, successive L1 subfamilies have emerged in each descendant primate germline. As revealed by case studies, the presently active human L1 subfamily can also mobilize during embryonic and brain development in vivo. It is unknown whether nonhuman primate L1s can similarly generate somatic insertions in the brain. Here we applied approximately 40× single-cell whole-genome sequencing (scWGS), as well as retrotransposon capture sequencing (RC-seq), to 20 hippocampal neurons from two rhesus macaques (Macaca mulatta). In one animal, we detected and PCR-validated a somatic L1 insertion that generated target site duplications, carried a short 5′ transduction, and was present in ∼7% of hippocampal neurons but absent from cerebellum and nonbrain tissues. The corresponding donor L1 allele was exceptionally mobile in vitro and was embedded in PRDM4, a gene expressed throughout development and in neural stem cells. Nanopore long-read methylome and RNA-seq transcriptome analyses indicated young retrotransposon subfamily activation in the early embryo, followed by repression in adult tissues. These data highlight endogenous macaque L1 retrotransposition potential, provide prototypical evidence of L1-mediated somatic mosaicism in a nonhuman primate, and allude to L1 mobility in the brain over the past 30 million years of human evolution.

中文翻译：

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发育中的恒河猴大脑的体细胞逆转录转座

逆转录转座子 LINE-1 (L1) 是人类基因组近期进化史的核心，并继续推动遗传多样性和种系发病机制。然而，体细胞 L1 活动的时空范围和生物学意义尚不明确，在其他灵长类动物中几乎没有探索过。从在猿和旧大陆猴子的分歧处活跃的单个 L1 谱系开始，连续的 L1 亚科在每个后代灵长类动物种系中出现。正如案例研究所揭示的，目前活跃的人类 L1 亚家族也可以在体内胚胎和大脑发育过程中动员。目前尚不清楚非人类灵长类动物 L1s 是否可以类似地在大脑中产生体细胞插入。在这里，我们应用了大约 40 倍的单细胞全基因组测序 (scWGS)，以及反转录转座子捕获测序 (RC-seq)，猕猴桃）。在一只动物中，我们检测并 PCR 验证了一个体细胞 L1 插入，该插入产生了靶位点重复，携带一个短的 5' 转导，并且存在于约 7% 的海马神经元中，但在小脑和非脑组织中不存在。相应的供体 L1 等位基因在体外具有极强的流动性，并嵌入PRDM4，在整个发育过程和神经干细胞中表达的基因。Nanopore 长读长甲基化组和 RNA-seq 转录组分析表明，早期胚胎中年轻的反转录转座子亚家族激活，随后在成人组织中受到抑制。这些数据突出了猕猴内源性 L1 逆转录转座的潜力，提供了非人类灵长类动物中 L1 介导的体细胞嵌合体的原型证据，并暗示了过去 3000 万年人类进化过程中大脑中 L1 的流动性。