569 research outputs found
A Unifying Theory of Biological Function
A new theory that naturalizes biological function is explained and compared with earlier etiological and causal role theories. Etiological theories explain functions from how they are caused over their evolutionary history. Causal role theories analyze how functional mechanisms serve the current capacities of their containing system. The new proposal unifies the key notions of both kinds of theories, but goes beyond them by explaining how functions in an organism can exist as factors with autonomous causal efficacy. The goal-directedness and normativity of functions exist in this strict sense as well. The theory depends on an internal physiological or neural process that mimics an organism’s fitness, and modulates the organism’s variability accordingly. The structure of the internal process can be subdivided into subprocesses that monitor specific functions in an organism. The theory matches well with each intuition on a previously published list of intuited ideas about biological functions, including intuitions that have posed difficulties for other theories
Interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response
Dramatic rise of mutators has been found to accompany adaptation of bacteria
in response to many kinds of stress. Two views on the evolutionary origin of
this phenomenon emerged: the pleiotropic hypothesis positing that it is a
byproduct of environmental stress or other specific stress response mechanisms
and the second order selection which states that mutators hitchhike to fixation
with unrelated beneficial alleles. Conventional population genetics models
could not fully resolve this controversy because they are based on certain
assumptions about fitness landscape. Here we address this problem using a
microscopic multiscale model, which couples physically realistic molecular
descriptions of proteins and their interactions with population genetics of
carrier organisms without assuming any a priori fitness landscape. We found
that both pleiotropy and second order selection play a crucial role at
different stages of adaptation: the supply of mutators is provided through
destabilization of error correction complexes or fluctuations of production
levels of prototypic mismatch repair proteins (pleiotropic effects), while rise
and fixation of mutators occur when there is a sufficient supply of beneficial
mutations in replication-controlling genes. This general mechanism assures a
robust and reliable adaptation of organisms to unforeseen challenges. This
study highlights physical principles underlying physical biological mechanisms
of stress response and adaptation
Monotonicity of Fitness Landscapes and Mutation Rate Control
A common view in evolutionary biology is that mutation rates are minimised.
However, studies in combinatorial optimisation and search have shown a clear
advantage of using variable mutation rates as a control parameter to optimise
the performance of evolutionary algorithms. Much biological theory in this area
is based on Ronald Fisher's work, who used Euclidean geometry to study the
relation between mutation size and expected fitness of the offspring in
infinite phenotypic spaces. Here we reconsider this theory based on the
alternative geometry of discrete and finite spaces of DNA sequences. First, we
consider the geometric case of fitness being isomorphic to distance from an
optimum, and show how problems of optimal mutation rate control can be solved
exactly or approximately depending on additional constraints of the problem.
Then we consider the general case of fitness communicating only partial
information about the distance. We define weak monotonicity of fitness
landscapes and prove that this property holds in all landscapes that are
continuous and open at the optimum. This theoretical result motivates our
hypothesis that optimal mutation rate functions in such landscapes will
increase when fitness decreases in some neighbourhood of an optimum, resembling
the control functions derived in the geometric case. We test this hypothesis
experimentally by analysing approximately optimal mutation rate control
functions in 115 complete landscapes of binding scores between DNA sequences
and transcription factors. Our findings support the hypothesis and find that
the increase of mutation rate is more rapid in landscapes that are less
monotonic (more rugged). We discuss the relevance of these findings to living
organisms
Competition of Escherichia coli DNA Polymerases I, II and III with DNA Pol IV in Stressed Cells
Escherichia coli has five DNA polymerases, one of which, the low-fidelity Pol IV or DinB, is required for stress-induced mutagenesis in the well-studied Lac frameshift-reversion assay. Although normally present at ∼200 molecules per cell, Pol IV is recruited to acts of DNA double-strand-break repair, and causes mutagenesis, only when at least two cellular stress responses are activated: the SOS DNA-damage response, which upregulates DinB ∼10-fold, and the RpoS-controlled general-stress response, which upregulates Pol IV about 2-fold. DNA Pol III was also implicated but its role in mutagenesis was unclear. We sought in vivo evidence on the presence and interactions of multiple DNA polymerases during stress-induced mutagenesis. Using multiply mutant strains, we provide evidence of competition of DNA Pols I, II and III with Pol IV, implying that they are all present at sites of stress-induced mutagenesis. Previous data indicate that Pol V is also present. We show that the interactions of Pols I, II and III with Pol IV result neither from, first, induction of the SOS response when particular DNA polymerases are removed, nor second, from proofreading of DNA Pol IV errors by the editing functions of Pol I or Pol III. Third, we provide evidence that Pol III itself does not assist with but rather inhibits Pol IV-dependent mutagenesis. The data support the remaining hypothesis that during the acts of DNA double-strand-break (DSB) repair, shown previously to underlie stress-induced mutagenesis in the Lac system, there is competition of DNA polymerases I, II and III with DNA Pol IV for action at the primer terminus. Up-regulation of Pol IV, and possibly other stress-response-controlled factor(s), tilt the competition in favor of error-prone Pol IV at the expense of more accurate polymerases, thus producing stress-induced mutations. This mutagenesis assay reveals the DNA polymerases operating in DSB repair during stress and also provides a sensitive indicator for DNA polymerase competition and choice in vivo
Mutability and Importance of a Hypermutable Cell Subpopulation that Produces Stress-Induced Mutants in Escherichia coli
In bacterial, yeast, and human cells, stress-induced mutation mechanisms are induced in growth-limiting environments and produce non-adaptive and adaptive mutations. These mechanisms may accelerate evolution specifically when cells are maladapted to their environments, i.e., when they are are stressed. One mechanism of stress-induced mutagenesis in Escherichia coli occurs by error-prone DNA double-strand break (DSB) repair. This mechanism was linked previously to a differentiated subpopulation of cells with a transiently elevated mutation rate, a hypermutable cell subpopulation (HMS). The HMS could be important, producing essentially all stress-induced mutants. Alternatively, the HMS was proposed to produce only a minority of stress-induced mutants, i.e., it was proposed to be peripheral. We characterize three aspects of the HMS. First, using improved mutation-detection methods, we estimate the number of mutations per genome of HMS-derived cells and find that it is compatible with fitness after the HMS state. This implies that these mutants are not necessarily an evolutionary dead end, and could contribute to adaptive evolution. Second, we show that stress-induced Lac+ mutants, with and without evidence of descent from the HMS, have similar Lac+ mutation sequences. This provides evidence that HMS-descended and most stress-induced mutants form via a common mechanism. Third, mutation-stimulating DSBs introduced via I-SceI endonuclease in vivo do not promote Lac+ mutation independently of the HMS. This and the previous finding support the hypothesis that the HMS underlies most stress-induced mutants, not just a minority of them, i.e., it is important. We consider a model in which HMS differentiation is controlled by stress responses. Differentiation of an HMS potentially limits the risks of mutagenesis in cell clones
Opposing effects of final population density and stress on Escherichia coli mutation rate
Evolution depends on mutations. For an individual genotype, the rate at which mutations arise is known to increase with various stressors (stress-induced mutagenesis-SIM) and decrease at high final population density (density-associated mutation-rate plasticity-DAMP). We hypothesised that these two forms of mutation-rate plasticity would have opposing effects across a nutrient gradient. Here we test this hypothesis, culturing Escherichia coli in increasingly rich media. We distinguish an increase in mutation rate with added nutrients through SIM (dependent on error-prone polymerases Pol IV and Pol V) and an opposing effect of DAMP (dependent on MutT, which removes oxidised G nucleotides). The combination of DAMP and SIM results in a mutation rate minimum at intermediate nutrient levels (which can support 7 × 10 cells ml ). These findings demonstrate a strikingly close and nuanced relationship of ecological factors-stress and population density-with mutation, the fuel of all evolution
Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector
Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02 TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1 μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos2Δϕ modulation for all ΣETPb ranges and particle pT
Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector
This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}4.6\;{\rm f}{{{\rm b}}^{-1}}{{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}|\eta |\lt 1.9{{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques
Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector
Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente
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