63 research outputs found
Maladaptation and the paradox of robustness in evolution
Background. Organisms use a variety of mechanisms to protect themselves
against perturbations. For example, repair mechanisms fix damage, feedback
loops keep homeostatic systems at their setpoints, and biochemical filters
distinguish signal from noise. Such buffering mechanisms are often discussed in
terms of robustness, which may be measured by reduced sensitivity of
performance to perturbations. Methodology/Principal Findings. I use a
mathematical model to analyze the evolutionary dynamics of robustness in order
to understand aspects of organismal design by natural selection. I focus on two
characters: one character performs an adaptive task; the other character
buffers the performance of the first character against perturbations. Increased
perturbations favor enhanced buffering and robustness, which in turn decreases
sensitivity and reduces the intensity of natural selection on the adaptive
character. Reduced selective pressure on the adaptive character often leads to
a less costly, lower performance trait. Conclusions/Significance. The paradox
of robustness arises from evolutionary dynamics: enhanced robustness causes an
evolutionary reduction in the adaptive performance of the target character,
leading to a degree of maladaptation compared to what could be achieved by
natural selection in the absence of robustness mechanisms. Over evolutionary
time, buffering traits may become layered on top of each other, while the
underlying adaptive traits become replaced by cheaper, lower performance
components. The paradox of robustness has widespread implications for
understanding organismal design
Tunable kinetic proofreading in a model with molecular frustration
In complex systems, feedback loops can build intricate emergent phenomena, so
that a description of the whole system cannot be easily derived from the
properties of the individual parts. Here we propose that inter-molecular
frustration mechanisms can provide non trivial feedback loops which can develop
nontrivial specificity amplification. We show that this mechanism can be seen
as a more general form of a kinetic proofreading mechanism, with an interesting
new property, namely the ability to tune the specificity amplification by
changing the reactants concentrations. This contrasts with the classical
kinetic proofreading mechanism in which specificity is a function of only the
reaction rate constants involved in a chemical pathway. These results are also
interesting because they show that a wide class of frustration models exists
that share the same underlining kinetic proofreading mechanisms, with even
richer properties. These models can find applications in different areas such
as evolutionary biology, immunology and biochemistry
First passage events in biological systems with non-exponential inter-event times
It is often possible to model the dynamics of biological systems as a series of discrete transitions between a finite set of observable states (or compartments). When the residence times in each state, or inter-event times more generally, are exponentially distributed, then one can write a set of ordinary differential equations, which accurately describe the evolution of mean quantities. Non-exponential inter-event times can also be experimentally observed, but are more difficult to analyse mathematically. In this paper, we focus on the computation of first passage events and their probabilities in biological systems with non-exponential inter-event times. We show, with three case studies from Molecular Immunology, Virology and Epidemiology, that significant errors are introduced when drawing conclusions based on the assumption that inter-event times are exponentially distributed. Our approach allows these errors to be avoided with the use of phase-type distributions that approximate arbitrarily distributed inter-event times
Conformational Proofreading: The Impact of Conformational Changes on the Specificity of Molecular Recognition
To perform recognition, molecules must locate and specifically bind their targets within a noisy biochemical environment with many look-alikes. Molecular recognition processes, especially the induced-fit mechanism, are known to involve conformational changes. This raises a basic question: Does molecular recognition gain any advantage by such conformational changes? By introducing a simple statistical-mechanics approach, we study the effect of conformation and flexibility on the quality of recognition processes. Our model relates specificity to the conformation of the participant molecules and thus suggests a possible answer: Optimal specificity is achieved when the ligand is slightly off target; that is, a conformational mismatch between the ligand and its main target improves the selectivity of the process. This indicates that deformations upon binding serve as a conformational proofreading mechanism, which may be selected for via evolution
Immunology and mathematics: crossing the divide
βIt's high time molecular biology became quantitative, it cries out to a physicist β¦ for modeling. Modeling isn't a crutch, it's the opposite; it's a way of suggesting experiments to do, to fill gaps in your understanding.β John Maddox, Editor of Nature 1966β73, and 1980β95
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