Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia

Caitlin Rippey, Tom Walsh, Suleyman Gulsuner, Matt Brodsky, Alexander Nord, Molly Gasperini, Sarah Pierce, Cailyn Spurrell, Bradley P. Coe, Niklas Krumm, Ming K. Lee, Jonathan Sebat, Jon M. McClellan, Mary Claire King

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)697-710
Number of pages14
JournalAmerican Journal of Human Genetics
Volume93
Issue number4
DOIs
StatePublished - Oct 3 2013
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Rippey, C., Walsh, T., Gulsuner, S., Brodsky, M., Nord, A., Gasperini, M., Pierce, S., Spurrell, C., Coe, B. P., Krumm, N., Lee, M. K., Sebat, J., McClellan, J. M., & King, M. C. (2013). Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia. American Journal of Human Genetics, 93(4), 697-710. https://doi.org/10.1016/j.ajhg.2013.09.004