Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis
Year: 2026
Type: preprint
Study design: Observational Study
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. 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.
Authors: Akshaya V. Annapragada, James R. White, Hope Orjuela, Adrianna Bartolomucci, Alice C. Eastman, Shashikant Koul, Kaui P. Lebarbenchon, Daniel C. Bruhm, Sarah Short, Keerti Boyapati, Noushin Niknafs, Carter Norton, Vishruth Girish, Nicholas A. Vulpescu, Sofia Velculescu, Julia Velculescu, Vilmos Adleff, Andrew Nelson, Zachariah H. Foda, Boris Winterhoff, Ronny Drapkin, Michael C. Schatz, Jillian Phallen, Robert B. Scharpf, Victor E. Velculescu
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214600859