The Landscape of L1 Retrotransposons in the Human Genome Is Shaped by Pre-insertion Sequence Biases and Post-insertion Selection

Summary L1 retrotransposonsare transposable elementsand major contributors of genetic variation in humans. Where L1integrates into the genome can directly impact human evolutionand disease. Here, we experimentally induced L1retrotransposition in cells and mapped integration sites at nucleotide resolution. At local scales, L1integration is mostly restricted by genome sequence biases and the specificity of the L1machinery. At regional scales, L1shows a broad capacity for integration into all chromatin states, in contrast to other known mobile genetic elements. However, integration is influenced by the replication timingof target regions, suggesting a link to host DNA replication. The distribution of new L1integrations differs from those of preexisting L1copies, which are significantly reshaped by natural selection. Our findings reveal that the L1machinery has evolved to efficiently target all genomic regions and underline a predominant role for post-integrative processes on the distribution of endogenous L1elements.