Traffic of genetic information between segmental duplications flanking the typical 22q11.2 deletion in velo-cardio-facial syndrome/DiGeorge syndrome

Abstract

Velo-cardio-facial syndrome/DiGeorge syndrome results from unequal crossing-over events between two 240-kb low-copy repeats termed LCR22 (LCR22-2 and LCR22-4) on Chromosome 22q11.2, comprised of modules, each of which are >99% identical in sequence. To delineate regions in the LCR22s that might contain hotspots for 22q11.2 rearrangements, we scanned the interval for increased rates of recombination with the hypothesis that these regions might be more prone to breakage. We generated an algorithm to detect sites of altered recombination by searching for single nucleotide polymorphic positions in BAC clones from different libraries mapped to LCR22-2 and LCR22-4. This method distinguishes single nucleotide polymorphisms from paralogous sequence variants and complex polymorphic positions. Sites of shared polymorphism are considered potential sites of gene conversion or double cross-over between the two LCR22s. We found an inverse correlation between regions of paralogous sequence variants that are unique to a given position within one LCR22 and clusters of shared polymorphic sites, suggesting that these clusters depict altered recombination and not remnants of ancestral single nucleotide polymorphisms. We postulate that most shared polymorphic sites are products of past transfers of DNA information between the LCR22s, suggesting that frequent traffic of genetic material may induce genomic instability in the two LCR22s. We also found that gaps up to 1.5 kb long can be transferred between LCR22s.

A preliminary comparative analysis of primate segmental duplications shows elevated substitution rates and a great-ape expansion of intrachromosomal duplications

“…The increased substitution rate did not significantly change if we excluded regions in chimpanzee that showed evidence of duplication shadowing, a phenomena that genomic sequence adjacent to duplication is predisposed to new duplication ). This suggests that the effect is particular to the region as opposed to being directly related to duplicated sequence as might be expected if gene conversion were responsible for the effect (Jackson et al 2005;Pavliček et al 2005).…”

“…A slower molecular clock in the humans may also contribute partially to the increase in the abundance of highly homologous segmental duplications observed for the human/ape genomes (see below). Estimating the age of duplication events, however, is confounded by the propensity for these sequences to undergo gene conversion (Hurles 2001;Skaletsky et al 2003;Jackson et al 2005;Pavliček et al 2005). Such homogenization events might erase patterns of divergence and lead to an underestimation of the true evolutionary age of the duplication.…”

Low copy repeats mediate distal chromosome 22q11.2 deletions: Sequence analysis predicts breakpoint mechanisms

“…The deletion breakpoints we analyzed are each located within a duplicated module containing the BCRL marker, suggesting that the sequences within this module may predispose the region to rearrangement. Interestingly, the region corresponding to the BCRL module within the 22q11 LCRs was previously predicted to be a potential rearrangement hotspot within LCR-A (LCR22-2) and LCR-D (LCR22-4) (Pavlicek et al 2005). This interval, designated ⌿BCR, is enriched in shared polymorphic sites (SPSs) and poor in paralogous sequence variants (PSVs), suggesting it as a region for gene conversion and consequently for meiotic crossover and rearrangement (Hurles et al 2004;Pavlicek et al 2005).…”

Homologous recombination between HERVs causes duplications in the AZFa region of men accidentally exposed to cesium-137 in Goiânia

“…It is not clear if they can also promote unequal crossover (ectopic exchange, non-allelic homologous recombination) between related DNA sequences or if they could drive genomic rearrangements, such as deletions and duplications, triggered by recombination-initiating DSB (Pavlicek et al, 2005). Such genome instability is of utmost importance given the frequency of segmental duplications in the human genome (Gasior et al, 2006).…”