Inversions play an important role in disease and evolution but are difficult to characterize because their breakpoints map to large repeats. We increased by sixfold the number (n = 1,069) of previously reported great ape inversions by using single-cell DNA template strand and long-read sequencing. We find that the X chromosome is most enriched (2.5-fold) for inversions, on the basis of its size and duplication content. There is an excess of differentially expressed primate genes near the breakpoints of large (>100 kilobases (kb)) inversions but not smaller events. We show that when great ape lineage-specific duplications emerge, they preferentially (approximately 75%) occur in an inverted orientation compared to that at their ancestral locus. We construct megabase-pair scale haplotypes for individual chromosomes and identify 23 genomic regions that have recurrently toggled between a direct and an inverted state over 15 million years. The direct orientation is most frequently the derived state for human polymorphisms that predispose to recurrent copy number variants associated with neurodevelopmental disease.
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Strand-seq data aligned to GRCh38 and ape-specific composite files are available at zenodo, (https://doi.org/10.5281/zenodo.3818043); the PacBio and Bionano datasets are reported in Supplementary Tables 11 and 14; Supplementary data are available at GitHub (https://github.com/daewoooo/ApeInversion_paper); the PacBio and Bionano inversion callset are available at GitHub (https://github.com/daewoooo/ApeInversion_paper/tree/master/Supplementary_datasets).
The primatR package is available at GitHub (https://github.com/daewoooo/primatR); the breakpointR package is available at GitHub (https://github.com/daewoooo/breakpointR) (devel branch); custom scripts are available at GitHub (https://github.com/daewoooo/ApeInversion_paper/tree/master/Custom_scripts); software releases at the publication date are available at Zenodo (https://doi.org/10.5281/zenodo.3556774).
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We thank T. Brown for assistance in editing this manuscript. In addition, we thank S. Pääbo for generously providing the bonobo (Ulindi) and chimpanzee (Dorien) cell lines used in this study, along with H. Kaessmann and E. Leushkin for access to the ape RNA-seq data. We acknowledge the technical assistance provided by A. Pang and A. Hastie, who provided the Bionano inversion calls for NHPs. We also thank the European Molecular Biology Laboratory Genomics Core facility, particularly V. Benes and J. Zimmermann, for assistance with automating the Strand-seq library generation. This work was supported, in part, by grants from the National Institutes of Health (NIH; grant nos. HG002385 and HG010169 to E.E.E.). A.D.S. was supported by an Alexander von Humboldt Foundation Research Fellowship. P.H. was supported by the NIH Pathway to Independence Award (National Human Genome Research Institute, no. K99HG011041). A.S. was supported by the NIH Genome Training Grant (T32, no. HG000035-23). J.O.K. was supported by a European Research Council Consolidator grant (no. 773026). S.C. was supported by a National Health and Medical Research Council CJ Martin Biomedical Fellowship (no. 1073726). E.E.E. is an investigator of the Howard Hughes Medical Institute.
E.E.E. is on the scientific advisory board of DNAnexus.
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Porubsky, D., Sanders, A.D., Höps, W. et al. Recurrent inversion toggling and great ape genome evolution. Nat Genet 52, 849–858 (2020). https://doi.org/10.1038/s41588-020-0646-x
BMC Genomics (2021)