SUMMARY
Phenotypic variability is a hallmark of diseases involving chromosome gains and losses, such as Down Syndrome and cancer. Allelic variances have been thought to be the sole cause of this heterogeneity. Here, we systematically examine the consequences of gaining and losing single or multiple chromosomes to show that the aneuploid state causes non-genetic phenotypic variability. Yeast cell populations harboring the same defined aneuploidy exhibit heterogeneity in cell cycle progression and response to environmental perturbations. Variability increases with degree of aneuploidy and is partly due to gene copy number imbalances, suggesting subtle changes in gene expression impact the robustness of biological networks and cause alternate behaviors when they occur across many genes. As inbred trisomic mice also exhibit variable phenotypes, we further propose that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuploidy.
West Nile virus (WNV) is a prototypical emerging virus for which no effective therapeutics currently exist. WNV uses programmed ؊1 ribosomal frameshifting (؊1 PRF) to synthesize the NS1 protein, a C terminally extended version of its nonstructural protein 1, the expression of which enhances neuroinvasiveness and viral RNA abundance. Here, the NS1 frameshift signals derived from four WNV strains were investigated to better understand ؊1 PRF in this quasispecies. Sequences previously predicted to promote ؊1 PRF strongly promote this activity, but frameshifting was significantly more efficient upon inclusion of additional 3 sequence information. The observation of different rates of ؊1 PRF, and by inference differences in the expression of NS1, may account for the greater degrees of pathogenesis associated with specific WNV strains. Chemical modification and mutational analyses of the longer and shorter forms of the ؊1 PRF signals suggests dynamic structural rearrangements between tandem stem-loop and mRNA pseudoknot structures in two of the strains. A model is suggested in which this is employed as a molecular switch to fine tune the relative expression of structural to non-structural proteins during different phases of the viral replication cycle.
Background: Yeast have been used to study hungtingtin toxicity.Results: Both HttQ103 and HttQP103 are toxic in yeast with [PSI+] prion. This toxicity is markedly rescued by a Sup35 fragment.Conclusion: Sequestration of the essential protein, Sup35, contributes to Htt toxicity in yeast.Significance: This research demonstrates the complex nature of Htt toxicity.
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