Replicative mechanisms of CNV formation preferentially occur as intrachromosomal events: evidence from Potocki-Lupski duplication syndrome

Abstract

Copy number variations (CNVs) in the human genome contribute significantly to disease. De novo CNV mutations arise via genomic rearrangements, which can occur in 'trans', i.e. via interchromosomal events, or in 'cis', i.e. via intrachromosomal events. However, what molecular mechanisms occur between chromosomes versus between or within chromatids has not been systematically investigated. We hypothesized that distinct CNV mutational mechanisms, based on their intrinsic properties, may occur in a biased intrachromosomal versus interchromosomal manner. Here, we studied 62 genomic duplications observed in association with sporadic Potocki-Lupski syndrome (PTLS), in which multiple mutational mechanisms appear to be operative. Intriguingly, more interchromosomal than intrachromosomal events were identified in recurrent PTLS duplications mediated by non-allelic homologous recombination, whereas the reciprocal distribution was found for replicative mechanisms and non-homologous end-joining, likely reflecting the differences in spacial proximity of homologous chromosomes during different mutational processes.

Figure 1.

PTLS-associated duplication types and the STR markers used for the parent-of-origin study. Schematic representation of 17p11.2 and partial 17p12 (centromere-cen, to the right) with LCRs (not to scale). The red horizontal bars depict the portions of the duplicated genomic intervals. LCR-mediated recurrent PTLS duplications: CR duplication between SMS-REPs, uncommon recurrent (Type I, UR1) duplications between LCR17pA and LCR17pD, uncommon recurrent (Type II, UR2) duplications between two LCRs of 24 kb in length. Nonrecurrent (NR) duplications have variable sizes and locations, some of which can have complex structures, for example, the triplicated intervals shown by blue bars. Three nonrecurrent duplications are chosen arbitrarily to represent the 16 NR duplications. The positions of seven STR markers are shown by green arrows.

Figure 2.

STR genotyping revealed duplication origins in 27 newly investigated families (F1–F27). Seven STR markers were listed in order from distal (top) to proximal positions (bottom) of human chromosome 17p. The duplicated alleles in patients and their origins in parental alleles were shadowed. The mother in F6 was a carrier of mosaic PTLS duplication.