Structural Variation Evolution at the 15q11-q13 Disease-Associated Locus

Abstract

The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for their discovery and precise genotyping. The 15q11-q13 locus is a hotspot of recurrent copy number variation associated with Prader–Willi/Angelman syndromes, developmental delay, autism, and epilepsy and is mediated by complex segmental duplications, many of which arose recently during evolution. To gain insight into the instability of this region, we characterized its architecture in human and nonhuman primates, reconstructing the evolutionary history of five different inversions that rearranged the region in different species primarily by accumulation of segmental duplications. Comparative analysis of human and nonhuman primate duplication structures suggests a human-specific gain of directly oriented duplications in the regions flanking the GOLGA cores and HERC segmental duplications, representing potential genomic drivers for the human-specific expansions. The increasing complexity of segmental duplication organization over the course of evolution underlies its association with human susceptibility to recurrent disease-associated rearrangements.

Structural polymorphism and diversity of human segmental duplications

“…This paralog specificity identifies those five single-copy genes as higher-priority candidates for functional analysis, given they are fixed in the human population. GOLGA paralogs mediate pathogenic microduplications and deletions at 15q11–13, q24, and q25 causing forms of intellectual delay, including Prader-Willi syndrome 36 – 40 . While we observe multi-gene deletions in these regions ( Figure 5C ), including genes such as the human-specific fusion gene CHRFAM7A whose deletion has been implicated in Alzheimer’s disease pathology 41 , none of these deletions extend beyond the SD into the unique critical regions for named syndromes in our samples.…”