Identification of human-rhesus macaque inversions using Strand-seq and characterization of chromatin architecture with Hi-C in lymphoblastoid cell lines.

Rhesus macaque is an Old World monkey that shared a common ancestor with human about 25 million years ago and is arguably the most important animal model for studies on human diseases. A deep understanding of its genetics is therefore required for both biomedical research and evolutionary studies. Among structural variants, inversions represent a driving force in speciation and have an important role in disease predisposition. Here we generated a genome-wide map of macaque inversions combining single cell template strand sequencing with cytogenetics. A total of 375 inversions ranging in size from 859 bp to 92 Mbp were identified, increasing by eight-fold the number of inversions previously reported between human and macaque. We identified 88 inversions within larger inversions, in a 'matryoshka' configuration, including four regions of chromosome breakage that have been reused throughout evolution. Interestingly, 19 inversions flanked by highly identical segmental duplications, overlap with recurrent copy-number variants associated with neurocognitive disorders, with nine of these inversions being still polymorphic in humans. In 17 cases we were able to define the lineage specificity of the disease-associated inversions and showed that the Hominidae orientation is always derived, suggesting that duplicated sequences likely played a fundamental role in generating inversions in humans and great apes, creating architectures that now predispose these regions to genetic instability associated with human disease. Finally, we identified 677 genes mapping at 150 inversions breakpoints, with some showing evidence of differential expression in human and macaque cell lines. Further studies aimed at investigating the functional significance of these genes in contributing to phenotypic differences among primates are required. This study represents a valuable resource towards understanding the biology and evolution of primate species.