Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements

Abstract

Submicroscopic structural variations, including deletions, duplications, inversions and more complex rearrangements, are widespread in normal human genomes. Inverted segmental duplications or highly identical low-copy repeat (LCR) sequences can mediate the formation of inversions and more complex structural rearrangements through non-allelic homologous recombination. In a patient with 7q36 inverted duplication/terminal deletion, we demonstrated the central role of a pair of short inverted LCRs in the vasoactive intestinal peptide receptor gene (VIPR2)-LCRs in generating the rearrangement. We also revealed a relatively common VIPR2-LCR-associated inversion polymorphism disrupting the gene in almost 1% of healthy subjects, and a small number of complex duplications/triplications. In genome-wide studies of several thousand patients, a significant association of rare microduplications with variable size, all involving VIPR2, with schizophrenia was recently described, suggesting that altered vasoactive intestinal peptide signaling is likely implicated in the pathogenesis of schizophrenia. Genetic testing for VIPR2-LCR-associated inversions should be performed on available cohorts of psychiatric patients to evaluate their potential pathogenic role.

Mechanisms underlying structural variant formation in genomic disorders

“…However, contrary to the challenge of predicting structural variant breakpoints using sequence motifs, LCRs do allow some degree of prediction of the occurrence of nonrecurrent rearrangements and support the hypothesis that the genomic architecture exerts multiple but distinct influences on structural variant formation genome-wide. This is exemplified by specific CGR structures such as DUP–TRP/INV–DUP that can be formed if highly identical inverted LCRs are used as substrates for BIR 7,33,34,130 . The presence of inverted repeats is hypothesized to provide a high degree of nucleotide sequence identity, which renders the region susceptible to undergoing ectopic template switching.…”

“…Importantly, DUP–TRP/INV–DUP can cause a much more severe clinical phenotype if the dosage-sensitive gene, that is, PLP1 or MECP2 , maps within the triplicated segment 7,33,131,132 . Therefore, the presence of inverted repeats near dosage-sensitive genes can indicate regions in the human genome that are susceptible to DUP–TRP/INV–DUP formation 53 , which has been proved to be of clinical relevance at different genomic loci 34,35,130 (TABLE 1). …”

Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

“…Replication-based mechanisms with potential iterative template switches either coupled or not with non-homologous end joining (NHEJ) underlie the formation of these inverted triplications embedded in duplications, frequently consisting of, at least, two breakpoint junctions (jct1 and jct2) generated in one single event. 13 DUP-TRP/INV-DUP was reported in 20% of the MECP2 CNV gains at Xq28, 13 at the PLP1 locus at Xq22, 14,15 at VIPR2 at 7q36, 16 and at 15q13.3. 17 We investigated the mechanism underlying CGRs found in association with segmental AOH in five families.…”

Targeting of vasoactive intestinal peptide receptor 2, VPAC2, a secretin family G-protein coupled receptor, to primary cilia

“…Mice lacking VPAC2 show altered circadian rhythms in locomotor behavior, neuronal firing and clock gene expression (Aton et al, 2005; Cutler et al, 2003; Harmar et al, 2002; Maywood et al, 2006). Recent studies have also shown that duplication of the VPAC2 gene, and the resulting higher than normal VPAC2 signaling in patients confer a significant risk to schizophrenia (Beri et al, 2012; Levinson et al, 2011; Vacic et al, 2011). …”