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

Flavia A.M. Maggiolini, Stuart Cantsilieris, Pietro D'Addabbo, Michele Manganelli, Bradley P. Coe, Beth L. Dumont, Ashley D. Sanders, Andy Wing Chun Pang, Mitchell R. Vollger, Orazio Palumbo, Pietro Palumbo, Maria Accadia, Massimo Carella, Evan E. Eichler, Francesca Antonacci

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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.

Original languageEnglish
Pages (from-to)e1008075
JournalPLoS Genetics
Volume15
Issue number3
DOIs
Publication statusPublished - Mar 1 2019

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ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Maggiolini, F. A. M., Cantsilieris, S., D'Addabbo, P., Manganelli, M., Coe, B. P., Dumont, B. L., Sanders, A. D., Pang, A. W. C., Vollger, M. R., Palumbo, O., Palumbo, P., Accadia, M., Carella, M., Eichler, E. E., & Antonacci, F. (2019). Genomic inversions and GOLGA core duplicons underlie disease instability at the 15q25 locus. PLoS Genetics, 15(3), e1008075. https://doi.org/10.1371/journal.pgen.1008075