Biology subjects

Flynn, J. M.

Publications and source records attributed to Flynn, J. M..

4 recordsLinked to original sources

bioRxiv2017

Pervasive contingency and entrenchment in a billion years of Hsp90 evolution

Although many potential mutations within proteins modulate each others effects1-4, the extent to which these epistatic interactions influenced the fitness effects of the sequence changes that actually occurred during historical evolution - and thus made molecular evolution contingent and irreversible - is controversial5-16. We addressed this question directly by precisely measuring the fitness effects in both extant and reconstructed ancestral sequence contexts of all historical amino acid substitutions that occurred during the billion-year evolutionary history of the heat shock protein 90 (Hsp90) ATPase domain beginning from a deep eukaryotic ancestor to modern Saccharomyces cerevisiae. We find a pervasive influence of epistasis on historical sequence evolution: the majority of the 98 derived states that evolved during history were deleterious at times before they happened, and the vast majority also became subsequently entrenched6, with the ancestral state becoming deleterious after its substitution. A few of these epistatic interactions were of massive fitness consequence, but the majority were of small but evolutionarily relevant effect size. We find that both the large- and small-effect epistasis were largely caused by specific interactions among sites rather than a general permissive or restrictive effect17. Our results highlight how epistasis continually opens and closes windows of mutational opportunity over evolutionary timescales, producing histories and biological states that reflect, in significant part, the transient internal constraints imposed by a proteins fleeting sequence states.

evolutionary biology↗

bioRxiv2017

Selection constrains high rates of satellite DNA mutation in Daphnia pulex

A long-standing evolutionary puzzle is that all eukaryotic genomes contain large amounts of tandemly-repeated satellite DNA whose composition varies greatly among even closely related species. To elucidate the evolutionary forces governing satellite dynamics, quantification of the rates and patterns of mutations in satellite DNA copy number and tests of its selective neutrality are necessary. Here we used whole-genome sequences of 28 mutation accumulation (MA) lines of Daphnia pulex in addition to six isolates from a non-MA population originating from the same progenitor to both estimate mutation rates of abundances of satellite sequences and evaluate the selective regime acting upon them. We found that mutation rates of individual satellite sequence \"kmers\" were both high and highly variable, ranging from additions/deletions of 0.29 - 105 copies per generation (reflecting changes of 0.12 - 0.80 percent per generation). Our results also provide evidence that new kmer sequences are often formed from existing ones. The non-MA population isolates showed a signal of either purifying or stabilizing selection, with 33 % lower variation in kmer abundance on average than the MA lines, although the level of selective constraint was not evenly distributed across all kmers. The changes between many pairs of kmers were correlated, and the pattern of correlations was significantly different between the MA lines and the non-MA population. Our study demonstrates that kmer sequences can experience extremely rapid evolution in abundance, which can lead to high levels of divergence in genome-wide satellite DNA composition between closely related species.

evolutionary biology↗

bioRxiv2016

Resource-Driven Encounters and the Induction of Disease Among Consumers

Submitted Manuscript 2016. Territorial animals share a variety of common resources, which can be a major driver of conspecific encounter rates. We examine how changes in resource availability influence the rate of encounters among individuals in a consumer population by implementing a spatially explicit model for resource visitation behavior by consumers. Using data from 2009 and 2010 in Etosha National Park, we verify our model's prediction that there is a saturation effect in the expected number of jackals that visit a given carcass site as carcasses become abundant. However, this does not directly imply that the overall resource-driven encounter rate among jackals decreases. This is because the increase in available carcasses is accompanied by an increase in the number of jackals that detect and potentially visit carcasses. Using simulations and mathematical analysis of our consumer-resource interaction model, we characterize key features of the relationship between resource-driven encounter rate and model parameters. These results are used to investigate a standing hypothesis that the outbreak of a fatal disease among zebras can potentially lead to an outbreak of an entirely different disease in the jackal population, a process we refer to as indirect induction of disease.

ecology↗

bioRxiv2016

Genome-wide survey of Pseudomonas aeruginosa PA14 reveals a role for the glyoxylate pathway and extracellular proteases in the limited utilization of mucin

Chronic airway infections by the opportunistic pathogen Pseudomonas aeruginosa are major cause of mortality in cystic fibrosis (CF) patients. While this bacterium has been extensively studied for its virulence mechanisms, biofilm growth and immune evasion within the CF airways, comparatively little is known about the nutrient sources that sustain its growth in vivo. Respiratory mucins represent a potentially abundant bioavailable nutrient source, though we have recently shown that canonical pathogens inefficiently use these host glycoproteins as a growth substrate. Yet, given that P. aeruginosa, particularly in its biofilm mode of growth is thought to grow slowly in vivo, the inefficient use of mucin glycoproteins may have relevance to its persistence within the CF airways. To this end, here we use whole genome fitness analysis combining transposon mutagenesis with high throughput sequencing (TnSeq) to identify genetic determinants required for P. aeruginosa growth using intact purified mucins as a sole carbon source. Our analysis reveals a biphasic growth phenotype, during which the glyoxylate pathway and amino acid biosynthetic machinery are required for mucin utilization. Secondary analyses confirmed the simultaneous liberation and consumption of acetate during mucin degradation and revealed a central role for the extracellular proteases LasB and AprA. Together, these studies identified the P. aeruginosa genes required for mucin-based nutrient acquisition and reveal a host-pathogen dynamic that may contribute to its persistence within the CF airways.

microbiology↗