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PreprintCC BY-NC-NDbioRxiv

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

  • A. V. Annapragada
  • J. White
  • H. Orjuela
  • A. Bartolomucci
  • A. Eastman
  • S. Koul
  • K. Lebarbenchon
  • D. Bruhm
  • S. Short
  • K. Boyapati
  • N. Niknafs
  • C. Norton
13 more authors
  • V. Girish
  • N. Vulpescu
  • S. Velculescu1
  • J. Velculescu1
  • V. Adleff
  • A. Nelson
  • Z. Foda
  • B. Winterhoff
  • R. Drapkin
  • M. Schatz
  • J. Phallen
  • R. Scharpf
  • V. Velculescu1
  1. 1Johns Hopkins University
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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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Cite

BibTeXRIS
BibTeX
@misc{annapragada2026structural,
  title = {{Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis}},
  author = {A. V. Annapragada and J. White and H. Orjuela and A. Bartolomucci and A. Eastman and S. Koul and K. Lebarbenchon and D. Bruhm and S. Short and K. Boyapati and N. Niknafs and C. Norton and V. Girish and N. Vulpescu and S. Velculescu and J. Velculescu and V. Adleff and A. Nelson and Z. Foda and B. Winterhoff and R. Drapkin and M. Schatz and J. Phallen and R. Scharpf and V. Velculescu},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.22.753313},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753313v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis
AU  - A. V. Annapragada
AU  - J. White
AU  - H. Orjuela
AU  - A. Bartolomucci
AU  - A. Eastman
AU  - S. Koul
AU  - K. Lebarbenchon
AU  - D. Bruhm
AU  - S. Short
AU  - K. Boyapati
AU  - N. Niknafs
AU  - C. Norton
AU  - V. Girish
AU  - N. Vulpescu
AU  - S. Velculescu
AU  - J. Velculescu
AU  - V. Adleff
AU  - A. Nelson
AU  - Z. Foda
AU  - B. Winterhoff
AU  - R. Drapkin
AU  - M. Schatz
AU  - J. Phallen
AU  - R. Scharpf
AU  - V. Velculescu
PY  - 2026
DA  - 2026/09/22
PB  - bioRxiv
DO  - 10.64898/2026.09.22.753313
UR  - https://www.biorxiv.org/content/10.64898/2026.09.22.753313v1
AB  - 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.
ER  -