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  • 1
    Language: English
    In: Science (New York, N.Y.), 07 April 2006, Vol.312(5770), pp.111-4
    Description: Five point mutations in a particular beta-lactamase allele jointly increase bacterial resistance to a clinically important antibiotic by a factor of approximately 100,000. In principle, evolution to this high-resistance beta-lactamase might follow any of the 120 mutational trajectories linking these alleles. However, we demonstrate that 102 trajectories are inaccessible to Darwinian selection and that many of the remaining trajectories have negligible probabilities of realization, because four of these five mutations fail to increase drug resistance in some combinations. Pervasive biophysical pleiotropy within the beta-lactamase seems to be responsible, and because such pleiotropy appears to be a general property of missense mutations, we conclude that much protein evolution will be similarly constrained. This implies that the protein tape of life may be largely reproducible and even predictable.
    Subject(s): Drug Resistance, Bacterial ; Evolution, Molecular ; Mutation ; Cefotaxime -- Pharmacology ; Escherichia Coli -- Drug Effects ; Beta-Lactamases -- Genetics
    ISSN: 0036-8075
    E-ISSN: 1095-9203
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  • 2
    Article
    Article
    2011
    ISSN: 1061-4036 
    In: Nature Genetics, 2011, Vol.43(5), p.398
    Description: [...] they sequenced patient-derived amplification products at a population level and defined sequences in terms of probabilities of allele occurrences for each locus. Interestingly, a model allowing main effects together with only intragenic interactions performs no worse than the MEEP model in all...
    Subject(s): Epistasis, Genetic–Virology ; Evolution, Molecular–Drug Effects ; Genes, Viral–Genetics ; HIV Infections–Isolation & Purification ; HIV-1–Physiology ; HIV-1–Genetics ; HIV-1–Genetics ; HIV-1–Genetics ; High-Throughput Screening Assays–Genetics ; Humans–Genetics ; Mutation–Genetics ; Virus Replication–Genetics ; Mutation ; Drug Resistance ; Genetics ; Antiretroviral Drugs ; Enzymes ; Evolution & Development;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 3
    In: Evolution, October 2013, Vol.67(10), pp.2957-2972
    Description: The functional synthesis uses experimental methods from molecular biology, biochemistry and structural biology to decompose evolutionarily important mutations into their more proximal mechanistic determinants. However these methods are technically challenging and expensive. Noting strong formal parallels between R.A. Fisher's geometric model of adaptation and a recent model for the phenotypic basis of protein evolution, we sought to use the former to make inferences into the latter using data on pairwise fitness epistasis between mutations. We present an analytic framework for classifying pairs of mutations with respect to similarity of underlying mechanism on this basis, and also show that these data can yield an estimate of the number of mutationally labile phenotypes underlying fitness effects. We use computer simulations to explore the robustness of our approach to violations of analytic assumptions and analyze several recently published datasets. This work provides a theoretical complement to the functional synthesis as well as a novel test of Fisher's geometric model.
    Subject(s): Adaptation ; Epistasis ; Fitness ; Models/Simulations ; Mutations ; Pleiotropy
    ISSN: 0014-3820
    E-ISSN: 1558-5646
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 27 March 2018, Vol.115(13), pp.3422-3427
    Description: The influence of population size () on natural selection acting on alleles that affect fitness has been understood for almost a century. As declines, genetic drift overwhelms selection and alleles with direct fitness effects are rendered neutral. Often, however, alleles experience so-called indirect selection, meaning they affect not the fitness of an individual but the fitness distribution of its offspring. Some of the best-studied examples of indirect selection include alleles that modify aspects of the genetic system such as recombination and mutation rates. Here, we use analytics, simulations, and experimental populations of to examine the influence of on indirect selection acting on alleles that increase the genomic mutation rate (mutators). Mutators experience indirect selection via genomic associations with beneficial and deleterious mutations they generate. We show that, as declines, indirect selection driven by linked beneficial mutations is overpowered by drift before drift...
    Subject(s): Experimental Evolution ; Indirect Selection ; Mutation Rate ; Mutators ; Population Size ; Evolution, Molecular ; Mutation ; Mutation Rate ; Population Density ; Selection, Genetic ; Saccharomyces Cerevisiae -- Genetics ; Saccharomyces Cerevisiae Proteins -- Genetics
    ISSN: 0027-8424
    E-ISSN: 1091-6490
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  • 5
    Article
    Article
    2011
    ISSN: 0014-3820 
    Language: English
    In: Evolution; international journal of organic evolution, February 2011, Vol.65(2), pp.523-36
    Description: We examine the behavior of sexual and asexual populations in modular multipeaked fitness landscapes and show that sexuals can systematically reach different, higher fitness adaptive peaks than asexuals. Whereas asexuals must move against selection to escape local optima, sexuals reach higher fitness peaks reliably because they create specific genetic variants that "skip over" fitness valleys, moving from peak to peak in the fitness landscape. This occurs because recombination can supply combinations of mutations in functional composites or "modules," that may include individually deleterious mutations. Thus when a beneficial module is substituted for another less-fit module by sexual recombination it provides a genetic variant that would require either several specific simultaneous mutations in an asexual population or a sequence of individual mutations some of which would be selected against. This effect requires modular genomes, such that subsets of strongly epistatic mutations are tightly...
    Subject(s): Evolution, Molecular ; Sex
    ISSN: 0014-3820
    E-ISSN: 1558-5646
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  • 6
    In: Evolution, April 2014, Vol.68(4), pp.1124-1138
    Description: Development introduces structured correlations among traits that may constrain or bias the distribution of phenotypes produced. Moreover, when suitable heritable variation exists, natural selection may alter such constraints and correlations, affecting the phenotypic variation available to subsequent selection. However, exactly how the distribution of phenotypes produced by complex developmental systems can be shaped by past selective environments is poorly understood. Here we investigate the evolution of a network of recurrent nonlinear ontogenetic interactions, such as a gene regulation network, in various selective scenarios. We find that evolved networks of this type can exhibit several phenomena that are familiar in cognitive learning systems. These include formation of a distributed associative memory that can “store” and “recall” multiple phenotypes that have been selected in the past, recreate complete adult phenotypic patterns accurately from partial or corrupted embryonic phenotypes, and “generalize” (by exploiting evolved developmental modules) to produce new combinations of phenotypic features. We show that these surprising behaviors follow from an equivalence between the action of natural selection on phenotypic correlations and associative learning, well‐understood in the context of neural networks. This helps to explain how development facilitates the evolution of high‐fitness phenotypes and how this ability changes over evolutionary time.
    Subject(s): Adaptation ; Associative Learning ; Evolvability ; Evo‐Devo
    ISSN: 0014-3820
    E-ISSN: 1558-5646
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  • 7
    In: Evolution, October 2010, Vol.64(10), pp.2921-2934
    Description: We report the results of two independent selection experiments that have exposed distinct populations of to different forms of thermal selection. A recombinant population derived from Arvin California and Zimbabwe isofemale lines was exposed to laboratory natural selection at two temperatures (: 18°C and 28°C). Microsatellite mapping identified quantitative trait loci (QTL) on the X‐chromosome between the replicate “Hot” and “Cold” populations. In a separate experiment, disruptive selection was imposed on an outbred California population for the “knockdown” temperature () in a thermal column. Microsatellite mapping of the “High” and “Low” populations also uncovered primarily X‐linked QTL. Notably, a marker in the locus at band 3A was significantly differentiated in both experiments. Finer scale mapping of the 3A region has narrowed the QTL to the gene region, which contains several candidate genes that function in circadian rhythms. The same allele that was increased in frequency in the High populations is significantly clinal in North America and is more common at the warm end of the cline (Florida vs. Maine; however, the cline was not apparent in Australia). Together, these studies show that independent selection experiments can uncover the same target of selection and that evolution in the laboratory can recapitulate putatively adaptive clinal variation in nature.
    Subject(s): Artificial Selection ; Circadian Rhythm ; Experimental Evolution ; Photoperiod ; Thermotolerance
    ISSN: 0014-3820
    E-ISSN: 1558-5646
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  • 8
    Article
    Article
    2015
    ISSN: 0176-1714 
    Language: English
    In: Social Choice and Welfare, 2015, Vol.44(2), pp.319-348
    Description: The welfare state provides social insurance for lifetime risks. In that framework welfare stigma in form of a social norm against living off (net-)transfers is introduced, and the impact of welfare stigma on self-insurance and social insurance that works through redistributive taxation is analyzed. It turns out that introducing welfare stigma reduces the socially optimal self-insurance and raises the socially optimal social insurance. It may be efficient for the society to operate at a point on its opportunity frontier where an increase in risk taking decreases mean post-tax income and welfare stigma. In the presence of moral hazard self-insurance efforts are invariant with respect to welfare stigma whereas social insurance increases upon introducing welfare stigma. Furthermore, it is shown that self-insurance and social insurance are inefficiently low or high depending on the preference intensity of the social norm. Fig. 1 Efficient risk taking in dependence of the social norm
    Subject(s): Welfare State ; Risk Theory ; Social Norms ; Social Security ; Taxation ; Stigma ; Sociology;
    ISSN: 0176-1714
    E-ISSN: 1432-217X
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  • 9
    In: PLoS ONE, 2012, Vol.7(12)
    Description: Few clinically effective approaches reduce CNS-white matter injury. After early in-vivo white matter infarct, NFκB-driven pro-inflammatory signals can amplify a relatively small amount of vascular damage, resulting in progressive endothelial dysfunction to create a severe ischemic lesion. This process can be minimized by 15-deoxy-Δ 12,14 -prostaglandin J2 (PGJ 2 ), an analog of the metabolically active PGD 2 metabolite. We evaluated PGJ 2 's effects and mechanisms using rodent anterior ischemic optic neuropathy (rAION); an in vivo white matter ischemia model. PGJ 2 administration systemically administered either acutely or 5 hours post-insult results in significant neuroprotection, with stereologic evaluation showing improved neuronal survival 30 days post-infarct. Quantitative capillary vascular analysis reveals that PGJ 2 improves perfusion at 1 day post-infarct by reducing tissue edema. Our results suggest that PGJ 2 acts by reducing NFκB signaling through preventing p65 nuclear localization and inhibiting inflammatory gene expression. Importantly, PGJ 2 showed no in vivo toxicity structurally as measured by optic nerve (ON) myelin thickness, functionally by ON-compound action potentials, on a cellular basis by oligodendrocyte precursor survival or changes in ON-myelin gene expression. PGJ 2 may be a clinically useful neuroprotective agent for ON and other CNS infarcts involving white matter, with mechanisms of action enabling effective treatment beyond the currently considered maximal time for intervention.
    Subject(s): Research Article ; Biology ; Medicine
    E-ISSN: 1932-6203
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  • 10
    In: NeuroReport, 2010, Vol.21(9), pp.662-666
    Description: Near-infrared light therapy is an emerging neurostimulation technology, but its cellular mechanism of action remains unresolved. Using standard intracellular recording techniques, we observed that 5–10 ms pulses of 1889 nm light depolarized the membrane potential for hundreds of milliseconds in more than 85% of dorsal root ganglion and nodose ganglion neurons tested. The laser-evoked depolarizations (LEDs) exhibited complex, multiphasic kinetics comprising fast and slow components. There was no discernable difference in the LEDs in intact ganglion neurons and in acutely isolated neurons. Thus, the LED sensor seems to reside within the neuronal membrane. The near-uniform distribution of responsive neurons increased membrane conductance, and the negative reversal potential value (−41±2.9 mV) suggests that LED is unrelated to the activation of heat-sensitive transient receptor potential cation channel subfamily V member 1 channels. The long duration of LEDs favors an involvement of second messengers.
    Subject(s): Cation Channels ; I.R. Radiation ; Membrane Conductance ; Sensory Neurons ; Dorsal Root Ganglia ; Light Effects ; Electrophysiological Recording ; Second Messengers ; Neurons ; Kinetics ; Nodose Ganglion ; Transient Receptor Potential Proteins ; Membrane Potential ; Neurophysiology & Biophysics;
    ISSN: 0959-4965
    E-ISSN: 1473558X
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