Human-specific gene evolution and structural diversity of the chromosome 16p11.2 autism CNV. X. Nuttle1, G. Giannuzzi2, M. H. Duyzend1, P. H. Sudmant1, O. Penn1, G. Chiatante3, M. Malig1, J. Huddleston1,4, L. Denman1, L. Harshman1, C. Baker1, A. Raja1,4, K. Penewit1, F. Antonacci3, R. Bernier5, A. Reymond2, E. E. Eichler1,4 1) Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; 2) Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland; 3) Department of Biology. University of Bari, Bari, Italy; 4) Howard Hughes Medical Institute, Seattle, WA, USA; 5) Department of Psychiatry, University of Washington, Seattle, WA, USA.

   Recurrent deletions and duplications at 16p11.2 are a major contributor to autism and also associate with schizophrenia and extremes of body mass index and head circumference. These events occur via nonallelic homologous recombination (NAHR) between directly oriented segmental duplications (BP4 and BP5) ~600 kbp apart. Using whole genome sequencing (WGS) data from 2,551 humans, 86 great apes, a Neanderthal, and a Denisovan, we observed extensive copy number variation in BP4 and BP5 in human populations and identified BOLA2 as a gene duplicated in Homo sapiens after our divergence from ancient hominins. Performing massively parallel and PacBio sequencing of large-insert clones from orangutan and chimpanzee, we generated complete sequence over the 16p11.2 locus in these apes and reconstructed its evolutionary history. We find three inversions occurred in the human lineage after divergence from orangutan, affecting > 1 Mbp of sequence, including 45 genes. In concert with these evolutionary inversions, > 950 kbp have been added to the region via segmental duplication. Comparative sequence analyses suggest that BOLA2 was part of an ~110 kbp segment that duplicated from BP5 to BP4 ~250 kya at the time when Homo sapiens emerged as a species. Modern humans carry at least one additional copy of BOLA2 (ranging from 3 to 14 diploid copies) in contrast to apes, Neanderthal, and Denisova, where the gene exists as two diploid copies. BOLA2 is thought to be involved in cell proliferation or cell cycle regulation. RT-PCR and RNA-seq suggest BOLA2 is widely expressed, and expression levels in lymphoblastoid cell lines correlate with copy number (r = 0.29). Using the same sequencing strategy as above, we completely sequenced four distinct human structural haplotypes at 16p11.2 (> 5 Mbp of sequence). We discover haplotypes where BP4 and BP5 differ by hundreds of kbp including tandem duplications of BOLA2, leading to likely differences in predisposition to NAHR. Leveraging our high quality human haplotype sequences, we are currently assaying BOLA2 copy number and refining breakpoints in > 125 patients with a 16p11.2 deletion or duplication. Our preliminary data suggest that breakpoints cluster near the Homo sapiens-specific duplications involving BOLA2. These findings raise the exciting possibility that predisposition to recurrent rearrangements associated with autism is linked to the emergence of novel duplicated genes in the last 250,000 years of our species' evolution.

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