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.

Keywords: copy number variants; core duplicons; evolution; inversions; segmental duplications.

Figure 1

BP2-BP3 inversion analysis. (a) UCSC Genome Browser view of the BP2-BP3 region in humans. The black bar represents the putative inversion; fosmid and BAC clones used for FISH experiments on interphase nuclei are indicated by red, green, and blue bars. Strand-seq data for chimpanzee, gorilla, orangutan, and macaque are reported, showing a direct orientation of the region for chimpanzee and gorilla and an inverted orientation for orangutan and macaque. (b) Minimiro sequence homology plots between humans and nonhuman primates (NHPs) for the 15q11-q13 region are depicted. Teal and orange lines connect the BP2-BP3 orthologous regions between humans and NHPs, in direct and inverted orientation, respectively. The remaining orthologous regions of the 15q11-13 locus are connected using gray lines. (c) FISH results on interphase nuclei for the BP2-BP3 inversion are shown for each analyzed species. The color order indicates probes’ relative orientation, with red–green–blue signals showing the direct orientation and green–red–blue signals showing inverted haplotypes. FISH analyses show that orangutan, macaque, and marmoset (outgroup) are all inverted when compared to the human reference genome orientation, while chimpanzee and gorilla are direct. The timing of species divergences is also shown at the top (mya = million years ago). GM12878 = Homo sapiens; PTR = Pan troglodytes; GGO = Gorilla gorilla; PPY = Pongo pygmaeus; MMU = Macaca mulatta; CJA = Callithrix jacchus.

Figure 2

Human sequence homology plots of the 15q11-13 region. (a) Minimiro comparison of the whole 15q11-13 human locus against itself (T2T CHM13v2.0/hs1). The five SD blocks involved in pathogenic rearrangements are depicted (BP1 to BP5). Colored lines connect paralogous SDs between different BPs. A detailed map of the SDs’ organization and their relative orientation is depicted for each BP. Larger arrows indicate duplication modules containing core duplicons widespread along the locus. (b) Minimiro comparison of BP1 versus BP3 highlights homologous SDs between them. Red and blue lines represent sequences showing a relative inverted and direct orientation between the two BPs, respectively. (c) Minimiro comparison of BP2 versus BP3 highlighting homologous SDs between the two BPs. Red lines represent sequences showing a relative inverted orientation between the two BPs, and blue lines a direct orientation. (d) Minimiro comparison of BP4 versus BP5 highlighting homologous SDs between the two BPs. Red lines represent sequences showing a relative inverted orientation between BP4 and BP5, and blue lines a direct orientation.

Figure 3

Sequence homology plots of human versus nonhuman primates. Minimiro comparison of the whole 15q11-13 human locus against NHP orthologous regions. Gray lines connect syntenic single-copy regions, while colored lines represent matches between duplication blocks. For each NHP, the duplication blocks are labeled with letters A to E, where a detailed map of the SDs’ organization and their relative orientations are depicted. Larger arrows indicate duplication modules containing core duplicons widespread along the locus.

Figure 4

15q11-13 evolutionary history. (a) Summary of all the 15q11-q13 haplotypes found in humans and NHPs. Each region is indicated using a different symbol (triangle, rhombus, square, star, and hexagon). Arrowheads indicate the orientation of the region found in this study with teal shades for the direct orientation and orange for the inverted. The human H2 haplotype data are from Porubsky and colleagues [25]. (b) Black arrows indicate when the rearrangement occurred during evolution. Teal symbols indicate the direct orientation, orange symbols indicate inversions and patterned symbols polymorphic inversions. Symbols are reported on the branch where the inversion occurred HSA = Homo sapiens; PTR = Pan troglodytes; GGO = Gorilla gorilla; PPY = Pongo pygmaeus; MMU = Macaca mulatta; CJA = Callithrix jacchus.