PT - JOURNAL ARTICLE AU - Mayanglambam Dhruba Singh AU - Matthew Jensen AU - Micaela Lasser AU - Emily Huber AU - Tanzeen Yusuff AU - Lucilla Pizzo AU - Brian Lifschutz AU - Inshya Desai AU - Alexis Kubina AU - Sneha Yennawar AU - Sydney Kim AU - Janani Iyer AU - Diego E. Rincon-Limas AU - Laura Anne Lowery AU - Santhosh Girirajan TI - <em>NCBP2</em>-mediated apoptosis contributes to developmental defects of the schizophrenia-associated 3q29 deletion AID - 10.1101/614750 DP - 2019 Jan 01 TA - bioRxiv PG - 614750 4099 - http://biorxiv.org/content/early/2019/04/22/614750.short 4100 - http://biorxiv.org/content/early/2019/04/22/614750.full AB - The chromosome 3q29 deletion confers &gt;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 &gt;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.