High rates of de novo 15q11q13 inversions in human spermatozoa

Semen samples from 10 control donors and 16 PWS fathers were processed and analyzed by triple-color FISH. Three differentially labeled BAC-clones were used: one proximal and two distal of the 15q11-q13 region. Signal associations allowed the discrimination between normal and inverted haplotypes, which were confirmed by laser-scanning confocal microscopy.Two types of inversions were detected which correspond to the segments involved in Class I and II PWS deletions. No significant differences were observed in the mean frequencies of inversions between controls and PWS fathers (3.59% ± 0.46 and 9.51% ± 0.87 vs 3.06% ± 0.33 and 10.07% ± 0.74). Individual comparisons showed significant increases of inversions in four PWS fathers (P < 0.05) previously reported as patients with increases of 15q11q13 deletions.Results suggest that the incidence of heterozygous inversion carriers in the general population could reach significant values. This situation could have important implications, as they have been described as predisposing haplotypes for genomic disorders. As a whole, results confirm the high instability of the 15q11-q13 region, which is prone to different types of de novo reorganizations by intrachromatid NAHR.The human genome has been proven to be a highly dynamic structure, showing a great number of structural and copy-number variations [1]. Four major mechanisms contribute to the genesis of variations: non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS) and retrotransposition [1]. The presence of segmental duplications or low-copy repeats (LCR) throughout the human genome plays a significant role in the formation of variation through NAHR [2,3]. LCRs are DNA fragments longer than 1 Kb in size which share more than 90% of sequence identity between paralogous copies [4]. They represent 5% of the human genome, and their interspersed nature and sequence identity provide a substrate for NAHR [5].D