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

• Published in: PLoS genetics Vol. 15; no. 3; p. e1008075
• Main Authors: Maggiolini, Flavia A. M., Cantsilieris, Stuart, D’Addabbo, Pietro, Manganelli, Michele, Coe, Bradley P., Dumont, Beth L., Sanders, Ashley D., Pang, Andy Wing Chun, Vollger, Mitchell R., Palumbo, Orazio, Palumbo, Pietro, Accadia, Maria, Carella, Massimo, Eichler, Evan E., Antonacci, Francesca
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.03.2019; Public Library of Science (PLoS)
• Subjects: Animals; Apes; Autoantigens - genetics; Biology and Life Sciences; Breakpoints; Chromosomal Instability; Chromosome 15; Chromosome Inversion; Chromosomes; Chromosomes, Human, Pair 15 - genetics; Evolution, Molecular; Fluorescence; Fluorescence in situ hybridization; Gene Dosage; Gene expression; Gene mapping; Gene Rearrangement; Genes; Genetic recombination; Genetic Variation; Genetics; Genomes; Golgi Matrix Proteins - genetics; Health aspects; Hominidae - genetics; Humans; Hybridization; Laboratories; Medicine; Multigene Family; Phylogeny; Primates; Primates - genetics; Quantitative trait loci; Recombination; Recombination, Genetic; Segmental Duplications, Genomic; Species Specificity; United States > US; Italy
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008075

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.