Inversion variants in human and primate genomes

Abstract

For many years, inversions have been proposed to be a direct driving force in speciation since they suppress recombination when heterozygous. Inversions are the most common large-scale differences among humans and great apes. Nevertheless, they represent large events easily distinguishable by classical cytogenetics, whose resolution, however, is limited. Here, we performed a genome-wide comparison between human, great ape, and macaque genomes using the net alignments for the most recent releases of genome assemblies. We identified a total of 156 putative inversions, between 103 kb and 91 Mb, corresponding to 136 human loci. Combining literature, sequence, and experimental analyses, we analyzed 109 of these loci and found 67 regions inverted in one or multiple primates, including 28 newly identified inversions. These events overlap with 81 human genes at their breakpoints, and seven correspond to sites of recurrent rearrangements associated with human disease. This work doubles the number of validated primate inversions larger than 100 kb, beyond what was previously documented. We identified 74 sites of errors, where the sequence has been assembled in the wrong orientation, in the reference genomes analyzed. Our data serve two purposes: First, we generated a map of evolutionary inversions in these genomes representing a resource for interrogating differences among these species at a functional level; second, we provide a list of misassembled regions in these primate genomes, involving over 300 Mb of DNA and 1978 human genes. Accurately annotating these regions in the genome references has immediate applications for evolutionary and biomedical studies on primates.

Identification of Structural Variation in Chimpanzees Using Optical Mapping and Nanopore Sequencing

“…From this, we identified 425 deletions and 59 inversions that had support from short-read genotyping and/or intersecting with a previously-discovered SV (Tables S7 and S8). In all, our discovery approach using ONT and BNG data achieved 88 novel deletions and 36 novel inversions when compared with the most recent genome-assembly alignment [23,26] and read-depth [22] approaches ( Figure 1A,B).…”

“…Genotype information was retrieved using bedtools query (v2.29.0). To assess whether a variant was novel to this study, calls were compared to previously reported deletions and inversions larger than 10 kbp found in any great ape or any variant discovered in chimpanzee [22,23,26] using bedtools intersect (v2.29.0) with 50% reciprocal overlap. SVs that were either (1) genotyped in one chimpanzee individual (1/1 or 0/1) or (2) reported as discovered in chimpanzee in previous studies, were selected to generate a higher confidence set (filter 1).…”

“…In order to narrow in on a higher-confidence set of SVs, we subsequently performed genotyping of this discovery set using short-read Illumina data from GAGP (>20-fold coverage) of all four chimpanzee subspecies (n = 25) (Table S2) using SVTyper [38]. We also compared our discovered SVs with previously-reported datasets from three recent whole-genome SV screens of chimpanzees [22,23,26], each using diverse genomic methods for discovery (Tables S5 and S6). From this, we identified 425 deletions and 59 inversions that had support from short-read genotyping and/or intersecting with a previously-discovered SV (Tables S7 and S8).…”

Analysis of structural variants in four African Cichlids highlights an association with developmental and immune related genes

“…Structural variation can provide important evolutionary novelty for speciation and the evolution of adaptive traits (Ohno 1970;Lynch 2002;Katju and Lynch 2006;Catacchio, et al 2018). For instance, gene duplication can lead to dosage effects, neofunctionalisation or subfunctionalisation events (Lynch 2002;Katju and Lynch 2006), while inverted regions can experience drastically reduced recombination rates (Catacchio, et al 2018). We took advantage of our SV dataset across 4 species, to investigate which genes are affected by duplication or inversion events.…”

“…Inversions result in supressed recombination when heterozygous, and might act as a protection against gene flow for specific haplotypes (McGaugh and Noor 2012). Inversions might raise in frequency, up to fixation, possibly leading to isolation and even speciation events (Kirkpatrick 2010;Catacchio, et al 2018). Studies in Drosophila melanogaster provided strong evidence for their involvement in adaptation.…”