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NCBP2-mediated apoptosis contributes to developmental defects of the schizophrenia-associated 3q29 deletion

Mayanglambam Dhruba Singh, Matthew Jensen, Micaela Lasser, Emily Huber, Tanzeen Yusuff, Lucilla Pizzo, Brian Lifschutz, Inshya Desai, Alexis Kubina, Sneha Yennawar, Sydney Kim, Janani Iyer, Diego E. Rincon-Limas, Laura Anne Lowery, Santhosh Girirajan
doi: https://doi.org/10.1101/614750
Mayanglambam Dhruba Singh
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Matthew Jensen
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Micaela Lasser
2Department of Biology, Boston College, Chestnut Hill, MA 02467 USA
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Emily Huber
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Tanzeen Yusuff
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Lucilla Pizzo
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Brian Lifschutz
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Inshya Desai
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Alexis Kubina
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Sneha Yennawar
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Sydney Kim
2Department of Biology, Boston College, Chestnut Hill, MA 02467 USA
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Janani Iyer
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
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Diego E. Rincon-Limas
3Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611 USA
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Laura Anne Lowery
2Department of Biology, Boston College, Chestnut Hill, MA 02467 USA
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Santhosh Girirajan
1Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802 USA
4Department of Anthropology, Pennsylvania State University, University Park, PA 16802 USA
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ABSTRACT

The chromosome 3q29 deletion confers >40-fold risk for schizophrenia and related neurodevelopmental disorders. Here, we used quantitative methods to assay Drosophila melanogaster and Xenopus laevis models with knockdown of individual 3q29 homologs in different tissues. We identified developmental and neuronal phenotypes for multiple 3q29 homologs, and specifically observed cellular defects due to altered cell cycle and apoptosis mechanisms. We screened 316 pairwise knockdowns of 3q29 genes in the developing eye, and identified 44 interactions between pairs of 3q29 genes and 34 interactions with other neurodevelopmental genes. In particular, NCBP2 synergistically enhanced the phenotypes of other 3q29 homologs in both Drosophila and X. laevis, leading to significant increases in apoptosis that disrupt cellular organization and brain morphology during development. The NCBP2-driven defects were rescued with overexpression of the apoptosis inhibitor Diap1/XIAP in both models. Our study implicates NCBP2-mediated genetic interactions within apoptosis pathways as a potential mechanism for pathogenicity of the 3q29 deletion.

SIGNIFICANCE Rare copy-number variants, or large deletions and duplications in the genome, are associated with a wide range of neurodevelopmental disorders. For example, the 3q29 deletion confers a >40-fold risk for schizophrenia. To understand the biological mechanisms underlying the pathogenicity of this deletion, we systematically tested 14 individual homologs and 316 pairwise interactions of 3q29 genes for neuronal, cellular, and developmental phenotypes in Drosophila melanogaster and Xenopus laevis models. We found that a key modifier gene, NCBP2, synergistically enhances the neurodevelopmental phenotypes of other 3q29 genes through disruption of apoptosis pathways. This study establishes a novel paradigm for the role of modifier genes within the region towards CNV pathogenicity and provides strong evidence for a mechanistic association between apoptosis and schizophrenia.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 22, 2019.
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NCBP2-mediated apoptosis contributes to developmental defects of the schizophrenia-associated 3q29 deletion
Mayanglambam Dhruba Singh, Matthew Jensen, Micaela Lasser, Emily Huber, Tanzeen Yusuff, Lucilla Pizzo, Brian Lifschutz, Inshya Desai, Alexis Kubina, Sneha Yennawar, Sydney Kim, Janani Iyer, Diego E. Rincon-Limas, Laura Anne Lowery, Santhosh Girirajan
bioRxiv 614750; doi: https://doi.org/10.1101/614750
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NCBP2-mediated apoptosis contributes to developmental defects of the schizophrenia-associated 3q29 deletion
Mayanglambam Dhruba Singh, Matthew Jensen, Micaela Lasser, Emily Huber, Tanzeen Yusuff, Lucilla Pizzo, Brian Lifschutz, Inshya Desai, Alexis Kubina, Sneha Yennawar, Sydney Kim, Janani Iyer, Diego E. Rincon-Limas, Laura Anne Lowery, Santhosh Girirajan
bioRxiv 614750; doi: https://doi.org/10.1101/614750

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