Genomic mosaicism generated by LINE-1 retrotransposition during early human embryonic development

Long INterspersed Element-1 (LINE-1 or L1) is a family of active retrotransposons that comprise around one fifth of our DNA. An average human genome may contain 80-100 retrotransposition-competent L1s (RC-L1s), and the mobility of RC-L1s continues to impact germline and somatic genomes and can cause genetic disorders. A fraction of heritable L1 insertions are thought to accumulate during early embryonic development. However, the timing, rate and impact of endogenous L1 retrotransposition during early stages of human embryonic development remain largely unknown. To learn about LINE-1 accumulation in humans, we have explored endogenous L1 expression and retrotransposition in human embryonic stem cells and developing human pre-implantation embryos. We found that L1 RNA and the L1-encoded ORF1 protein (ORF1p), which are essential components of the retrotransposition complex, are expressed at multiple stages during early human embryogenesis. Remarkably, in human blastocysts L1 RNA and ORF1p expression is not restricted to the inner cell mass (ICM) but is also detected in trophectodermal cells, which will give rise to part of the placenta. Next, using single-cell high-throughput L1 profiling assays, we identify and validate a small number of de novo L1 insertions in human pre-implantation embryos, including a full-length L1 insertion and a retrotransposition event within gene ETS1 that may impact its expression. Finally, consistent with L1 expression pattern, we demonstrated that retrotransposition could also occur in extraembryonic tissues, leading to the accumulation of non-heritable insertions during pregnancy. Thus, we have demonstrated that endogenous L1s can generate potentially heritable and non-heritable insertions during human embryonic development, contributing to inter-individual genetic variation.

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Prof. Wolf Reik
The Brian Heap Seminar Room