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 controls level of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the pitpn vb tremor mutation and the Eya1 BOR model of human branchiootorenal syndrome. Positional complementation cloning identifies Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between mRNA export receptor and pre-mRNA processing. Population structure of the suppressing allele in wild M. m. castaneus suggests selective advantage. A congenic Mvb1 CAST allele is a useful tool for modifying gene expression from existing mutations and could be used to manipulate engineered mutations containing retroviral elements.Mus musculus is a complex species group with subpopulations that have diverged and hybridized since becoming commensal with humans some 10,000 years ago. Allopatric divergence and re-hybridization of mouse lineages are thought to contribute to the diversity and activity of retroviral elements in the current mouse genomes 1,2 . Host genes that can NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript influence the expression of newly introduced (or newly mobilized) viral elements might be selected for variants that blunt these effects. Our results suggest that Mvb1 is such a locus.Mvb1 was originally identified as a strain-derived locus that modifies the neurological mutant, vibrator 3. The vibrator (vb) mutation is a hypomorphic allele of the phosphatidylinositol transfer protein α (PITPα) gene (pitpn) caused by the insertion of an endogenous retrovirus (intracisternal A particle, or IAP) into the fourth intron of the gene, resulting in 5 to 10-fold loss of PITPα expression. Homozygous vibrator mice show severe action tremor, progressive degeneration of interneurons in the brain stem and spinal cord, and uniform juvenile lethality. However, vibrator mice carrying Mvb1 alleles from the wild-derived CAST/Ei inbred strain show reduced tremor severity and survive to adulthood. In principle, this could be due to a change in physiological requirement for PITPα function or to a change in the steady-state expression level of PITPα derived from the mutant allele. RESULTS Mvb1 is a dosage-sensitive modifier of vibrator RNA accumulationMvb1 modifies the severity of vibrator tremor and the associated juvenile lethality 3 . To examine this effect in more detail, we monitored the longevity of vb mutant mice congenic on a C57BL/6J (B6) strain background with zero, one or two CAST/Ei alleles of Mvb1 ( Figure 1a). Consistent with our behavioral observations, the longevity data indicate a semi-dominant mode of action and high penetrance.To extend these observations to the cellular level, we examined histology of vibrator animals homozygous for either the B6 or CAST allele of Mvb1 (Figure 1b To ask whether Mvb1 acts by altering RNA levels from the mutant...

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