Formation of Chimeric Genes by Copy-Number Variation as a Mutational Mechanism in Schizophrenia

Chimeric genes can be caused by structural genomic rearrangements that fuse together portions of two different genes to create a novel gene. We hypothesize that brain-expressed chimeras may contribute to schizophrenia. Individuals with schizophrenia and control individuals were screened genome wide for copy-number variants (CNVs) that disrupted two genes on the same DNA strand. Candidate events were filtered for predicted brain expression and for frequency < 0.001 in an independent series of 20,000 controls. Four of 124 affected individuals and zero of 290 control individuals harbored such events (p = 0.002); a 47 kb duplication disrupted MATK and ZFR2, a 58 kb duplication disrupted PLEKHD1 and SLC39A9, a 121 kb duplication disrupted DNAJA2 and NETO2, and a 150 kb deletion disrupted MAP3K3 and DDX42. Each fusion produced a stable protein when exogenously expressed in cultured cells. We examined whether these chimeras differed from their parent genes in localization, regulation, or function. Subcellular localizations of DNAJA2-NETO2 and MAP3K3-DDX42 differed from their parent genes. On the basis of the expression profile of the MATK promoter, MATK-ZFR2 is likely to be far more highly expressed in the brain during development than the ZFR2 parent gene. MATK-ZFR2 includes a ZFR2-derived isoform that we demonstrate localizes preferentially to neuronal dendritic branch sites. These results suggest that the formation of chimeric genes is a mechanism by which CNVs contribute to schizophrenia and that, by interfering with parent gene function, chimeras may disrupt critical brain processes, including neurogenesis, neuronal differentiation, and dendritic arborization

Formation of Chimeric Genes by Copy Number Variation as a Mutational Mechanism in Schizophrenia

Thesis (Ph.D.)--University of Washington, 2013Chimeric genes are caused by structural genomic rearrangements that fuse together portions of two different genes to create a novel gene. Chimeras may differ from their parent genes in localization, regulation, or function. We screened 122 individuals with schizophrenia and 120 controls for germline rearrangements anywhere in the genome leading to chimeras. Three cases and zero controls harbored such events: fusions of MATK to ZFR2, of DNAJA2 to NETO2, and of MAP3K3 to DDX42. Each fusion produces a stable protein when exogenously expressed in cultured cells. Temporal expression data indicate that the parent genes of all three chimeras are expressed in the brain during development. We detected the chimeric transcripts of DNAJA2-NETO2 and MAP3K3-DDX42 in patient lymphoblasts; parent genes of the MATK-ZFR2 chimera are expressed only in the brain. Formation of chimeras involved loss of critical domains of parent genes. Subcellular localizations of DNAJA2-NETO2 and MAP3K3-DDX42 are dramatically altered compared to their parent genes. The MATK-ZFR2 chimera includes a novel, frame-shifting splice variant of the previously uncharacterized ZFR2 gene. In contrast with the nuclear localization of full-length ZFR2, frameshifted ZFR2 localizes preferentially to dendritic branch sites, and its chimera is predicted to be highly overexpressed during development. Germline chimeric mutations in schizophrenia provide a new model for functional interpretation of structural variation in human illness, and implicate new genes and pathways in schizophrenia pathogenesis

Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.

Genes disrupted in schizophrenia may be revealed by&nbsp;de novo mutations in affected persons from otherwise&nbsp;healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13&nbsp;weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain