Structure of Chromosomal Duplicons and their Role in Mediating Human Genomic Disorders

Abstract

Chromosome-specific low-copy repeats, or duplicons, occur in multiple regions of the human genome. Homologous recombination between different duplicon copies leads to chromosomal rearrangements, such as deletions, duplications, inversions, and inverted duplications, depending on the orientation of the recombining duplicons. When such rearrangements cause dosage imbalance of a developmentally important gene(s), genetic diseases now termed genomic disorders result, at a frequency of 0.7–1/1000 births. Duplicons can have simple or very complex structures, with variation in copy number from 2 to >10 repeats, and each varying in size from a few kilobases in length to hundreds of kilobases. Analysis of the different duplicons involved in human genomic disorders identifies features that may predispose to recombination, including large size and high sequence identity between the recombining copies, putative recombination promoting features, and the presence of multiple genes/pseudogenes that may include genes expressed in germ cells. Most of the chromosome rearrangements involve duplicons near pericentromeric regions, which may relate to the propensity of such regions to accumulate duplicons. Detailed analyses of the structure, polymorphic variation, and mechanisms of recombination in genomic disorders, as well as the evolutionary origin of various duplicons will further our understanding of the structure, function, and fluidity of the human genome.

Interchromosomal segmental duplications of the pericentromeric region on the human Y chromosome

“…Such highly duplicated regions with a locally increased number of recombinationpromoting CAGGG repeats are prone to chromosomal rearrangements (Ji et al 2000;Samonte and Eichler 2002;Stankiewicz and Lupski 2002). These rearrangements might lead to an abnormal phenotype by disruption or dosage alteration of the involved genes.…”

Recurrent rearrangements in the proximal 15q11–q14 region: a new breakpoint cluster specific to unbalanced translocations

“…There is, therefore, no evidence that the mechanism of rearrangements involving BP6 is different from those involving the other BPs. Moreover, we demonstrate that BP6, like all five BPs described, previously 18 contains LCR15-duplicon elements that are known to facilitate recombination events at meiosis and to promote rearrangements, either intrachromosomal 35 or interchromosomal. 36 One possible reason for the lack of inv dup (15) chromosomes having a breakpoint within BP6 could be the viability of the resulting phenotype.…”

Simple detection of genomic microdeletions and microduplications using QMPSF in patients with idiopathic mental retardation

“…2 -4 Other uncharacterised recombinational hotspots may also key roles, especially in subtelomeric regions where chromosomal rearrangements are found in about 5% of the patients with idiopathic MR. 5 -7 Thus, genome architectural features are involved in the origin of recurrent deleterious DNA rearrangements. 3,8,9 The use of FISH has significantly improved the diagnosis of microdeletion syndromes suggested by clinical evidence. Nevertheless, recent descriptions of microduplication syndromes in patients with MR have highlighted the wide phenotypic variability complicating their clinical recognition.…”