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

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.Author summary Human chromosome 15 derived from a fission event that occurred in the ancestor of great apes. Following inactivation of the ancestral centromere at 15q25 a dispersal of segmental duplications took place, providing templates for ectopic recombination and predisposing the region to genomic instability. Different disease-associated microdeletions and chromosomal markers have been described with breakpoints mapping within these segmental duplications. To gain insight into the instability at 15q25, we sought to analyze this region in human and nonhuman primates using multiple genomics techniques and demonstrated the presence of two independent inversion events that occurred during great apes evolution. One of these inversions is still polymorphic in humans and may cause, in conjunction with a GOLGA core duplicona 14 kbp chromosome 15 repeat, susceptibility to non-allelic homologous recombination leading to pathogenic recurrent rearrangements. Our results support the existence of a strong relationship between inversions and core duplicons and reinforce the hypothesis that GOLGA repeats play a fundamental role both in disease and evolution.