Vahan B Indjeian and Andrew W Murray. 2007. “
Budding yeast mitotic chromosomes have an intrinsic bias to biorient on the spindle.” Curr Biol, 17, 21, Pp. 1837-46.
Publisher's VersionAbstractBACKGROUND: Chromosomes must biorient on the mitotic spindle, with the two sisters attached to opposite spindle poles. The spindle checkpoint detects unattached chromosomes and monitors biorientation by detecting the lack of tension between two sisters attached to the same pole. After the spindle has been depolymerized and allowed to reform, budding yeast sgo1 mutants fail to biorient their sister chromatids and die as cells divide. RESULTS: In sgo1 mutants, chromosomes attach to microtubules normally but cannot reorient if both sisters attach to the same pole. The mutants' fate depends on the position of the spindle poles when the chromosomes attach to microtubules. If the poles have separated, sister chromatids biorient, but if the poles are still close, sister chromatids often attach to the same pole, missegregate, and cause cell death. CONCLUSIONS: These observations argue that budding yeast mitotic chromosomes have an intrinsic, geometric bias to biorient on the spindle. When the poles have already separated, attaching one kinetochore to one pole predisposes its sister to attach to the opposite pole, allowing the cells to segregate the chromosomes correctly. When the poles have not separated, the second kinetochore eventually attaches to either of the two poles randomly, causing orientation errors that are corrected in the wild-type but not in sgo1 mutants. In the absence of spindle damage, sgo1 cells divide successfully, suggesting that kinetochores only make stable attachments to microtubules after the cells have entered mitosis and separated their spindle poles.
Nicholas T Ingolia and Andrew W Murray. 2007. “
Positive-feedback loops as a flexible biological module.” Curr Biol, 17, 8, Pp. 668-77.
Publisher's VersionAbstractBACKGROUND: Bistability in genetic networks allows cells to remember past events and to make discrete decisions in response to graded signals. Bistable behavior can result from positive feedback, but feedback loops can have other roles in signal transduction as well. RESULTS: We introduced positive feedback into the budding-yeast pheromone response to convert it into a bistable system. In the presence of feedback, transient induction with high pheromone levels caused persistent pathway activation, whereas at lower levels a fraction of cells became persistently active but the rest inactivated completely. We also generated mutations that quantitatively tuned the basal and induced expression levels of the feedback promoter and showed that they qualitatively changed the behavior of the system. Finally, we developed a simple stochastic model of our positive-feedback system and showed the agreement between our simulations and experimental results. CONCLUSIONS: The positive-feedback loop can display several different behaviors, including bistability, and can switch between them as a result of simple mutations.
Michael M. Desai, Daniel S Fisher, and Andrew W Murray. 2007. “
The speed of evolution and maintenance of variation in asexual populations.” Curr Biol, 17, 5, Pp. 385-94.
Publisher's VersionAbstractBACKGROUND: The rate at which beneficial mutations accumulate determines how fast asexual populations evolve, but this is only partially understood. Some recent clonal-interference models suggest that evolution in large asexual populations is limited because smaller beneficial mutations are outcompeted by larger beneficial mutations that occur in different lineages within the same population. This analysis assumes that the important mutations fix one at a time; it ignores multiple beneficial mutations that occur in the lineage of an earlier beneficial mutation, before the first mutation in the series can fix. We focus on the effects of such multiple mutations. RESULTS: Our analysis predicts that the variation in fitness maintained by a continuously evolving population increases as the logarithm of the population size and logarithm of the mutation rate and thus yields a similar logarithmic increase in the speed of evolution. To test these predictions, we evolved asexual budding yeast in glucose-limited media at a range of population sizes and mutation rates. CONCLUSIONS: We find that their evolution is dominated by the accumulation of multiple mutations of moderate effect. Our results agree with our theoretical predictions and are inconsistent with the one-by-one fixation of mutants assumed by recent clonal-interference analysis.