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

Annapragada, A. V.; White, J.; Orjuela, H.; Bartolomucci, A.; Eastman, A.; Koul, S.; Lebarbenchon, K.; Bruhm, D.; Short, S.; Boyapati, K.; Niknafs, N.; Norton, C.; Girish, V.; Vulpescu, N.; Velculescu, S.; Velculescu, J.; Adleff, V.; Nelson, A.; Foda, Z.; Winterhoff, B.; Drapkin, R.; Schatz, M.; Phallen, J.; Scharpf, R.; Velculescu, V.

doi:10.64898/2026.09.22.753313

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bioRxiv · 10.64898/2026.09.22.753313

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

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Abstract

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.

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Annapragada, A. V., White, J., Orjuela, H., Bartolomucci, A., Eastman, A., Koul, S., Lebarbenchon, K., Bruhm, D., Short, S., Boyapati, K., Niknafs, N., Norton, C., Girish, V., Vulpescu, N., Velculescu, S., Velculescu, J., Adleff, V., Nelson, A., Foda, Z., Winterhoff, B., Drapkin, R., Schatz, M., Phallen, J., Scharpf, R., Velculescu, V.. 2026-09-28. Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis. https://doi.org/10.64898/2026.09.22.753313

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