Non-allelic recombination between homologous repetitive elements contributes to evolution and human genetic disorders. Here, we combine short- and long-DNA read sequencing of repeat elements with a new bioinformatics pipeline to show that somatic recombination of Alu and L1 elements is widespread in the human genome. Our analysis uncovers tissue-specific non-allelic homologous recombination hallmarks; moreover, we find that centromeres and cancer-associated genes are enriched for retroelements that may act as recombination hotspots. We compare recombination profiles in human-induced pluripotent stem cells and differentiated neurons and find that the neuron-specific recombination of repeat elements accompanies chromatin changes during cell-fate determination. Finally, we report that somatic recombination profiles are altered in Parkinson’s and Alzheimer’s disease, suggesting a link between retroelement recombination and genomic instability in neurodegeneration. This work highlights a significant contribution of the somatic recombination of repeat elements to genomic diversity in health and disease.

同源重复元素之间的非等位基因重组有助于进化和人类遗传疾病。在这里，我们将重复元素的短和长 DNA 读取测序与新的生物信息学管道相结合，以表明 Alu 和 L1 元素的体细胞重组在人类基因组中广泛存在。我们的分析揭示了组织特异性非等位基因同源重组标志；此外，我们发现着丝粒和癌症相关基因富含可能作为重组热点的逆转录元件。我们比较了人类诱导多能干细胞和分化神经元中的重组谱，发现在细胞命运决定过程中，重复元件的神经元特异性重组伴随着染色质变化。最后，我们报告说，帕金森病和阿尔茨海默病的体细胞重组谱发生了改变，这表明神经变性中的逆转录元件重组与基因组不稳定性之间存在联系。这项工作突出了重复元素的体细胞重组对健康和疾病基因组多样性的重要贡献。