![]() ![]() Mvb1 is a semi-dominant modifier of vibrator mRNA levelĪ, Dosage-sensitive impact of Mvb1 alleles on lifespan of vb homozygotes. musculus approximately 2000–3000 years ago 8. molossinus, thought to have arisen by hybridization between M. Consistent with this selection bias, we show that the IAP-suppressing CAST/Ei allele is the major allele in wild Mus musculus castaneus mice in Southeast Asia and a frequent minor allele in the related Japanese subspecies M. This suggests an orientation-sensitive selective pressure, which could also promote genetic variants that suppress the effects of such insertions, particularly in zones of hybridization among wild mouse populations. Interestingly, we find a strong bias against CTE-containing insertions in introns and against sense orientation for elements that are found in introns in the public draft mouse genome. Nxf1 protein is known to bind and mediate export of constitutive transport elements (CTEs) in the unspliced genomes of several retroviruses, including rodent IAPs 6, and other retroelements, including human LINEs 7. We identify Mvb1 by a positional complementation strategy as an allele of the mRNA nuclear export factor Nxf1. We show that Mvb1 also modifies Eya1 BOR, a model of human branchiootorenal dystrophy caused by insertion of an IAP element (the class most frequently associated with spontaneous mutations in mice) inserted into introns in the sense orientation 5. We show that suppressing Mvb1 alleles elevate steady-state level of correctly processed pitpn mRNA derived from vibrator mutant alleles, creating an in vivo titration of this gene product. Here we examine the mechanism of Mvb1-mediated suppression by demonstrating its effect on vibrator RNA expression, by examining its effects on other retrovirus-associated mutations (selected as examples of different retrovirus families and different classes of insertion sites irrespective of family or class frequency), and by positional identification the Mvb1 gene. ![]() Modifier genes that act on retroviral insertions might be especially useful, as such insertions comprise approximately 15% of spontaneous mutations in laboratory mice 2, 4. 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. However, vibrator mice carrying Mvb1 alleles from the wild-derived CAST/Ei inbred strain show reduced tremor severity and survive to adulthood. Homozygous vibrator mice show severe action tremor, progressive degeneration of interneurons in the brain stem and spinal cord, and uniform juvenile lethality. 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. Mvb1 was originally identified as a strain-derived locus that modifies the neurological mutant, vibrator 3. Our results suggest that Mvb1 is such a locus. Host genes that can influence the expression of newly introduced (or newly mobilized) viral elements might be selected for variants that blunt these effects. 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. ![]() ![]() Mus musculus is a complex species group with subpopulations that have diverged and hybridized since becoming commensal with humans some 10,000 years ago. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |