Université Côte d'Azur, Inserm, CNRS, IRCAN, Nice, France.
Institut de Génétique Humaine, University of Montpellier, CNRS, Montpellier, France.
Mol Cell. 2019 May 2;74(3):555-570.e7. doi: 10.1016/j.molcel.2019.02.036. Epub 2019 Apr 4.
L1 retrotransposons are transposable elements and major contributors of genetic variation in humans. Where L1 integrates into the genome can directly impact human evolution and disease. Here, we experimentally induced L1 retrotransposition in cells and mapped integration sites at nucleotide resolution. At local scales, L1 integration is mostly restricted by genome sequence biases and the specificity of the L1 machinery. At regional scales, L1 shows a broad capacity for integration into all chromatin states, in contrast to other known mobile genetic elements. However, integration is influenced by the replication timing of target regions, suggesting a link to host DNA replication. The distribution of new L1 integrations differs from those of preexisting L1 copies, which are significantly reshaped by natural selection. Our findings reveal that the L1 machinery has evolved to efficiently target all genomic regions and underline a predominant role for post-integrative processes on the distribution of endogenous L1 elements.
L1 反转录转座子是可移动的遗传元件,也是人类遗传变异的主要贡献者。L1 整合到基因组中的位置会直接影响人类的进化和疾病。在这里,我们在细胞中实验诱导 L1 反转录转座,并以核苷酸分辨率绘制整合位点。在局部尺度上,L1 的整合主要受到基因组序列偏向性和 L1 机制特异性的限制。在区域尺度上,L1 显示出广泛的整合到所有染色质状态的能力,与其他已知的可移动遗传元件形成对比。然而,整合受到目标区域复制时间的影响,这表明与宿主 DNA 复制有关。新的 L1 整合的分布与预先存在的 L1 拷贝的分布不同,这些拷贝的分布受到自然选择的显著重塑。我们的研究结果表明,L1 机制已经进化到可以有效地靶向所有基因组区域,并强调了整合后过程在分布内源性 L1 元件中的主要作用。