Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis.

UNLABELLED: Somatic mosaicism contributes to genomic variation, yet postzygotic structural variants remain under-characterized. We performed long- and short-read WGS from multiple individuals (n=47 normal tissues; n=168 samples) and identified mosaic structural variants in all individuals and germ layers, impacting a median 285.2 kb/genome. Nearly half of breakpoints were independently validated, with tissue distributions reflecting both early and late developmental origins. Most mosaic variants were repeat-mediated and 8.3% overlapped functional elements, an enrichment compared to germline variants. To extend these analyses in samples where long-read sequencing is infeasible, we measured repeat alterations from short-read sequencing, recapitulating mosaic tissue-specific differences. We characterized tumor- and tissue-specific variation in repeats across 15 cancer types and found tumor-related repeat variation to be similar in scale to that of normal mosaic variation. Tracking repeat changes in cell-free DNA provided a noninvasive approach for tumor monitoring. Our analyses revealed widespread repeat-driven structural variation in health and disease.

HIGHLIGHTS: Multi-tissue long-read sequencing reveals widespread mosaic structural variants in normal tissues.Mosaic structural variation is largely repeat-mediated and has functional consequences.Alignment-free approaches enable analyses of repeat elements and large structural variants from short-read sequencing.Structural variation in repeat elements further occurs throughout tumorigenesis and may be detected in tumor tissues as well as through cell-free DNA liquid biopsies.