MBI Publications for Biology (6)
B. Stigler and H. Chamberlin
A regulatory network modeled from wild-type gene expression data guides functional predictions in Caenorhabditis elegans developmentBMC Systems BiologyVol. 6 No. 77 (Accepted)
Complex gene regulatory networks underlie many cellular and developmental processes. While a variety of experimental approaches can be used to discover how genes interact, few biological systems have been systematically evaluated to the extent required for an experimental definition of the underlying network. Therefore, the development of computational methods that can use limited experimental data to define and model a gene regulatory network would provide a useful tool to evaluate many important but incompletely understood biological processes. Such methods can assist in extracting all relevant information from data that are available, identify unexpected regulatory relationships and prioritize future experiments.
To facilitate the analysis of gene regulatory networks, we have developed a computational modeling pipeline method that complements traditional evaluation of experimental data. For a proof-of-concept example, we have focused on the gene regulatory network in the nematode C. elegans that mediates the developmental choice between mesodermal (muscle) and ectodermal (skin) cell fates in the embryonic C lineage. We have used gene expression data to build two models: a knowledge-driven model based on gene expression changes following gene perturbation experiments, and a data-driven mathematical model derived from time-course gene expression data recovered from wild-type animals. We show that both models can identify a rich set of network gene interactions. Importantly, the mathematical model built only from wild-type data can predict interactions demonstrated by the perturbation experiments better than chance, and better than an existing knowledge-driven model built from the same data set. The mathematical model also provides new biological insight, including a dissection of zygotic from maternal functions of a key transcriptional regulator, PAL-1, and identification of non-redundant activities of the T-box genes tbx-8 and tbx-9.
This work provides a strong example for a mathematical modeling approach that solely uses wild-type data to predict an underlying gene regulatory network. The modeling approach complements traditional methods of data analysis, suggesting non-intuitive network relationships and guiding future experiments.
Stochastic mechano-chemical kinetics of molecular motors: a multidisciplinary enterprise from a physicistâ€™s perspectivepp. 370 (Submitted)
AbstractAmolecularmotor ismade of either a singlemacromolecule or amacromolecular
complex. Just like their macroscopic counterparts, molecular
motors â€œtransduceâ€? input energy into mechanical work. All the nanomotors
considered here operate under isothermal conditions far from equilibrium.
Moreover, one of the possible mechanisms of energy transduction,
called Brownian ratchet, does not even have any macroscopic counterpart.
But, molecular motor is not synonymous with Brownian ratchet; a large
number of molecular motors execute a noisy power stroke, rather than
operating as Brownian ratchet. We review not only the structural design
and stochastic kinetics of individual single motors, but also their coordination,
cooperation and competition as well as the assembly of multimodule
motors in various intracellular kinetic processes. Although all
the motors considered here execute mechanical movements, efficiency and
power output are not necessarily good measures of performance of some
motors. Among the intracellular nano-motors, we consider the porters,
sliders and rowers, pistons and hooks, exporters, importers, packers and
movers as well as those that also synthesize, manipulate and degrade
â€œmacromolecules of lifeâ€?. We review mostly the quantitative models for
the kinetics of these motors. We also describe several of those motordriven
intracellular stochastic processes for which quantitative models are
yet to be developed. In part I, we discuss mainly the methodology and
the generic models of various important classes of molecular motors. In
part II, we review many specific examples emphasizing the unity of the
basic mechanisms as well as diversity of operations arising from the differences
in their detailed structure and kinetics. Multi-disciplinary research
is presented here from the perspective of physicists.
A. Sharma and D. Chowdhury
Error correction during DNA replicationPhysical Review EVol. 86 No. 011913 (2012)
AbstractDNA polymerase (DNAP) is a dual-purpose enzyme that plays two opposite roles in two different situations
during DNA replication. It plays its a normal role as a polymerase catalyzing the elongation of a new DNA
molecule by adding a monomer. However, it can switch to the role of an exonuclease and shorten the same
DNA by cleavage of the last incorporated monomer from the nascent DNA. Just as misincorporated nucleotides
can escape exonuclease causing a replication error, the correct nucleotide may get sacrificed unnecessarily by
erroneous cleavage. The interplay of polymerase and exonuclease activities of a DNAP is explored here by
developing a minimal stochastic kinetic model of DNA replication. Exact analytical expressions are derived for
a few key statistical distributions; these characterize the temporal patterns in the mechanical stepping and the
chemical (cleavage) reaction. The Michaelis-Menten-like analytical expression derived for the average rates of
these two processes not only demonstrate the effects of their coupling, but are also utilized to measure the extent
of replication error and erroneous cleavage.
V. Krivan and R. Cressman
Competition in di-and tri-trophic food web modulesJournal of Theoretical BiologyVol. 343 (2013) pp. 127-137
AbstractCompetition in di-and tri-trophic food web modules with many competing species is studied.The food web modules considered are apparent competition between n species sharing a single predator and a diamond-like food web with a single resource,a single top predator and many competing middle species.The predators have either fixed preferences for their prey,or they switch between available prey in away that maximizes their fitness. Dependence of these food web dynamics on environmental carrying capacity and food web connectance is studied.The results predict that optimal flexible for aging strongly weakens apparent competition and promotes species coexistence. Food web robustness (defined here as the proportion of surviving species) does not decrease with increased connectance in these food-webs. Moreover, it is shown that flexible prey switching leads to the same population equilibria as in corresponding food webs with highly specialized predators. The results show that flexible for aging behavior by predators can have very strong impact on species richness, as well as the response of communities to changes in resource enrichment and food web connectance when compared to the same food-web topology with inflexible top predators. Several results on global stability using Lyapunov functions areprovided.
Behavioral refuges and predator-prey coexistenceJournal of Theoretical BiologyVol. 339 (2014) pp. 112-121
AbstractThe effects of a behavioral refuge caused either by the predator optimal foraging or prey adaptive antipredator behavior on the Gause predator-prey model are studied. It is shown that both of these mechanisms promote predator-prey coexistence either at an equilibrium, or along a limit cycle. Adaptive prey refuge use leads to hysteresis in prey antipredator behavior which allows predator-prey coexistence along a limit cycle. Similarly, optimal predator foraging leads to sigmoidal functional responses with a potential to stabilize predator-prey population dynamics at an equilibrium, or along a limit cycle.
N. Beckman and H. Rogers
Consequences of Seed Dispersal for Plant Recruitment in Tropical Forests: Interactions within the SeedscapeBiotropicaVol. 45 No. 6 (2014) pp. 666-681
AbstractSeed dispersal sets the stage for the suite of biotic and abiotic interactions that determine the fate of individual seeds. In this review, we first focus on how dispersal influences the "seedscape", or the combination of abiotic, biotic, and spatial factors that affect the probability of germination once a seed has reached its final location. We review recent papers that examine the effect of dispersers on (1) the quality of the habitat in which a seed lands; (2) the distance seeds are dispersed from the parent tree; and (3) the density and composition of plants within the neighborhood of a seed following deposition. Next, we explore methods used to scale these processes up to the level of populations. We highlight demographic models that integrate across multiple life history stages and predict the impact of dispersal in variable environments on population growth. We also review studies that analyze existing spatial patterns of trees within large forest plots and use various strategies to infer the processes that led to those patterns. We continue to scale up from populations to communities, and discuss three approaches that have been taken to understand how dispersal may affect diversity and abundance in the community. We finish by highlighting several areas of research that are particularly promising for future directions of study.