1,787 research outputs found
Multi-locus approaches for the measurement of selection on correlated genetic loci
The study of ecological speciation is inherently linked to the study of selection. Methods for estimating phenotypic selection within a generation based on associations between trait values and fitness (e.g., survival) of individuals are established. These methods attempt to disentangle selection acting directly on a trait from indirect selection caused by correlations with other traits via multivariate statistical approaches (i.e., inference of selection gradients). The estimation of selection on genotypic or genomic variation could also benefit from disentangling direct and indirect selection on genetic loci. However, achieving this goal is difficult with genomic data because the number of potentially correlated genetic loci (p) is very large relative to the number of individuals sampled (n). In other words, the number of model parameters exceeds the number of observations (p ≫ n). We present simulations examining the utility of whole genome regression approaches (i.e., Bayesian sparse linear mixed models) for quantifying direct selection in cases where p ≫ n. Such models have been used for genome-wide association mapping and are common in artificial breeding. Our results show they hold promise for studies of natural selection in the wild, and thus of ecological speciation. But we also demonstrate important limitations to the approach and discuss study designs required for more robust inferences
Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch
Cellular transformations which involve a significant phenotypical change of
the cell's state use bistable biochemical switches as underlying decision
systems. In this work, we aim at linking cellular decisions taking place on a
time scale of years to decades with the biochemical dynamics in signal
transduction and gene regulation, occuring on a time scale of minutes to hours.
We show that a stochastic bistable switch forms a viable biochemical mechanism
to implement decision processes on long time scales. As a case study, the
mechanism is applied to model the initiation of follicle growth in mammalian
ovaries, where the physiological time scale of follicle pool depletion is on
the order of the organism's lifespan. We construct a simple mathematical model
for this process based on experimental evidence for the involved genetic
mechanisms. Despite the underlying stochasticity, the proposed mechanism turns
out to yield reliable behavior in large populations of cells subject to the
considered decision process. Our model explains how the physiological time
constant may emerge from the intrinsic stochasticity of the underlying gene
regulatory network. Apart from ovarian follicles, the proposed mechanism may
also be of relevance for other physiological systems where cells take binary
decisions over a long time scale.Comment: 14 pages, 4 figure
The transition between stochastic and deterministic behavior in an excitable gene circuit
We explore the connection between a stochastic simulation model and an
ordinary differential equations (ODEs) model of the dynamics of an excitable
gene circuit that exhibits noise-induced oscillations. Near a bifurcation point
in the ODE model, the stochastic simulation model yields behavior dramatically
different from that predicted by the ODE model. We analyze how that behavior
depends on the gene copy number and find very slow convergence to the large
number limit near the bifurcation point. The implications for understanding the
dynamics of gene circuits and other birth-death dynamical systems with small
numbers of constituents are discussed.Comment: PLoS ONE: Research Article, published 11 Apr 201
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Myosin-I nomenclature.
We suggest that the vertebrate myosin-I field adopt a common nomenclature system based on the names adopted by the Human Genome Organization (HUGO). At present, the myosin-I nomenclature is very confusing; not only are several systems in use, but several different genes have been given the same name. Despite their faults, we believe that the names adopted by the HUGO nomenclature group for genome annotation are the best compromise, and we recommend universal adoption
Simple, Fast and Accurate Implementation of the Diffusion Approximation Algorithm for Stochastic Ion Channels with Multiple States
The phenomena that emerge from the interaction of the stochastic opening and
closing of ion channels (channel noise) with the non-linear neural dynamics are
essential to our understanding of the operation of the nervous system. The
effects that channel noise can have on neural dynamics are generally studied
using numerical simulations of stochastic models. Algorithms based on discrete
Markov Chains (MC) seem to be the most reliable and trustworthy, but even
optimized algorithms come with a non-negligible computational cost. Diffusion
Approximation (DA) methods use Stochastic Differential Equations (SDE) to
approximate the behavior of a number of MCs, considerably speeding up
simulation times. However, model comparisons have suggested that DA methods did
not lead to the same results as in MC modeling in terms of channel noise
statistics and effects on excitability. Recently, it was shown that the
difference arose because MCs were modeled with coupled activation subunits,
while the DA was modeled using uncoupled activation subunits. Implementations
of DA with coupled subunits, in the context of a specific kinetic scheme,
yielded similar results to MC. However, it remained unclear how to generalize
these implementations to different kinetic schemes, or whether they were faster
than MC algorithms. Additionally, a steady state approximation was used for the
stochastic terms, which, as we show here, can introduce significant
inaccuracies. We derived the SDE explicitly for any given ion channel kinetic
scheme. The resulting generic equations were surprisingly simple and
interpretable - allowing an easy and efficient DA implementation. The algorithm
was tested in a voltage clamp simulation and in two different current clamp
simulations, yielding the same results as MC modeling. Also, the simulation
efficiency of this DA method demonstrated considerable superiority over MC
methods.Comment: 32 text pages, 10 figures, 1 supplementary text + figur
Global parameter identification of stochastic reaction networks from single trajectories
We consider the problem of inferring the unknown parameters of a stochastic
biochemical network model from a single measured time-course of the
concentration of some of the involved species. Such measurements are available,
e.g., from live-cell fluorescence microscopy in image-based systems biology. In
addition, fluctuation time-courses from, e.g., fluorescence correlation
spectroscopy provide additional information about the system dynamics that can
be used to more robustly infer parameters than when considering only mean
concentrations. Estimating model parameters from a single experimental
trajectory enables single-cell measurements and quantification of cell--cell
variability. We propose a novel combination of an adaptive Monte Carlo sampler,
called Gaussian Adaptation, and efficient exact stochastic simulation
algorithms that allows parameter identification from single stochastic
trajectories. We benchmark the proposed method on a linear and a non-linear
reaction network at steady state and during transient phases. In addition, we
demonstrate that the present method also provides an ellipsoidal volume
estimate of the viable part of parameter space and is able to estimate the
physical volume of the compartment in which the observed reactions take place.Comment: Article in print as a book chapter in Springer's "Advances in Systems
Biology
The presentation and management of post-partum choriocarcinoma
Post-partum choriocarcinoma is a rare complication of pregnancy. We have analysed a series of nine consecutive patients presenting with choriocarcinoma after a full-term non-molar pregnancy. All patients were managed at the Supraregional Trophoblastic Disease Screening and Treatment Centre at Weston Park Hospital, Sheffield between 1987 and 1996. All presented with persistent primary or secondary post-partum haemorrhage. Treatment with multiagent chemotherapy (initially methotrexate, dactinomycin and etoposide) was successful in all cases. Early diagnosis is important because this rare condition is potentially curable with appropriate chemotherapy. © 1999 Cancer Research Campaig
Correcting the Site Frequency Spectrum for Divergence-Based Ascertainment
Comparative genomics based on sequenced referenced genomes is essential to hypothesis generation and testing within population genetics. However, selection of candidate regions for further study on the basis of elevated or depressed divergence between species leads to a divergence-based ascertainment bias in the site frequency spectrum within selected candidate loci. Here, a method to correct this problem is developed that obtains maximum-likelihood estimates of the unascertained allele frequency distribution using numerical optimization. I show how divergence-based ascertainment may mimic the effects of natural selection and offer correction formulae for performing proper estimation into the strength of selection in candidate regions in a maximum-likelihood setting
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Genes responsive to rapamycin and serum deprivation are clustered on chromosomes and undergo re-organization within local chromatin environments.
Supplementary materials are available at University of Toronto: https://tspace.library.utoronto.ca/handle/1807/9982
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