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Genomic inversions and GOLGA core duplicons underlie disease instability at the 15q25 locus

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Item Type:Article
Title:Genomic inversions and GOLGA core duplicons underlie disease instability at the 15q25 locus
Creators Name:Maggiolini, F.A.M. and Cantsilieris, S. and D'Addabbo, P. and Manganelli, M. and Coe, B.P. and Dumont, B.L. and Sanders, A.D. and Pang, A.W.C. and Vollger, M.R. and Palumbo, O. and Palumbo, P. and Accadia, M. and Carella, M. and Eichler, E.E. and Antonacci, F.
Abstract:Human chromosome 15q25 is involved in several disease-associated structural rearrangements, including microdeletions and chromosomal markers with inverted duplications. Using comparative fluorescence in situ hybridization, strand-sequencing, single-molecule, real-time sequencing and Bionano optical mapping analyses, we investigated the organization of the 15q25 region in human and nonhuman primates. We found that two independent inversions occurred in this region after the fission event that gave rise to phylogenetic chromosomes XIV and XV in humans and great apes. One of these inversions is still polymorphic in the human population today and may confer differential susceptibility to 15q25 microdeletions and inverted duplications. The inversion breakpoints map within segmental duplications containing core duplicons of the GOLGA gene family and correspond to the site of an ancestral centromere, which became inactivated about 25 million years ago. The inactivation of this centromere likely released segmental duplications from recombination repression typical of centromeric regions. We hypothesize that this increased the frequency of ectopic recombination creating a hotspot of hominid inversions where dispersed GOLGA core elements now predispose this region to recurrent genomic rearrangements associated with disease.
Keywords:Autoantigens, Chromosomal Instability, Chromosome Inversion, Gene Dosage, Gene Rearrangement, Genetic Recombination, Genomic Segmental Duplications, Golgi Matrix Proteins, Hominidae, Pair 15 Human Chromosomes, Phylogeny, Primates, Molecular Evolution, Multigene Family, Species Specificity, Animals
Source:PLoS Genetics
Publisher:Public Library of Science
Page Range:e1008075
Date:27 March 2019
Official Publication:https://doi.org/10.1371/journal.pgen.1008075
PubMed:View item in PubMed

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