High rates of de novo 15q11q13 inversions in human spermatozoa

Abstract

Low-Copy Repeats predispose the 15q11-q13 region to non-allelic homologous recombination. We have already demonstrated that a significant percentage of Prader-Willi syndrome (PWS) fathers have an increased susceptibility to generate 15q11q13 deletions in spermatozoa, suggesting the participation of intrachromatid exchanges. This work has been focused on assessing the incidence of de novo 15q11q13 inversions in spermatozoa of control donors and PWS fathers in order to determine the basal rates of inversions and to confirm the intrachromatid mechanism as the main cause of 15q11q13 anomalies.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.

Genome-wide association tests of inversions with application to psoriasis

“…We considered the over-dominant model because the presence of an inverted and a non-inverted segment may cause a secondary, deleterious rearrangement (Feuk 2010; Osborne et al 2001; Gimelli et al 2003; Molina et al 2012). Compared to the full model, an over-dominant model should have a greater power because the inversion heterozygous are compared to a pool of the two homozygous.…”

Consideration of the haplotype diversity at nonallelic homologous recombination hotspots improves the precision of rearrangement breakpoint identification

“…It is reasonable to assume that features present in addition to PRDM9‐binding sites, such as structural variants (CNVs) of the recombining paralogs or chromatin accessibility, can also influence NAHR frequency (Antonacci et al., ; Carvalho & Lupski, ; Cuscó et al., ; Vergés, Molina, Geán, Vidal, & Blanco, , ). Polymorphic large inversions present in the transmitting parents have been identified that predispose to NAHR‐mediated rearrangements involving a number of different human genes (Antonacci et al., ; Bayés, Magano, Rivera, Flores, & Pérez Jurado, ; Gimelli et al., ; Hobart et al., ; Koolen et al., ; Molina, Anton, Vidal, & Blanco, ; Osborne et al., ; Scherer et al., ; Sharp et al., ; Small, Iber, & Warren, ; Visser et al., ). Further studies will be required to investigate whether polymorphic CNVs within the paralogs or inversions of the regions located between the paralogs involved in NAHR occur disproportionately more often in the transmitting parents of patients with type‐1 NF1 deletions.…”

Deletions and duplications of the 22q11.2 region in spermatozoa from DiGeorge/velocardiofacial fathers

“…Nevertheless, in several recurrent genomic disorders, some haplotypes have been suggested to predispose to NAHR events. In this sense, inversions of the critical regions have been reported in the fathers of children affected by deletion syndromes: Williams-Beuren [ 18 - 20 ], Prader-Willi [ 21 ], Angelman [ 22 ], Smith-Magenis [ 23 ] and 17q21.31 microdeletion [ 24 ], among several others [ 25 ]. In addition, copy number variations in the LCRs which flank critical regions have been described in fathers with affected offspring: Smith-Magenis syndrome [ 26 ], Williams-Beuren syndrome [ 27 ] or 16p12.1 microdeletion disease [ 28 ].…”

“…Fluorescence in situ hybridization (FISH) based methodologies in decondensed sperm nuclei allow the identification of gametes carrying deletions, duplications and inversions with a high sensitivity and specificity [ 21 , 35 , 36 ]. These interphase analyses, carried out in a large number of spermatozoa, offers the possibility of performing cell by cell analyses, thus assessing the incidence of rare events such as NAHR, and to establish a direct relationship between the genomic architecture and chromosomal instability during meiosis.…”