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Extreme clustering of type-1 NF1 deletion breakpoints co-locating with G-quadruplex forming sequences

(2018) HUMAN GENETICS. 137(6-7). p.511-520
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Organization
Abstract
The breakpoints of type-1 NF1 deletions encompassing 1.4-Mb are located within NF1-REPa and NF1-REPc, which exhibit a complex structure comprising different segmental duplications in direct and inverted orientation. Here, we systematically assessed the proportion of type-1 NF1 deletions caused by nonallelic homologous recombination (NAHR) and those mediated by other mutational mechanisms. To this end, we analyzed 236 unselected type-1 deletions and observed that 179 of them (75.8%) had breakpoints located within the NAHR hotspot PRS2, whereas 39 deletions (16.5%) had breakpoints located within PRS1. Sixteen deletions exhibited breakpoints located outside of these NAHR hotspots but were also mediated by NAHR. Taken together, the breakpoints of 234 (99.2%) of the 236 type-1 NF1 deletions were mediated by NAHR. Thus, NF1-REPa and NF1-REPc are strongly predisposed to recurrent NAHR, the main mechanism underlying type-1 NF1 deletions. We also observed a non-random overlap between type-1 NF1-deletion breakpoints and G-quadruplex forming sequences (GQs) as well as regions flanking PRDM9(A) binding-sites. These findings imply that GQs and PRDM9(A) binding-sites contribute to the clustering of type-1 deletion breakpoints. The co-location of both types of sequence was at its highest within PRS2, indicative of their synergistic contribution to the greatly increased NAHR activity within this hotspot.
Keywords
NONALLELIC HOMOLOGOUS RECOMBINATION, NEUROFIBROMATOSIS TYPE-1, HUMAN GENOME, HOT-SPOTS, DNA, HOTSPOTS, MICRODELETIONS, PRDM9, INSTABILITY, HUMANS

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Citation

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MLA
Summerer, Anna, Victor-Felix Mautner, Meena Upadhyaya, et al. “Extreme Clustering of Type-1 NF1 Deletion Breakpoints Co-locating with G-quadruplex Forming Sequences.” HUMAN GENETICS 137.6-7 (2018): 511–520. Print.
APA
Summerer, A., Mautner, V.-F., Upadhyaya, M., Claes, K., Högel, J., Cooper, D. N., Messiaen, L., et al. (2018). Extreme clustering of type-1 NF1 deletion breakpoints co-locating with G-quadruplex forming sequences. HUMAN GENETICS, 137(6-7), 511–520.
Chicago author-date
Summerer, Anna, Victor-Felix Mautner, Meena Upadhyaya, Kathleen Claes, Josef Högel, David N Cooper, Ludwine Messiaen, and Hildegard Kehrer-Sawatzki. 2018. “Extreme Clustering of Type-1 NF1 Deletion Breakpoints Co-locating with G-quadruplex Forming Sequences.” Human Genetics 137 (6-7): 511–520.
Chicago author-date (all authors)
Summerer, Anna, Victor-Felix Mautner, Meena Upadhyaya, Kathleen Claes, Josef Högel, David N Cooper, Ludwine Messiaen, and Hildegard Kehrer-Sawatzki. 2018. “Extreme Clustering of Type-1 NF1 Deletion Breakpoints Co-locating with G-quadruplex Forming Sequences.” Human Genetics 137 (6-7): 511–520.
Vancouver
1.
Summerer A, Mautner V-F, Upadhyaya M, Claes K, Högel J, Cooper DN, et al. Extreme clustering of type-1 NF1 deletion breakpoints co-locating with G-quadruplex forming sequences. HUMAN GENETICS. 2018;137(6-7):511–20.
IEEE
[1]
A. Summerer et al., “Extreme clustering of type-1 NF1 deletion breakpoints co-locating with G-quadruplex forming sequences,” HUMAN GENETICS, vol. 137, no. 6–7, pp. 511–520, 2018.
@article{8582490,
  abstract     = {The breakpoints of type-1 NF1 deletions encompassing 1.4-Mb are located within NF1-REPa and NF1-REPc, which exhibit a complex structure comprising different segmental duplications in direct and inverted orientation. Here, we systematically assessed the proportion of type-1 NF1 deletions caused by nonallelic homologous recombination (NAHR) and those mediated by other mutational mechanisms. To this end, we analyzed 236 unselected type-1 deletions and observed that 179 of them (75.8%) had breakpoints located within the NAHR hotspot PRS2, whereas 39 deletions (16.5%) had breakpoints located within PRS1. Sixteen deletions exhibited breakpoints located outside of these NAHR hotspots but were also mediated by NAHR. Taken together, the breakpoints of 234 (99.2%) of the 236 type-1 NF1 deletions were mediated by NAHR. Thus, NF1-REPa and NF1-REPc are strongly predisposed to recurrent NAHR, the main mechanism underlying type-1 NF1 deletions. We also observed a non-random overlap between type-1 NF1-deletion breakpoints and G-quadruplex forming sequences (GQs) as well as regions flanking PRDM9(A) binding-sites. These findings imply that GQs and PRDM9(A) binding-sites contribute to the clustering of type-1 deletion breakpoints. The co-location of both types of sequence was at its highest within PRS2, indicative of their synergistic contribution to the greatly increased NAHR activity within this hotspot.},
  author       = {Summerer, Anna and Mautner, Victor-Felix and Upadhyaya, Meena and Claes, Kathleen and Högel, Josef and Cooper, David N and Messiaen, Ludwine and Kehrer-Sawatzki, Hildegard},
  issn         = {0340-6717},
  journal      = {HUMAN GENETICS},
  keywords     = {NONALLELIC HOMOLOGOUS RECOMBINATION,NEUROFIBROMATOSIS TYPE-1,HUMAN GENOME,HOT-SPOTS,DNA,HOTSPOTS,MICRODELETIONS,PRDM9,INSTABILITY,HUMANS},
  language     = {eng},
  number       = {6-7},
  pages        = {511--520},
  title        = {Extreme clustering of type-1 NF1 deletion breakpoints co-locating with G-quadruplex forming sequences},
  url          = {http://dx.doi.org/10.1007/s00439-018-1904-1},
  volume       = {137},
  year         = {2018},
}

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