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

• Published in: Human genetics 2018-07, Vol.137 (6-7), p.511-520
• Main Authors: Summerer, Anna, Mautner, Victor-Felix, Upadhyaya, Meena, Claes, Kathleen B. M., Högel, Josef, Cooper, David N., Messiaen, Ludwine, Kehrer-Sawatzki, Hildegard
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Breakpoints; Gene Function; Homologous recombination; Human Genetics; Metabolic Diseases; Molecular Medicine; Original Investigation
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-018-1904-1

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.