Biology subjects

Joshua B Plotkin

Publications and source records attributed to Joshua B Plotkin.

5 recordsLinked to original sources

bioRxiv2016

Epistasis and the dynamics of reversion in molecular evolution

Recent studies of protein evolution contend that the longer an amino acid substitution is present at a site, the less likely it is to revert to the amino acid previously occupying that site. Here we study this phenomenon of decreasing reversion rates rigorously, and in a much more general context. We show that, under weak mutation and for arbitrary fitness landscapes, reversion rates decrease with time for any site that is involved in at least one epistatic interaction. Specifically, we prove that, at stationarity, the hazard function of the distribution of waiting times until reversion is strictly decreasing for any such site. Thus, in the presence of epistasis, the longer a particular character has been absent from a site, the less likely the site will revert to its prior state. We also explore several examples of this general result, which share a common pattern whereby the probability of having reverted increases rapidly at short times to some substantial value before becoming almost flat after a few substitutions at other sites. This pattern indicates a characteristic tendency for reversion to occur either almost immediately after the initial substitution or only after a very long time.

Evolutionary Biology↗

bioRxiv2016

Assortative mating can impede or facilitate fixation of underdominant alleles

Although underdominant mutations have undoubtedly fixed between divergent species, classical models of population genetics suggest underdominant alleles should be purged quickly, except in small or subdivided populations. Here we study the fixation of underdominant alleles at loci that also influence mate choice, such as loci encoding coloration patterns visible to mates and predators alike. We analyze a mechanistic model of positive assortative mating in which individuals have n chances to sample compatible mates. This one-parameter model naturally spans the two classical extremes of random mating (n = 1) and complete assortment (n [->] {infty}), and yet it produces a complex form of sexual selection that depends non-monotonically on the number of mating opportunities, n. The resulting interaction between viability selection and sexual selection can either inhibit or facilitate fixation of underdominant alleles, compared to random mating. As the number of mating opportunities increases, underdominant alleles can fix at rates that even approach the neutral substitution rate. This result is counterintuitive because sexual selection and underdominance each suppress rare alleles in this model, and yet in combination they can promote the fixation of rare alleles. This phenomenon constitutes a new mechanism for the fixation of underdominant alleles in large populations, and it illustrates how incorporating life history characteristics can alter the predictions of population-genetic models for evolutionary change.

Evolutionary Biology↗

bioRxiv2015

Host-pathogen coevolution and the emergence of broadly neutralizing antibodies in chronic infections

The vertebrate adaptive immune system provides a flexible and diverse set of molecules to neutralize pathogens. Yet, viruses such as HIV can cause chronic infections by evolving as quickly as the adaptive immune system, forming an evolutionary arms race. Here we introduce a mathematical framework to study the coevolutionary dynamics of antibodies with antigens within a host. We focus on changes in the binding interactions between the antibody and antigen populations, which result from the underlying stochastic evolution of genotype frequencies driven by mutation, selection, and drift. We identify the critical viral and immune parameters that determine the distribution of antibody-antigen binding affinities. We also identify definitive signatures of coevolution that measure the reciprocal response between antibodies and viruses, and we introduce experimentally measurable quantities that quantify the extent of adaptation during continual coevolution of the two opposing populations. Using this analytical framework, we infer rates of viral and immune adaptation based on time-shifted neutralization assays in two HIV-infected patients. Finally, we analyze competition between clonal lineages of antibodies and characterize the fate of a given lineage in terms of the state of the antibody and viral populations. In particular, we derive the conditions that favor the emergence of broadly neutralizing antibodies, which may be useful in designing a vaccine against HIV.

Evolutionary Biology↗

bioRxiv2015

The evolutionary advantage of heritable phenotypic heterogeneity

Phenotypic plasticity is an evolutionary driving force in diverse biological processes, including the adaptive immune system, the development of neoplasms, and the bacterial acquisition of drug resistance. It is essential, therefore, to understand the evolutionary advantage of an allele that confers cells the ability to express a range of phenotypes. Of particular importance is to understand how this advantage of phenotypic plasticity depends on the degree of heritability of non-genetically encoded phenotypes between generations, which can induce irreversible evolutionary changes in the population. Here, we study the fate of a new mutation that allows the expression of multiple phenotypic states, introduced into a finite population otherwise composed of individuals who can express only a single phenotype. We analyze the fixation probability of such an allele as a function of the strength of inter-generational phenotypic heritability, called memory, the variance of expressible phenotypes, the rate of environmental changes, and the population size. We find that the fate of a phenotypically plastic allele depends fundamentally on the environmental regime. In a constant environment, the fixation probability of a plastic allele always increases with the degree of phenotypic memory. In periodically fluctuating environments, by contrast, there is an optimum phenotypic memory that maximizes the probability of the plastic alleles fixation. This same optimum value of phenotypic memory also maximizes geometric mean fitness, in steady state. We interpret these results in the context of previous studies in an infinite-population framework. We also discuss the implications of our results for the design of therapies that can overcome resistance, in a variety of diseases.

Evolutionary Biology↗

bioRxiv2015

Improved ribosome-footprint and mRNA measurements provide insights into dynamics and regulation of yeast translation

Ribosome-footprint profiling provides genome-wide snapshots of translation, but technical challenges can confound its analysis. Here, we use improved methods to obtain ribosome-footprint profiles and mRNA abundances that more faithfully reflect gene expression in Saccharomyces cerevisiae. Our results support proposals that both the beginning of coding regions and codons matching rare tRNAs are more slowly translated. They also indicate that emergent polypeptides with as few as three basic residues within a 10-residue window tend to slow translation. With the improved mRNA measurements, the variation attributable to translational control in exponentially growing yeast was less than previously reported, and most of this variation could be predicted with a simple model that considered mRNA abundance, upstream open reading frames, cap-proximal structure and nucleotide composition, and lengths of the coding and 5-untranslated regions. Collectively, our results reveal key features of translational control in yeast and provide a framework for executing and interpreting ribosome-profiling studies.

Genomics↗