Non-allelic homologous recombination of Alu and LINE-1 elements generates somatic complexity in human genomes.

Millions of Alu and LINE-1 copies in our genomes contribute to evolution and genetic disorders via non-allelic homologous recombination (NAHR), but the somatic extent of these rearrangements has not been systematically investigated. Here we combined high-throughput capture and sequencing of repeat elements with a new bioinformatic pipeline to show that somatic NAHR of Alu and LINE-1 elements is common in human genomes. We describe tissue-specific hallmarks of NAHR, and show that retroelements acting as recombination hotspots are enriched in cancer genes and structural variants. Analysis of recombination in human induced pluripotent stem cells and differentiated neurons revealed a neuron-specific recombination signature suggesting that the emergence of cell type-specific recombination profiles accompanies cell-fate determination. Finally, we found that somatic NAHR profiles are altered in Parkinson9s and Alzheimer9s disease, indicating a link between retroelements recombination and genomic instability in neurodegeneration. This work shows that somatic recombination of repeat elements contributes massively to genomic diversity, and that extensive recombinogenic activity of retroelements may act as a grey eminence in the transition from health to disease.