PMID: 15644218;Abstract:
Soluble dimeric prion protein (PrP-Fc 2) binds to the disease-associated prion protein PrP Sc, and inhibits prion replication when expressed in transgenic mice. Prion inhibition is effective even if PrP-Fc 2 is expressed at low levels, suggesting that its affinity for PrP Sc is higher than that of monomeric PrP C. Here, we model prion accumulation as an exponential replication cycle of prion elongation and breakage. The exponential growth rate corresponding to this cycle is reflected in the incubation period of the disease. We use a mathematical model to calculate the exponential growth rate, and fit the model to in vivo data on prion incubation times corresponding to different levels of PrP C and PrP-Fc 2. We find an excellent fit of the model to the data. Surprisingly, targeting of PrP Sc can be effective at concentrations of PrP-Fc 2 lower than that of PrP C, even if PrP-Fc 2 and PrP C have the same affinity for PrP Sc. The best fit of our model to data predicts that the replicative prion consists of PrP Sc oligomers with a mean size of four to 15 units. © 2004 Elsevier Ltd. All rights reserved.
PMID: 17720926;PMCID: PMC2034656;Abstract:
Phenotypic loss is an important evolutionary force in nature but the mechanism(s) responsible for loss remains unclear. We used both simulation and multiple-regression approaches to analyze data on the loss of sporulation, a complex bacterial developmental process, during experimental evolution of Bacillus subtilis. Neutral processes of mutational degradation alone were sufficient to explain loss-of-sporulation ability in four of five populations, while evidence that selection facilitated mutational loss was found for only one population. These results are discussed in the context of the evolution of sporulation in particular and phenotypic loss in general. Copyright © 2007 by the Genetics Society of America.
Evolutionary biology has a complex relationship with ideas of chance, purpose, and progress. Probability plays a subtle role; strikingly, founding figures in statistics were motivated by evolutionary questions. The findings of evolutionary biology have been used both in support of narratives of progress, and in their deconstruction. Likewise, professional biologists bring to their scientific work a set of preconceptions about chance and progress, grounded in their philosophical, religious, and/or political views. From the religious side, questions of purpose are ever-present. We explore this interplay in five broad categories: chance, progress, intelligence, eugenics, and the evolution of religious practices, each the subject of a semester long symposium. The intellectual influence of evolutionary biology has had a broad societal impact in these areas. Based on our experience, we draw attention to a number of relevant facts that, while accepted by experts in their respective fields, may be unfamiliar outside them. We list common areas of miscommunication, including specific examples and discussing causes: sometimes semantics and sometimes more substantive knowledge barriers. We also make recommendations for those attempting similar dialogue.
PMID: 19917766;PMCID: PMC2828720;Abstract:
Epigenetically inherited aggregates of the yeast prion [PSI+] cause genomewide readthrough translation that sometimes increases evolvability in certain harsh environments. The effects of natural selection on modifiers of [PSI+] appearance have been the subject of much debate. It seems likely that [PSI+] would be at least mildly deleterious in most environments, but this may be counteracted by its evolvability properties on rare occasions. Indirect selection on modifiers of [PSI+] is predicted to depend primarily on the spontaneous [PSI+] appearance rate, but this critical parameter has not previously been adequately measured. Here we measure this epimutation rate accurately and precisely as 5.8 × 10-7 per generation, using a fluctuation test. We also determine that genetic "mimics" of [PSI1] account for up to 80% of all phenotypes involving general nonsense suppression. Using previously developed mathematical models, we can now infer that even in the absence of opportunities for adaptation, modifiers of [PSI+] are only weakly deleterious relative to genetic drift. If we assume that the spontaneous [PSI+] appearance rate is at its evolutionary optimum, then opportunities for adaptation are inferred to be rare, such that the [PSI+] system is favored only very weakly overall. But when we account for the observed increase in the [PSI+] appearance rate in response to stress, we infer much higher overall selection in favor of [PSI+] modifiers, suggesting that [PSI+]-forming ability may be a consequence of selection for evolvability. Copyright © 2010 by the Genetics Society of America.
PMID: 10866229;Abstract:
Viral load fluctuates during the natural course of asymptomatic HIV-1 infection. It is often assumed that these fluctuations are random around a set point or underlying growth trend. Using longitudinal data, we tested whether fluctuations in viral load can be better explained by changes in CD4+ T-cell count than by a set point or trend of exponential growth. The correspondence between viral load and CD4+ T-cell count could be described by a simple mathematical relation. Using a bootstrapping approach, the hypothesis that viral load fluctuations are random around a set point was rejected with p .00005. The hypothesis that viral load fluctuations are random around a trend of exponential growth was rejected with p .005. Viral load data was explained better by changes in CD4+ T-cell counts than by a set point or by a trend of exponential growth. The implications of this finding for improved prognostication discussed.
