Recombination of Repeat Elements Generates Somatic Complexity in Human Genomes

SummaryThe recombination of millions of Alu and L1 copies in our genomes contributes to evolution and genetic disorders, but the somatic extent of these rearrangements has not been systematically investigated. Here we combine short and long-reads reads DNA sequencing with a new bioinformatic pipeline to show that somatic recombination of Alu and L1 elements is common in human genomes. We report new tissue-specific recombination hallmarks, and show that retroelements acting as recombination hotspots are enriched in centromeres and cancer genes. We compare recombination profiles in induced pluripotent stem cells and differentiated neurons and show that neuron-specific recombination of repeat elements accompanies chromatin reorganization during cell-fate determination. Finally, we find that somatic recombination profiles are altered in Parkinson’s and Alzheimer’s 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 in health and disease.