Biology subjects

Thomas, P. J.

Publications and source records attributed to Thomas, P. J..

4 recordsLinked to original sources

bioRxiv2022

Noise source importance in linear stochastic models of biological systems that grow, shrink, wander, or persist

While noise is an important factor in biology, biological processes often involve multiple noise sources, whose relative importance can be unclear. Here we develop tools that quantify the importance of noise sources in a network based on their contributions to variability in a quantity of interest. We generalize the edge importance measures proposed by Schmidt and Thomas [1] for first-order reaction networks whose steady-state variance is a linear combination of variance produced by each directed edge. We show that the same additive property extends to a general family of stochastic processes subject to a set of linearity assumptions, whether in discrete or continuous state or time. Our analysis applies to both expanding and contracting populations, as well as populations obeying a martingale ("wandering") at long times. We show that the original Schmidt-Thomas edge importance measure is a special case of our more general measure, and is recovered when the model satisfies a conservation constraint ("persists"). In the growing and wandering cases we show that the choice of observables (measurements) used to monitor the process does not influence which noise sources are important at long times. In contrast, in the shrinking or persisting case, which noise sources are important depends on what is measured. We also generalize our measures to admit models with affine moment update equations, which admit additional limiting scenarios, and arise naturally after linearization. We illustrate our results using examples from cell biology and ecology: (i) a model for the dynamics of the inositol trisphospate receptor, (ii) a model for an endangered population of white-tailed eagles, and (iii) a model for wood frog dispersal. Author summaryBiological processes are frequently subject to an ensemble of independent noise sources. Noise sources produce fluctuations that propagate through the system, driving fluctuations in quantities of interest such as population size or ion channel configuration. We introduce a measure that quantifies how much variability each noise source contributes to any given quantity of interest. Using these methods, we identify which binding events contribute significantly to fluctuations in the state of a molecular signalling channel, which life history events contribute the most variability to an eagle population before and after a successful conservation effort rescued the population from the brink of extinction, and which dispersal events, at what times, matter most to variability in the recolonization of a series of ponds by wood frogs after a drought.

ecology↗

bioRxiv2021

A Comparison of Weighted Stochastic Simulation Methods

1Rare events are of particular interest in biology because rare biochemical events may be catastrophic to a biological system. To estimate the probability of rare events, several weighted stochastic simulation methods have been developed. Unfortunately, the robustness of these methods is questionable. Here, an analysis of weighted stochastic simulation methods is presented. The methods considered here fail to accomplish the task of rare event simulation, in general, suggesting that new methods are necessary to adequately study rare biological events.

systems biology↗

bioRxiv2021

Cheater suppression and spite through quorum sensing

The evolutionary consequences of quorum sensing in regulating bacterial cooperation are not fully understood. In this study, we reveal unexpected consequences of regulating public good production through quorum sensing on bacterial population dynamics, showing that quorum sensing can be a collectively harmful alternative to unregulated production. We analyze a birth-death model of bacterial population dynamics accounting for public good production and the presence of non-producing cheaters. Our model demonstrates that when demographic noise is a factor, the consequences of controlling public good production according to quorum sensing depend on the cost of public good production and the presence of non-public fitness benefits. When public good production is inexpensive, quorum sensing is a destructive alternative to unconditional production, in terms of the mean population extinction time. When costs are higher, quorum sensing becomes a constructive strategy for the producing strain, both stabilizing cooperation and decreasing the risk of population extinction.

biophysics↗

bioRxiv2021

Role of transmembrane spanning domain 1 in cystic fibrosis transmembrane conductance regulator folding

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein that disrupt its folding pathway. The most common mutation causing CF is a deletion of phenylalanine at position 508 ({Delta}F508). CFTR contains five domains that each form cotranslational structures that interact with other domains as they are produced and folded. CFTR is comprised of two transmembrane spanning domains (TMDs), two nucleotide binding domains (NBDs) and a unique regulatory region (R). The first domain translated, TMD1, forms interdomain interactions with the other domains in CFTR. In TMD1, long intracellular loops extend into the cytoplasm and interact with both NBDs via coupling helices and with TMD2 via transmembrane spans (TMs). We examined mutations in TMD1 to determine the impact on individual domain and multidomain constructs. We found that mutations in a TM span or in the cytosolic ICLs interfere with specific steps in the hierarchical folding of CFTR. TM1 CF-causing mutants, G85E and G91R, directly affect TMD1, whereas most ICL1 and ICL2 mutant effects become apparent in the presence of TMD2. A single mutant in ICL2 worsened CFTR trafficking in the presence of NBD2, supporting its role in the ICL2-NBD2 interface. Mutation of hydrophobic residues in ICL coupling helices tended to increased levels of pre-TMD2 biogenic intermediates but caused ER accumulation in the presence of TMD2. This suggests a tradeoff between transient stability during translation and final structure. NBD2 increased the efficiency of mutant trafficking from the ER, consistent with stabilization of the full-length constructs. While the G85E and G91R mutants in TM1 have immediately detectable effects, most of the studied mutant effects and the {Delta}F508 mutant are apparent after production of TMD2, supporting this intermediate as a major point of recognition by protein quality control.

molecular biology↗