Singh MD , Jensen M , Lasser M , Huber E , Yusuff T , Pizzo L , Lifschutz B , Desai I , Kubina A , Yennawar S , Kim S , Iyer J , Rincon-Limas DE , Lowery LA , Girirajan S .

R01 GM121907 NIGMS NIH HHS , R01 MH109651 NIMH NIH HHS, T32 GM102057 NIGMS NIH HHS

             apoptotic process
             brain development

                microcephaly
                DiGeorge syndrome
                schizophrenia
                Nijmegen breakage syndrome

Xla Wt + fbxo45 MO (Table 1, Fig.8 D E)
Xla Wt + fbxo45 MO (Table 1, Sup. Fig. 13 col 3)
Xla Wt + fbxo45 MO + ncbp2 MO (Table 1)
Xla Wt + ncbp2 MO (Table 1)
Xla Wt + ncbp2 MO (Table 1, Fig. 8 A B C)
Xla Wt + ncbp2 MO (Table 1, Fig. 8 D E)
Xla Wt + ncbp2 MO (Table 1, Sup. Fig. 13 col 2)
Xla Wt + pak2 MO (Table 1, Fig. 8 A B C)
Xla Wt + pak2 MO (Table 1, Sup. Fig. 13 col 4)

	Fig 1. Strategy for identifying cellular phenotypes and genetic interactions of homologs of 3q29 genes. We first knocked down individual or pairs of 14 Drosophila homologs of human genes in the 3q29 region using tissue-specific RNAi. After screening for global phenotypes of RNAi lines for individual homologs of 3q29 genes, we tested 314 pairwise gene interactions using the fly eye, and found that Cbp20 (NCBP2) enhanced the phenotypes of other homologs of 3q29 genes and also interacted with homologs of known neurodevelopmental genes outside of the 3q29 region. Next, we assayed for deeper cellular and neuronal phenotypes of flies with individual and pairwise knockdown of homologs of 3q29 genes, and observed cellular defects due to disrupted apoptosis and cell cycle mechanisms. We confirmed our results by rescuing cellular phenotypes with overexpression of the apoptosis inhibitor Diap1 and by analyzing genes differentially expressed with knockdown of homologs of 3q29 genes. Finally, we tested a subset of three homologs of 3q29 genes in the X. laevis vertebrate model system by injecting two- or four-cell stage embryos with GFP and morpholinos (MOs) for X. laevis homologs of 3q29 genes to observe abnormal eye morphology, as well as injecting one cell with GFP and MOs at the two-cell stage to observe abnormal brain morphology. We found similar developmental defects in X. laevis to those observed in Drosophila, including increased apoptosis that was enhanced with pairwise knockdown of homologs of 3q29 genes and rescued with overexpression of the apoptosis inhibitor xiap. X. laevis embryo diagrams were produced by Nieuwkoop and Faber [117] and adapted from Xenbase [120]. https://doi.org/10.1371/journal.pgen.1008590.g001
	Fig 2. Neurodevelopmental defects in flies with knockdown of individual homologs of 3q29 genes. (A) Percentage of flies with tissue-specific RNAi knockdown of homologs of 3q29 genes (listed with their human counterparts) that manifest lethality or developmental phenotypes. (B) Eight homologs of 3q29 genes with pan-neuronal RNAi knockdown showed defects in climbing ability over ten days (two-way repeated measures ANOVA, p<1×10−4, df = 8, F = 21.097). Data represented show mean ± standard deviation of 10 independent groups of 10 flies for each homolog. (C) Representative brightfield adult eye images of flies with eye-specific GMR-GAL4;UAS-Dicer2 (scale bar = 100 μm) RNAi knockdown of individual homologs of 3q29 genes show rough eye phenotypes. The boxplot shows Flynotyper-derived phenotypic scores for eyes with knockdown of homologs of 3q29 genes (n = 10–14, *p < 0.05, one-tailed Mann–Whitney test with Benjamini-Hochberg correction). (D) Boxplot of adult eye area in flies with GMR-GAL4 RNAi knockdown of fly homologs of 3q29 genes (n = 13–16, *p < 0.05, two-tailed Mann–Whitney test with Benjamini-Hochberg correction). (E) Confocal images of pupal eyes (scale bar = 5 μm) stained with anti-DLG (top) and larval eye discs (scale bar = 30 μm) stained with anti-pH3 (middle) and anti-dcp1 (bottom) illustrate cellular defects posterior to the morphogenetic furrow (white box) upon knockdown of select fly homologs of 3q29 genes. Yellow circles in DLG images indicate cone cell defects, white circles indicate bristle cell defects, yellow arrows indicate rotation defects, and yellow arrowheads indicate secondary cell defects. We note that pupal eye images were taken at a higher intensity for lines with knockdown of dlg1 to account for reduced expression of DLG (see Methods), as these images were only for visualization of cell boundaries in the pupal eye and not for any quantitative analysis. (F) Boxplot of pH3-positive cells in larval eye discs of flies with knockdown of homologs of 3q29 genes (n = 9–12, *p < 0.05, two-tailed Mann–Whitney test with Benjamini-Hochberg correction). (G) Boxplot of dcp1-positive cells in larval eye discs of flies with knockdown of homologs of 3q29 genes (n = 11–12, *p < 0.05, two-tailed Mann–Whitney test with Benjamini-Hochberg correction). All boxplots indicate median (center line), 25th and 75th percentiles (bounds of box), and minimum and maximum (whiskers), with red dotted lines representing the control median. Results for a subset of climbing ability, adult eye area, and pH3 staining experiments were replicated in independent experimental batches (S14 Fig). A list of full genotypes for fly crosses used in these experiments is provided in S2 File. https://doi.org/10.1371/journal.pgen.1008590.g002
	Table 1. Summary of major experiments for knockdown of homologs of 3q29 genes show widespread cellular and neuronal defects. https://doi.org/10.1371/journal.pgen.1008590.t001
	Fig 3. Screening for pairwise interactions of fly homologs of 3q29 genes in the Drosophila eye and nervous system. (A) Heatmap showing average changes in phenotypic scores for pairwise GMR-GAL4 RNAi knockdown of fly homologs of 3q29 genes in the adult eye, compared with recombined lines for individual homologs of 3q29 genes crossed with controls. Gray boxes indicate crosses without available data. Boxplots of phenotypic scores for pairwise knockdown of (B) Cbp20 and (C) dlg1 with other fly homologs of 3q29 genes are shown (n = 5–14, *p < 0.05, two-tailed Mann–Whitney test with Benjamini-Hochberg correction). Green arrows indicate an example pair of reciprocal lines showing enhanced phenotypes compared with their respective single-hit recombined controls. Crosses with the mutant line Tsf2KG01571 are included along with RNAi lines for other homologs of 3q29 genes, as eye-specific RNAi knockdown of Tsf2 was lethal. (D) Representative brightfield adult eye images of flies with pairwise knockdown of fly homologs of 3q29 genes (scale bar = 100 μm) show enhancement (Enh.) of rough eye phenotypes compared with recombined lines for individual homologs of 3q29 genes crossed with controls. (E) Representative confocal images of larval eye discs stained with anti-chaoptin (scale bar = 30 μm) illustrate enhanced defects (Enh.) in axon targeting (white arrows) from the retina to the optic lobes of the brain with eye-specific knockdown of Cbp20/dlg1 and Cbp20/Fsn compared with Cbp20 knockdown. Note that n = 9–17 larval eye disc preparations were assessed for each tested interaction. (F) Flies with pan-neuronal Elav-GAL4 pairwise knockdown of homologs of 3q29 genes showed enhanced defects in climbing ability over ten days (two-way repeated measures ANOVA, p<4.00×10−4, df = 2, F = 7.966) compared with recombined Cbp20 knockdown crossed with control. Data represented show mean ± standard deviation of 10 independent groups of 10 flies for each line tested. Results for the climbing assays were replicated in an independent experimental batch (S14 Fig). All boxplots indicate median (center line), 25th and 75th percentiles (bounds of box), and minimum and maximum (whiskers), with red dotted lines representing the control median. A list of full genotypes for fly crosses used in these experiments is provided in S2 File. https://doi.org/10.1371/journal.pgen.1008590.g003
	Fig 4. Connectivity of 3q29 genes in human gene interaction databases. (A) Genetic interactions of 3q29 genes in the context of a general human gene interaction network (GeneMania). The strongly connected component includes 11/21 total 3q29 genes. Black-shaded nodes represent the input 3q29 genes, while grey nodes represent connector genes in the network. Edge color represents the interaction data source (purple: co-expression, orange: predicted interaction), while edge thickness represents weighted scores for each interaction. (B) Genetic interactions of 19 genes in the 3q29 region in the context of a brain-specific human gene interaction network (GIANT). Large nodes represent the input 3q29 genes, while small nodes represent connector genes in the network. Edge color represents the weighted score for each interaction, from low connectivity (green) to high connectivity (red). (C) Histograms and smoothed normal distributions showing the average connectivity among genes in the 3q29 region (blue) along with two other large CNVs, 16p11.2 (red) and 22q11.2 deletion (green), within a brain-specific gene interaction network. Average connectivity is measured as the shortest weighted distance between two genes, with lower distances representing higher connectivity. Genes within the 3q29 and 22q11.2 deletions were not significantly more connected to each other (p>0.05, one-tailed Mann-Whitney test with Benjamini-Hochberg correction) than random sets of 21 genes throughout the genome (grey). However, genes within the 16p11.2 region were significantly more connected to each other than the random gene sets (p = 0.003, one-tailed Mann-Whitney test with Benjamini-Hochberg correction). (D) Pairwise connectivity of individual 3q29 genes within a brain-specific gene interaction network, excluding six genes not present in the network (RNF168, ZDHHC19, LRRC33, OSTalpha, SMCO1, and TCTEX1D2). Average connectivity is measured as the shortest weighted distance between two genes, with lower values representing higher connectivity. Underlined genes have a higher average connectivity (p<0.05, one-tailed Mann-Whitney test with Benjamini-Hochberg correction) to other genes in the region compared with random sets of 21 genes throughout the genome. https://doi.org/10.1371/journal.pgen.1008590.g004
	Fig 5. Cellular phenotypes with pairwise knockdown of fly homologs of 3q29 genes. (A) Representative brightfield adult eye images (scale bar = 100 μm) show that heterozygous GMR-GAL4 RNAi knockdown of dlg1 enhanced the rough eye phenotype and necrotic patches (yellow circles) of flies heterozygous or homozygous for Cbp20 RNAi. (B) Representative confocal images of pupal eyes (scale bar = 5 μm) stained with anti-DLG illustrate enhanced defects in ommatidial organization upon concomitant knockdown of Cbp20 with other fly homologs of 3q29 genes compared with Cbp20 knockdown. Yellow circles in DLG images indicate cone cell defects, white circles indicate bristle cell defects, yellow arrows indicate rotation defects, and yellow arrowheads indicate secondary cell defects. We note that pupal eye images were taken at a higher intensity for lines with knockdown of Cbp20/dlg1 to account for reduced expression of DLG (see Methods), as these images were only for visualization of cell boundaries in the pupal eye and not for any quantitative analysis. (C) Representative confocal images of pupal eyes (scale bar = 5 μm) stained with Phalloidin illustrate enhanced defects in photoreceptor cell count and organization upon concomitant knockdown of Cbp20 and other fly homologs of 3q29 genes compared with Cbp20 knockdown. (D) Representative confocal images of larval eye discs (scale bar = 30 μm) stained with anti-dcp1 (top) and anti-pH3 (bottom) show enhanced defects in apoptosis and cell proliferation with pairwise knockdown of Cbp20 and other fly homologs of 3q29 genes compared with recombined Cbp20 knockdown crossed with controls. (E) Boxplot of dcp1-positive cells in the larval eye discs of flies with pairwise knockdown of homologs of 3q29 genes (n = 10–11, *p < 0.05, two-tailed Mann–Whitney test with Benjamini-Hochberg correction). (F) Boxplot of pH3-positive cells in the larval eye discs of flies with pairwise knockdown of homologs of 3q29 genes (n = 10–12, *p < 0.05, two-tailed Mann–Whitney test with Benjamini-Hochberg correction). All boxplots indicate median (center line), 25th and 75th percentiles (bounds of box), and minimum and maximum (whiskers), with red dotted lines representing the control median. A list of full genotypes for fly crosses used in these experiments is provided in S2 File. https://doi.org/10.1371/journal.pgen.1008590.g005
	Fig 6. Rescue of cellular phenotypes due to knockdown of fly homologs of 3q29 genes with overexpression of the apoptosis inhibitor Diap1. (A) Representative brightfield adult eye images (scale bar = 100 μm) show rescue of rough eye phenotypes for flies with concomitant GMR-GAL4 RNAi knockdown of Cbp20 or dlg1 and overexpression of Diap1, as well as enhanced (Enh.) phenotypes with overexpression of caspase-9 homolog Dronc. (B) Boxplot of phenotypic scores for flies with knockdown of Cbp20 or dlg1 and overexpression of Diap1 or Dronc (n = 8–9, *p < 0.05, two-tailed Mann–Whitney test with Benjamini-Hochberg correction) is shown. (C) Box plot showing area of necrotic patches in adult fly eyes with knockdown of Cbp20 and overexpression of Dronc (n = 9, *p = 1.14×10−4, one-tailed Mann–Whitney test with Benjamini-Hochberg correction) is shown. (D) Confocal images of pupal eyes (scale bar = 5 μm) stained with anti-DLG illustrate the rescue of ommatidial organization defects due to knockdown of Cbp20 or dlg1 upon overexpression of Diap1. Yellow circles in DLG images indicate cone cell defects, white circles indicate bristle cell defects, yellow arrows indicate rotation defects, and yellow arrowheads indicate secondary cell defects. We note that pupal eye images were taken at a higher intensity for lines with knockdown of dlg1 to account for reduced expression of DLG (see Methods), as these images were only for visualization of cell boundaries in the pupal eye and not for any quantitative analysis. (E) Larval eye discs (scale bar = 30 μm) stained with anti-dcp1 show rescue of apoptosis phenotypes observed in flies with Cbp20 and dlg1 knockdown upon Diap1 overexpression as well as enhanced (Enh.) phenotypes upon Dronc overexpression. (F) Boxplot of dcp1-positive cells in the larval eye discs of flies with knockdown of Cbp20 or dlg1 and Diap1 or Dronc overexpression (n = 9–18, *p < 0.05, two-tailed Mann–Whitney test with Benjamini-Hochberg correction). (G) Representative confocal images of larval eye discs stained with anti-chaoptin (scale bar = 30 μm) illustrate the suppression (Supp.) of axon targeting defects (white arrows) observed in flies due to knockdown of Cbp20 or dlg1 with overexpression of Diap1. Note that n = 8–18 larval eye disc preparations were assessed for each interaction cross tested. All boxplots indicate median (center line), 25th and 75th percentiles (bounds of box), and minimum and maximum (whiskers), with red dotted lines representing the control median. A list of full genotypes for fly crosses used in these experiments is provided in S2 File. https://doi.org/10.1371/journal.pgen.1008590.g006
	Fig 7. Pairwise interactions between fly homologs of 3q29 genes and other neurodevelopmental genes. (A) Heatmap showing the average changes in phenotypic scores for the GMR-GAL4 pairwise RNAi knockdown of fly homologs for 3q29 genes and other neurodevelopmental genes (along with their human counterparts) in the adult eye, compared with recombined lines for individual homologs of 3q29 genes crossed with controls. (B) Representative brightfield adult eye images of flies with pairwise knockdown of fly homologs for 3q29 genes and known neurodevelopmental genes (scale bar = 100 μm) show enhancement (Enh.) or suppression (Supp.) of rough eye phenotypes and necrotic patches compared with flies with knockdown of individual homologs of neurodevelopmental genes. A list of full genotypes for fly crosses used in these experiments is provided in S2 File. https://doi.org/10.1371/journal.pgen.1008590.g007
	Fig 8. Developmental phenotypes observed with knockdown of homologs of 3q29 genes in X. laevis models. (A) To study brain morphology upon knockdown of X. laevis homologs of genes in the 3q29 region, one cell in a two-cell embryo was injected with single or multiple MOs for homologs of 3q29 genes while the other cell remained uninjected. Representative images of stage 47 X. laevis tadpoles (scale bar = 500 μm) with MO knockdown of ncbp2, fxbo45 and pak2 show morphological defects and decreased size, including decreased forebrain (highlighted in red on the control image) and midbrain (highlighted in yellow) area, compared with control tadpoles. Pairwise knockdown of fbxo45 and ncbp2 enhanced these phenotypes, which were also rescued with overexpression of xiap. (B) Box plot of forebrain area in X. laevis models with knockdown of homologs of 3q29 genes, normalized to controls (n = 30–63, *p < 0.05, two-tailed Welch’s T-test with Benjamini-Hochberg correction). Red box indicates rescue of decreased ncbp2 forebrain area with overexpression of the apoptosis inhibitor xiap. (C) Box plot of midbrain area in X. laevis models with knockdown of homologs of 3q29 genes, normalized to controls (n = 30–63, *p < 0.05, two-tailed Welch’s T-test with Benjamini-Hochberg correction). Red box indicates rescue of decreased ncbp2 midbrain area with overexpression of the apoptosis inhibitor xiap. (D) Western blot analysis of X. laevis whole embryos show increased intensity of cleaved caspase-3 bands at 19kD and 17kD with knockdown of homologs of 3q29 genes, including enhanced caspase-3 levels with knockdown of multiple homologs of 3q29 genes and rescued levels with xiap overexpression. β-actin was used as a loading control on the same blot. Representative western blot images shown are cropped; the full blots for both replicates are provided in S12 Fig. (E) Quantification of western blot band intensity for caspase-3 levels, normalized to the loading control. Red box indicates rescue of increased caspase-3 levels with overexpression of the apoptosis inhibitor xiap. All boxplots indicate median (center line), 25th and 75th percentiles (bounds of box), and minimum and maximum (whiskers), with red dotted lines representing the control median. The data shown for the brain area experiments represent pooled results of three experimental batches, and were normalized to the respective controls from each batch. X. laevis embryo diagrams were produced by Nieuwkoop and Farber [117] and adapted from Xenbase [120]. https://doi.org/10.1371/journal.pgen.1008590.g008
	Fig 9. Interactions between NCBP2 and other homologs of 3q29 genes contribute to neurodevelopmental defects through conserved cellular pathways. (A) We identified 44 interactions between pairs of Drosophila homologs of 3q29 genes. With the exception of Ulp1 (SENP5), the cellular phenotypes of each homolog were significantly enhanced with simultaneous knockdown of Cbp20. While other homologs of 3q29 genes also interact with each other, our data suggest that Cbp20 is a key modulator of cellular phenotypes within the deletion region. (B) Schematic representing the network context of NCBP2 and other genes in the 3q29 region towards neurodevelopmental phenotypes. We propose that the effects of NCBP2 disruption propagate through a network of functionally-related genes, including other 3q29 genes (highlighted in blue), leading to a cascade of disruptions in key biological mechanisms, including apoptosis and cell cycle pathways. These pathways jointly contribute towards the observed neurodevelopmental phenotypes. https://doi.org/10.1371/journal.pgen.1008590.g009
	Figure S12. Quantification of 3q29 morpholino knockdown and apoptosis marker levels in X. laevis models. (A) Electrophoretic gels show decreased expression of homologs of 3q29 genes due to morpholino (MO) knockdown at various concentrations in X. laevis embryos. Three replicates (uninjected and two MO concentrations) were performed for each morpholino, and band intensities were compared with expression of ODC1 controls taken from the same cDNA samples and run on gels processed in parallel. (B) Quantification of expression for homologs of 3q29 genes at different MO concentrations, as measured by band intensity ratio to ODC1 controls (n = 3 replicates, *p<0.05, two-tailed Welch’s T-test with Benjamini-Hochberg correction). (C) Full images of western blots for quantification of cleaved caspase-3 levels in X. laevis embryos with MO knockdown of homologs of 3q29 genes. Two replicate experiments were performed, and the intensity of bands at 19kD and 17kD (green arrows), corresponding with cleaved caspase-3, were normalized to those for the β-actin loading controls. Embryos injected with control MO, uninjected embryos, and embryos treated with 30% EtOH as a positive control were included with the embryos injected with 3q29 MOs. https://doi.org/10.1371/journal.pgen.1008590.s012
	Figure S13. Eye phenotypes observed with knockdown of homologs of 3q29 genes in X. laevis models. (A) Representative eye images of stage 42 X. laevis tadpoles with MO knockdown of homologs of 3q29 genes (scale bar = 500 μm) show defects in eye size and morphology compared with the control (top). These defects were rescued with co-injection and overexpression of mRNA for homologs of 3q29 genes, as well as overexpression of the apoptosis inhibitor xiap for ncbp2 (bottom). (B) Box plot of eye area in X. laevis models with knockdown of homologs of 3q29 genes, normalized to controls, is shown (n = 48–71, *p < 0.05, two-tailed Welch’s T-test with Benjamini-Hochberg correction). Models with ncbp2 knockdown and xiap overexpression showed an increased eye size compared with ncbp2 knockdown. (C) Box plot of eye area in X. laevis models with knockdown of homologs of 3q29 genes and overexpression of mRNA for homologs of 3q29 genes, normalized to controls, is shown (n = 56–63, *p < 0.05, two-tailed Welch’s T-test with Benjamini-Hochberg correction). All boxplots indicate median (center line), 25th and 75th percentiles (bounds of box), and minimum and maximum (whiskers), with red dotted lines representing the control median. The data shown for the eye area experiments represent pooled results of three experimental batches, and were normalized to the respective controls from each batch. https://doi.org/10.1371/journal.pgen.1008590.s013

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