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A natural allele of Nxf1 suppresses retrovirus insertional mutations


Endogenous retroviruses have shaped the evolution of mammalian genomes. Host genes that control the effects of retrovirus insertions are therefore of great interest. The modifier-of-vibrator-1 locus (Mvb1) controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the Pitpnvb tremor mutation and the Eya1BOR model of human branchiootorenal syndrome. Positional complementation cloning identifies Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between the mRNA export receptor and pre-mRNA processing. Population structure of the suppressive allele in wild Mus musculus castaneus suggests selective advantage. A congenic Mvb1CAST allele is a useful tool for modifying gene expression from existing mutations and could be used to manipulate engineered mutations containing retroviral elements.

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Figure 1: Mvb1 is a semidominant modifier of vibrator mRNA level.
Figure 2: Mvb1 modifies Eya1BOR phenotypes and RNA level.
Figure 3: Recombination and physical map of the Mvb1 interval.
Figure 4: Transgenic complementation of Mvb1.
Figure 5: Nxf1 alleles in inbred strains and wild mice.
Figure 6: Model for Nxf1 modifier activity on retrovirus insertional mutations.


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We thank A. Ryan for advice and assistance with electrophysiology; X-D. Fu and C. J. Wills for discussions; M. Rosenfeld, R. Kolodner and A. Wynshaw-Boris for comments on draft manuscripts; A. Miyanohara for assistance with viral packaging; the UCSD Cancer Center Transgenic Mouse Facility for transgenic mouse production; and I. Kalcheva for assistance with BAC sequencing. This work was supported by grants from the US National Institutes of Health (B.A.H. and E.K.) and the Medical Research Service of the US Department of Veterans Affairs (E.K.). B.A.H. is a Pew Scholar in the Biomedical Sciences.

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Correspondence to Bruce A Hamilton.

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A provisional patent application related to this work has been filed by the University of California. The application claims in part a digenic system for gene regulation in transgenic cells and animals.

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Floyd, J., Gold, D., Concepcion, D. et al. A natural allele of Nxf1 suppresses retrovirus insertional mutations. Nat Genet 35, 221–228 (2003).

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