Other Chromosome Rearrangements Mediated By Cryptic Paracentric Inversion

Osborne et al. (30) observed a heterozygous inversion of the Williams-Beuren syndrome region in 4 of 12 parents transmitting the disease-related chromosome. Their data had been fully confirmed by Bayes et al. (31), who found that one-third of the transmitting progenitors were heterozygous for an inversion between the centromeric and the telomeric segmental duplications at 7q11.23, which are in opposite orientation. The mechanism by which the inversion generates an interstitial deletion is probably owing to the fact that the normal and the inverted chromosome synapse for all their length and "balloon out" at the inversion region, thus allowing NAHR between the segmental duplications lying in opposite orientation (Fig. 5).

We also demonstrated that the t(4;8)(p16;p23) recurrent translocation, reported in several cases (32) either in the balanced or unbalanced form, is mediated by two pairs of homologous OR-gene clusters located at 4p16 and 8p23, respectively (33). In five de novo cases of unbalanced and balanced translocations, all of maternal origin, we could demonstrate a double heterozygous inversion between the two pairs of OR-gene clusters at 4p16 and 8p23 in all the mothers. It seems likely that the two pairs of homologous chromosomes cannot synapse in their distal short arm regions involved in the inversion and this allows the occurrence of a cross-ingover between homologous regions located into nonhomologous chromosomes (Fig. 6). 4p16 and 8p23 heterozygous inversion was detected in 12.5% (4/40) and 26% (13/50) of control subjects, respectively, whereas 2.5% (1/40) were scored as double heterozygous.

Heterozygous cryptic inversions as the basis of unbalanced rearrangements have also been found in mothers having a 15q11-q13 deleted Angelman syndrome (AS) child (34). The inversion was detected in the mothers of four out six AS cases with the breakpoint 2-3 (BP2/3) 15q11-q13 deletion, but not in seven mothers of AS because of paternal uniparental disomy 15. The BP2-BP3 chromosome 15q11-q13 inversion was detected in 4 of 44 subjects (9%) of the general population.

From these data it emerges that the heterozygous inversion between homologous segmental duplications is an important mechanism causing abnormal synapsis and NAHR and, thus, that

Fig. 5. Possible mechanism explaining how the paracentric inversion may lead to a deleted recombinant chromosome. The abnormal synapsis created by the inversion allows recombination between identical or nearly identical segmental duplications (gray blocks, A and B). Arrows indicate the occurrence of recombination. Chess-patterned circles indicate the centromeres.

Fig. 5. Possible mechanism explaining how the paracentric inversion may lead to a deleted recombinant chromosome. The abnormal synapsis created by the inversion allows recombination between identical or nearly identical segmental duplications (gray blocks, A and B). Arrows indicate the occurrence of recombination. Chess-patterned circles indicate the centromeres.

these types of inversions constitute an important factor for susceptibility to the occurrence of unbalanced chromosome rearrangements. However, it is also clear that not all recurrent rearrangements can be explained by this mechanism: Saitta et al. (35) did not find evidence of inversion of 22q11.2 in the chromosome that becomes deleted in subjects with a DiGeorge/ velocardiofacial syndrome phenotype. Similarly, several researchers could not find any inversion at 15q11-q13 in the fathers of deletion Prader-Willi syndrome subjects. Thus, it seems obvious that other mechanisms beyond to the inversion may cause synapsis displacement between homologous segmental duplications, in turn, leading to NAHR.

Recent studies (36,37) demonstrated the existence of large segments of the genome, ranging in size from 100 kb to 2 Mb, varying several folds in copy number in the human population and

Fig. 6. The recurrent translocation t(4;8)(p16;p23) is mediated by two pairs of olfactory receptor gene clusters at 4p16 and 8p23 (yellow and orange blocks). Double heterozygous inversions between these two segmental duplications prevent a normal synapsis to occur along each pair of homologous chromosomes and allows nonallelic homologous recombination between nonhomologous chromosomes.

Fig. 6. The recurrent translocation t(4;8)(p16;p23) is mediated by two pairs of olfactory receptor gene clusters at 4p16 and 8p23 (yellow and orange blocks). Double heterozygous inversions between these two segmental duplications prevent a normal synapsis to occur along each pair of homologous chromosomes and allows nonallelic homologous recombination between nonhomologous chromosomes.

denominated large-scale copy number variations (LCVs). A higher than expected association between LCVs and known segmental duplications has been noted both by Iafrate et al. and Sebat et al. (36,37). It has been demonstrated that the instability of some genomic regions is owing to the presence of segmental duplications (38). This suggests that LCVs and genomic rearrangements might have a common mechanistic basis (39).

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