Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination

Lusine Nazaryan-Petersen, Birgitte Bertelsen, Mads Bak, Lars Jønson, Niels Tommerup, Dustin C. Hancks, Zeynep Tümer

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Chromothripsis (CTH) is a phenomenon where multiple localized double-stranded DNA breaks result in complex genomic rearrangements. Although the DNA-repair mechanisms involved in CTH have been described, the mechanisms driving the localized "shattering" process remain unclear. High-throughput sequence analysis of a familial germline CTH revealed an inserted SVAE retrotransposon associated with a 110-kb deletion displaying hallmarks of L1-mediated retrotransposition. Our analysis suggests that the SVAE insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1-endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110-kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1-endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline.

Original languageEnglish (US)
Pages (from-to)385-395
Number of pages11
JournalHuman Mutation
Volume37
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Homologous Recombination
Alu Elements
Retroelements
Endonucleases
DNA Cleavage
Double-Stranded DNA Breaks
Mutagens
DNA Repair
Chromatin
Sequence Analysis
Chromothripsis
DNA

Keywords

  • Alu
  • Chromothripsis
  • L1
  • LINE-1
  • NAHR
  • Nonallelic homologous recombination
  • SINE-VNTR-Alu
  • SVA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Nazaryan-Petersen, L., Bertelsen, B., Bak, M., Jønson, L., Tommerup, N., Hancks, D. C., & Tümer, Z. (2016). Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination. Human Mutation, 37(4), 385-395. https://doi.org/10.1002/humu.22953

Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination. / Nazaryan-Petersen, Lusine; Bertelsen, Birgitte; Bak, Mads; Jønson, Lars; Tommerup, Niels; Hancks, Dustin C.; Tümer, Zeynep.

In: Human Mutation, Vol. 37, No. 4, 01.04.2016, p. 385-395.

Research output: Contribution to journalArticle

Nazaryan-Petersen, L, Bertelsen, B, Bak, M, Jønson, L, Tommerup, N, Hancks, DC & Tümer, Z 2016, 'Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination', Human Mutation, vol. 37, no. 4, pp. 385-395. https://doi.org/10.1002/humu.22953
Nazaryan-Petersen, Lusine ; Bertelsen, Birgitte ; Bak, Mads ; Jønson, Lars ; Tommerup, Niels ; Hancks, Dustin C. ; Tümer, Zeynep. / Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination. In: Human Mutation. 2016 ; Vol. 37, No. 4. pp. 385-395.
@article{ed41f61cc13a41e8a3ec4e87e8520d00,
title = "Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination",
abstract = "Chromothripsis (CTH) is a phenomenon where multiple localized double-stranded DNA breaks result in complex genomic rearrangements. Although the DNA-repair mechanisms involved in CTH have been described, the mechanisms driving the localized {"}shattering{"} process remain unclear. High-throughput sequence analysis of a familial germline CTH revealed an inserted SVAE retrotransposon associated with a 110-kb deletion displaying hallmarks of L1-mediated retrotransposition. Our analysis suggests that the SVAE insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1-endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110-kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1-endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline.",
keywords = "Alu, Chromothripsis, L1, LINE-1, NAHR, Nonallelic homologous recombination, SINE-VNTR-Alu, SVA",
author = "Lusine Nazaryan-Petersen and Birgitte Bertelsen and Mads Bak and Lars J{\o}nson and Niels Tommerup and Hancks, {Dustin C.} and Zeynep T{\"u}mer",
year = "2016",
month = "4",
day = "1",
doi = "10.1002/humu.22953",
language = "English (US)",
volume = "37",
pages = "385--395",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination

AU - Nazaryan-Petersen, Lusine

AU - Bertelsen, Birgitte

AU - Bak, Mads

AU - Jønson, Lars

AU - Tommerup, Niels

AU - Hancks, Dustin C.

AU - Tümer, Zeynep

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Chromothripsis (CTH) is a phenomenon where multiple localized double-stranded DNA breaks result in complex genomic rearrangements. Although the DNA-repair mechanisms involved in CTH have been described, the mechanisms driving the localized "shattering" process remain unclear. High-throughput sequence analysis of a familial germline CTH revealed an inserted SVAE retrotransposon associated with a 110-kb deletion displaying hallmarks of L1-mediated retrotransposition. Our analysis suggests that the SVAE insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1-endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110-kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1-endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline.

AB - Chromothripsis (CTH) is a phenomenon where multiple localized double-stranded DNA breaks result in complex genomic rearrangements. Although the DNA-repair mechanisms involved in CTH have been described, the mechanisms driving the localized "shattering" process remain unclear. High-throughput sequence analysis of a familial germline CTH revealed an inserted SVAE retrotransposon associated with a 110-kb deletion displaying hallmarks of L1-mediated retrotransposition. Our analysis suggests that the SVAE insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1-endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110-kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1-endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline.

KW - Alu

KW - Chromothripsis

KW - L1

KW - LINE-1

KW - NAHR

KW - Nonallelic homologous recombination

KW - SINE-VNTR-Alu

KW - SVA

UR - http://www.scopus.com/inward/record.url?scp=84960473461&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960473461&partnerID=8YFLogxK

U2 - 10.1002/humu.22953

DO - 10.1002/humu.22953

M3 - Article

C2 - 26929209

AN - SCOPUS:84960473461

VL - 37

SP - 385

EP - 395

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 4

ER -