Palindromic GOLGA core duplicon promotes 15q13.3 microdeletion, inversion polymorphisms, and large-scale primate structural variation. M. Y. Dennis1,7, F. Antonacci1,7, J. Huddleston1,2, P. H. Sudmant1, K. Meltz Steinberg3, T. A. Graves3, M. Malig1, L. Vives1, L. Denman1, C. Baker1, C. T. Amemiya4, A. Stuart4, W. J. Tang4, B. Munson4, J. A. Rosenfeld5, L. G. Shaffer5,6, R. K. Wilson3, E. E. Eichler1,2 1) Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; 2) Howard Hughes Medical Institute, Seattle, WA, USA; 3) The Genome Institute at Washington University, Washington University School of Medicine, St. Louis, MO, USA; 4) Benaroya Research Institute at Virginia Mason, Seattle, WA, USA; 5) Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA, USA; 6) Paw Print Genetics, Genetic Veterinary Sciences, Inc., Spokane, WA, USA; 7) These authors contributed equally to this work.

   Microdeletions of chromosome 15q13.3 are one of the most common recurrent structural variants associated with intellectual disability, schizophrenia, autism, and epilepsy. Non-allelic homologous recombination of flanking segmental duplications (SDs) at this locus mediates the formation of structural variants; however, the complex architecture of these SDs has yet to be fully described. Utilizing Illumina short-read, capillary, and PacBio sequencing, we comprehensively characterized these SDs in humans and nonhuman primates. We discovered and characterized five alternate structural configurations of the 15q13.3 region in humans ranging in size from 2 to 3 Mbp; these configurations arose as a result of human-specific expansions of SDs in conjunction with two independent evolutionary inversion eventsa 2 Mbp inversion () and a smaller 203 kbp inversion (), never before reported. Interestingly, the inversion is population stratified with frequencies ranging from less than 5% in Asian to as high as 40% in European populations. We show that both inversion polymorphism breakpoints map to a GOLGA core duplicona primate-specific chromosome 15 repeat of 15 kbpembedded within a larger 58 kbp inverted repeat (or palindrome). These changes led to the formation of two different structural configurations predisposing to 15q13.3 and CHRNA7 microdeletions, respectively. Remarkably, the same GOLGA-flanked palindrome that promoted two independent inversion events in humans also demarcated the breakpoints of the recurrent 15q13.3 microdeletions as well as an expansion of SDs in the human lineage and an independent inversion in chimpanzee. Overall, these results provide direct evidence for the role of this core duplicon and its palindromic architecture in evolutionary and disease-related instability of chromosome 15.

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