Paul D Sniegowski

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (49)389.24 Total impact

  • Y Raynes, P D Sniegowski
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    ABSTRACT: Because genes that affect mutation rates are themselves subject to mutation, mutation rates can be influenced by natural selection and other evolutionary forces. The population genetics of mutation rate modifier alleles has been a subject of theoretical interest for many decades. Here, we review experimental contributions to our understanding of mutation rate modifier dynamics. Numerous evolution experiments have shown that mutator alleles (modifiers that elevate the genomic mutation rate) can readily rise to high frequencies via genetic hitchhiking in non-recombining microbial populations. Whereas these results certainly provide an explanatory framework for observations of sporadically high mutation rates in pathogenic microbes and in cancer lineages, it is nonetheless true that most natural populations have very low mutation rates. This raises the interesting question of how mutator hitchhiking is suppressed or its phenotypic effect reversed in natural populations. Very little experimental work has addressed this question; with this in mind, we identify some promising areas for future experimental investigation.Heredity advance online publication, 21 May 2014; doi:10.1038/hdy.2014.49.
    Heredity 05/2014; · 4.11 Impact Factor
  • Y Raynes, A L Halstead, P D Sniegowski
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    ABSTRACT: In the absence of recombination, a mutator allele can spread through a population by hitchhiking with beneficial mutations that appear in its genetic background. Theoretical studies over the past decade have shown that the survival and fixation probability of beneficial mutations can be severely reduced by population size bottlenecks. Here, we use computational modelling and evolution experiments with the yeast S. cerevisiae to examine whether population bottlenecks can affect mutator dynamics in adapting asexual populations. In simulation, we show that population bottlenecks can inhibit mutator hitchhiking with beneficial mutations and are most effective at lower beneficial mutation supply rates. We then subjected experimental populations of yeast propagated at the same effective population size to three different bottleneck regimes and observed that the speed of mutator hitchhiking was significantly slower at smaller bottlenecks, consistent with our theoretical expectations. Our results, thus, suggest that bottlenecks can be an important factor in mutation rate evolution and can in certain circumstances act to stabilize or, at least, delay the progressive elevation of mutation rates in asexual populations. Additionally, our findings provide the first experimental support for the theoretically postulated effect of population bottlenecks on beneficial mutations and demonstrate the usefulness of studying mutator frequency dynamics for understanding the underlying dynamics of fitness-affecting mutations.
    Journal of Evolutionary Biology 12/2013; · 3.48 Impact Factor
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    ABSTRACT: The hypothesis that evolvability - the capacity to evolve by natural selection - is itself the object of natural selection is highly intriguing but remains controversial due in large part to a paucity of direct experimental evidence. The antigenic variation mechanisms of microbial pathogens provide an experimentally tractable system to test whether natural selection has favored mechanisms that increase evolvability. Many antigenic variation systems consist of paralogous unexpressed 'cassettes' that recombine into an expression site to rapidly alter the expressed protein. Importantly, the magnitude of antigenic change is a function of the genetic diversity among the unexpressed cassettes. Thus, evidence that selection favors among-cassette diversity is direct evidence that natural selection promotes antigenic evolvability. We used the Lyme disease bacterium, Borrelia burgdorferi, as a model to test the prediction that natural selection favors amino acid diversity among unexpressed vls cassettes and thereby promotes evolvability in a primary surface antigen, VlsE. The hypothesis that diversity among vls cassettes is favored by natural selection was supported in each B. burgdorferi strain analyzed using both classical (dN/dS ratios) and Bayesian population genetic analyses of genetic sequence data. This hypothesis was also supported by the conservation of highly mutable tandem-repeat structures across B. burgdorferi strains despite a near complete absence of sequence conservation. Diversification among vls cassettes due to natural selection and mutable repeat structures promotes long-term antigenic evolvability of VlsE. These findings provide a direct demonstration that molecular mechanisms that enhance evolvability of surface antigens are an evolutionary adaptation. The molecular evolutionary processes identified here can serve as a model for the evolution of antigenic evolvability in many pathogens which utilize similar strategies to establish chronic infections.
    PLoS Pathogens 11/2013; 9(11):e1003766. · 8.14 Impact Factor
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    ABSTRACT: In classical population genetics, mutation–selection balance refers to the equilibrium frequency of a deleterious allele established and maintained under two opposing forces: recurrent mutation, which tends to increase the frequency of the allele; and selection, which tends to decrease its frequency. In a haploid population, if μ denotes the per capita rate of production of the deleterious allele by mutation and s denotes the selective disadvantage of carrying the allele, then the classical mutation–selection balance frequency of the allele is approximated by μ/s. This calculation assumes that lineages carrying the mutant allele in question—the 'focal allele'—do not accumulate deleterious mutations linked to the focal allele. In principle, indirect selection against the focal allele caused by such additional mutations can decrease the frequency of the focal allele below the classical mutation–selection balance. This effect of indirect selection will be strongest in an asexual population, in which the entire genome is in linkage. Here, we use an approach based on a multitype branching process to investigate this effect, analyzing lineage dynamics under mutation, direct selection, and indirect selection in a non-adapting asexual population. We find that the equilibrium balance between recurrent mutation to the focal allele and the forces of direct and indirect selection against the focal allele is closely approximated by γμ/(s + U) (s = 0 if the focal allele is neutral), where γ ≈ eθθ−(ω+θ)(ω + θ)(Γ(ω + θ) − Γ(ω + θ,θ)), , and ; U denotes the genomic deleterious mutation rate and denotes the geometric mean selective disadvantage of deleterious mutations elsewhere on the genome. This mutation–selection balance for asexual populations can remain surprisingly invariant over wide ranges of the mutation rate.
    Journal of Statistical Mechanics Theory and Experiment 02/2013; 2013(01):P01013. · 1.87 Impact Factor
  • Paul Sniegowski, Yevgeniy Raynes
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    ABSTRACT: Two recent reports combine mutation accumulation and whole-genome sequencing to measure mutation rates in microbes with unusual genome sizes and life cycles. The results are broadly consistent with the hypothesis that genetic drift plays a role in shaping genomic mutation rates across a wide range of taxa.
    Current biology: CB 02/2013; 23(4):R147-9. · 10.99 Impact Factor
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    Philip J Gerrish, Alexandre Colato, Paul D Sniegowski
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    ABSTRACT: When mutation rates are low, natural selection remains effective, and increasing the mutation rate can give rise to an increase in adaptation rate. When mutation rates are high to begin with, however, increasing the mutation rate may have a detrimental effect because of the overwhelming presence of deleterious mutations. Indeed, if mutation rates are high enough: (i) adaptive evolution may be neutralized, resulting in a zero (or negative) adaptation rate despite the continued availability of adaptive and/or compensatory mutations, or (ii) natural selection may be neutralized, because the fitness of lineages bearing adaptive and/or compensatory mutations-whether established or newly arising-is eroded by excessive mutation, causing such lineages to decline in frequency. We apply these two criteria to a standard model of asexual adaptive evolution and derive mathematical expressions-some new, some old in new guise-delineating the mutation rates under which either adaptive evolution or natural selection is neutralized. The expressions are simple and require no a priori knowledge of organism- and/or environment-specific parameters. Our discussion connects these results to each other and to previous theory, showing convergence or equivalence of the different results in most cases.
    Journal of The Royal Society Interface 01/2013; 10(85):20130329. · 4.91 Impact Factor
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    ABSTRACT: Cancer initiation, progression, and the emergence of therapeutic resistance are evolutionary phenomena of clonal somatic cell populations. Studies in microbial experimental evolution and the theoretical work inspired by such studies are yielding deep insights into the evolutionary dynamics of clonal populations, yet there has been little explicit consideration of the relevance of this rapidly growing field to cancer biology. Here, we examine how the understanding of mutation, selection, and spatial structure in clonal populations that is emerging from experimental evolution may be applicable to cancer. Along the way, we discuss some significant ways in which cancer differs from the model systems used in experimental evolution. Despite these differences, we argue that enhanced prediction and control of cancer may be possible using ideas developed in the context of experimental evolution, and we point out some prospects for future research at the interface between these traditionally separate areas.
    Current biology: CB 09/2012; 22(17):R762-71. · 10.99 Impact Factor
  • Yevgeniy Raynes, Matthew R Gazzara, Paul D Sniegowski
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    ABSTRACT: Mutators have been shown to hitchhike in asexual populations when the anticipated beneficial mutation supply rate of the mutator subpopulation, NU(b) (for subpopulation of size N and beneficial mutation rate U(b)) exceeds that of the wild-type subpopulation. Here, we examine the effect of total population size on mutator dynamics in asexual experimental populations of Saccharomyces cerevisiae. Although mutators quickly hitchhike to fixation in smaller populations, mutator fixation requires more and more time as population size increases; this observed delay in mutator hitchhiking is consistent with the expected effect of clonal interference. Interestingly, despite their higher beneficial mutation supply rate, mutators are supplanted by the wild type in very large populations. We postulate that this striking reversal in mutator dynamics is caused by an interaction between clonal interference, the fitness cost of the mutator allele, and infrequent large-effect beneficial mutations in our experimental populations. Our work thus identifies a potential set of circumstances under which mutator hitchhiking can be inhibited in natural asexual populations, despite recent theoretical predictions that such populations should have a net tendency to evolve ever-higher genomic mutation rates.
    Evolution 07/2012; 66(7):2329-34. · 4.86 Impact Factor
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    Philip J Gerrish, Paul D Sniegowski
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    ABSTRACT: A metaphor for adaptation that informs much evolutionary thinking today is that of mountain climbing, where horizontal displacement represents change in genotype, and vertical displacement represents change in fitness. If it were known a priori what the 'fitness landscape' looked like, that is, how the myriad possible genotypes mapped onto fitness, then the possible paths up the fitness mountain could each be assigned a probability, thus providing a dynamical theory with long-term predictive power. Such detailed genotype-fitness data, however, are rarely available and are subject to change with each change in the organism or in the environment. Here, we take a very different approach that depends only on fitness or phenotype-fitness data obtained in real time and requires no a priori information about the fitness landscape. Our general statistical model of adaptive evolution builds on classical theory and gives reasonable predictions of fitness and phenotype evolution many generations into the future.
    Journal of The Royal Society Interface 04/2012; 9(74):2268-78. · 4.91 Impact Factor
  • Philip J. Gerrish, Paul D. Sniegowski
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    ABSTRACT: Fisher’s “fundamental theorem of natural selection” is famously robust and versatile but, frustratingly, it is dynamically insufficient: it can only predict how fitness will evolve over the course of a single generation. Consequently, his theorem has not been used for predicting the course of evolution but instead for detecting natural selection. His theorem employs only one facet of the fitness distribution, namely, the variance, and thus does not take advantage of all the available information. The theory we have developed shares some common ground with Fisher’s theorem, but takes full advantage of the available information by employing the higher moments of the fitness distribution in addition to the variance. The theory developed here suggests: 1) a way to non-parametrically infer the distribution of mutational effects that feeds ongoing evolution, and 2) a framework for predicting fitness (and fitness-related) evolution.
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    Yevgeniy Raynes, Matthew R Gazzara, Paul D Sniegowski
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    ABSTRACT: In asexual populations, mutators may be expected to hitchhike with associated beneficial mutations. In sexual populations, recombination is predicted to erode such associations, inhibiting mutator hitchhiking. To investigate the effect of recombination on mutators experimentally, we compared the frequency dynamics of a mutator allele (msh2Δ) in sexual and asexual populations of Saccharomyces cerevisiae. Mutator strains increased in frequency at the expense of wild-type strains in all asexual diploid populations, with some approaching fixation in 150 generations of propagation. Over the same period of time, mutators declined toward loss in all corresponding sexual diploid populations as well as in haploid populations propagated asexually. We report the first experimental investigation of mutator dynamics in sexual populations. We show that a strong mutator quickly declines in sexual populations while hitchhiking to high frequency in asexual diploid populations, as predicted by theory. We also show that the msh2Δ mutator has a high and immediate realized cost that is alone sufficient to explain its decline in sexual populations. We postulate that this cost is indirect; namely, that it is due to a very high rate of recessive lethal or strongly deleterious mutation. However, we cannot rule out the possibility that msh2Δ also has unknown directly deleterious effects on fitness, and that these effects may differ between haploid asexual and sexual populations. Despite these reservations, our results prompt us to speculate that the short-term cost of highly deleterious recessive mutations can be as important as recombination in preventing mutator hitchhiking in sexual populations.
    BMC Evolutionary Biology 06/2011; 11:158. · 3.29 Impact Factor
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    ABSTRACT: Experimental studies have shown that a mutator allele can readily hitchhike to fixation with beneficial mutations in an asexual population having a low, wild-type mutation rate. Here, we show that a genotype bearing two mutator alleles can supplant a population already fixed for one mutator allele. Our results provide experimental support for recent theory predicting that mutator alleles will tend to accumulate in asexual populations by hitchhiking with beneficial mutations, causing an ever-higher genomic mutation rate.
    Biology letters 01/2011; 7(3):422-4. · 3.35 Impact Factor
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    ABSTRACT: Gene expression is a dynamic trait, and the evolution of gene regulation can dramatically alter the timing of gene expression without greatly affecting mean expression levels. Moreover, modules of co-regulated genes may exhibit coordinated shifts in expression timing patterns during evolutionary divergence. Here, we examined transcriptome evolution in the dynamical context of the budding yeast cell-division cycle, to investigate the extent of divergence in expression timing and the regulatory architecture underlying timing evolution. Using a custom microarray platform, we obtained 378 measurements for 6,263 genes over 18 timepoints of the cell-division cycle in nine strains of S. cerevisiae and one strain of S. paradoxus. Most genes show significant divergence in expression dynamics at all scales of transcriptome organization, suggesting broad potential for timing changes. A model test comparing expression level evolution versus timing evolution revealed a better fit with timing evolution for 82% of genes. Analysis of shared patterns of timing evolution suggests the existence of seven dynamically-autonomous modules, each of which shows coherent evolutionary timing changes. Analysis of transcription factors associated with these gene modules suggests a modular pleiotropic source of divergence in expression timing. We propose that transcriptome evolution may generally entail changes in timing (heterochrony) rather than changes in levels (heterometry) of expression. Evolution of gene expression dynamics may involve modular changes in timing control mediated by module-specific transcription factors. We hypothesize that genome-wide gene regulation may utilize a general architecture comprised of multiple semi-autonomous event timelines, whose superposition could produce combinatorial complexity in timing control patterns.
    Genome biology 10/2010; 11(10):R105. · 10.30 Impact Factor
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    Paul D Sniegowski, Philip J Gerrish
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    ABSTRACT: We discuss the dynamics of adaptive evolution in asexual (clonal) populations. The classical 'periodic selection' model of clonal evolution assumed that beneficial mutations are very rare and therefore substitute unfettered into populations as occasional, isolated events. Newer models allow for the possibility that beneficial mutations are sufficiently common to coexist and compete for fixation within populations. Experimental evolution studies in microbes provide empirical support for stochastic models in which both selection and mutation are strong effects and clones compete for fixation; however, the relative importance of competition among clones bearing mutations of different selective effects versus competition among clones bearing multiple mutations remains unresolved. We provide some new theoretical results, moreover, suggesting that population dynamics consistent with the periodic selection model can arise even in a deterministic model that can accommodate a very high beneficial mutation rate.
    Philosophical Transactions of The Royal Society B Biological Sciences 04/2010; 365(1544):1255-63. · 6.23 Impact Factor
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    ABSTRACT: The occurrence of mutator phenotypes among laboratory-generated and clinical levofloxacin-resistant strains of Streptococcus pneumoniae was determined using fluctuation analysis. The in vitro selection for levofloxacin-resistant mutants of strain D39, each with point mutations in both gyrA and parC or parE, was not associated with a significant change in the mutation rate. Two of eight clinical isolates resistant to levofloxacin (MIC, >8 microg/ml) had estimated mutation rates of 1.2 x 10(-7) and 9.4 x 10(-8) mutations per cell division, indicating potential mutator phenotypes, compared to strain D39, which had an estimated mutation rate of 1.4 x 10(-8) mutations per cell division. The levofloxacin-resistant isolates with the highest mutation rates showed evidence of dysfunctional mismatch repair and contained missense mutations in mut genes at otherwise highly conserved sites. The association of hypermutability in levofloxacin-resistant S. pneumoniae clinical isolates with mutations in DNA mismatch repair genes provides further evidence that mismatch repair mutants may have a selective advantage in the setting of antibiotic pressure, facilitating the development of further antibiotic resistance.
    Antimicrobial Agents and Chemotherapy 09/2007; 51(9):3225-9. · 4.57 Impact Factor
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    ABSTRACT: The intricate adjustment of organisms to their environment demonstrates the effectiveness of natural selection. But Darwin himself recognized that certain biological features could limit this effectiveness, features that generally reduce the efficiency of natural selection or yield suboptimal adaptation. Genetic linkage is known to be one such feature, and here we show theoretically that it can introduce a more sinister flaw: when there is complete linkage between loci affecting fitness and loci affecting mutation rate, positive natural selection and recurrent mutation can drive mutation rates in an adapting population to intolerable levels. We discuss potential implications of this finding for the early establishment of recombination, the evolutionary fate of asexual populations, and immunological clearance of clonal pathogens.
    Proceedings of the National Academy of Sciences 05/2007; 104(15):6266-71. · 9.74 Impact Factor
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    ABSTRACT: In plants and animals, new biological species clearly have arisen as a byproduct of genetic divergence in allopatry. However, our understanding of the processes that generate new microbial species remains limited [1] despite the large contribution of microbes to the world's biodiversity. A recent hypothesis claims that microbes lack biogeographical divergence because their population sizes are large and their migration rates are presumably high [2, 3]. In recapitulating the classic microbial-ecology dictum that "everything is everywhere, and the environment selects"[4, 5], this hypothesis casts doubt on whether geographic divergence promotes speciation in microbes. To date, its predictions have been tested primarily with data from eubacteria and archaebacteria [6-8]. However, this hypothesis's most important implication is in sexual eukaryotic microbes, where migration and genetic admixture are specifically predicted to inhibit allopatric divergence and speciation [9]. Here, we use nuclear-sequence data from globally distributed natural populations of the yeast Saccharomyces paradoxus to investigate the role of geography in generating diversity in sexual eukaryotic microbes. We show that these populations have undergone allopatric divergence and then secondary contact without genetic admixture. Our data thus support the occurrence of evolutionary processes necessary for allopatric speciation in sexual microbes.
    Current Biology 04/2007; 17(5):407-11. · 9.49 Impact Factor
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    ABSTRACT: In sexual microbes, mating occurs by fusion of individual cells. This complete fitness investment suggests that cell behaviour could potentially mediate prezygotic isolation between microbial species, a topic about which very little is known. To investigate this possibility, we conducted individual cell mate choice trials and mass-culture mating propensity assays with isolates from sympatric natural populations of the closely related yeasts Saccharomyces cerevisiae and Saccharomyces paradoxus. Although we found no evidence for active species recognition in mate choice, we observed a marked difference in mating propensity between these two species. We briefly discuss the possibility that this mating propensity difference may contribute to reproductive isolation between S. cerevisiae and S. paradoxus in nature.
    Biology letters 01/2007; 2(4):553-6. · 3.35 Impact Factor
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    Paul D Sniegowski, Helen A Murphy
    Current Biology 11/2006; 16(19):R831-4. · 9.49 Impact Factor
  • Paul D Sniegowski
    New Phytologist 06/2005; 166(2):360-2. · 6.74 Impact Factor

Publication Stats

2k Citations
389.24 Total Impact Points


  • 1997–2014
    • University of Pennsylvania
      • Department of Biology
      Philadelphia, Pennsylvania, United States
  • 2012–2013
    • University of New Mexico
      • Center for Evolutionary and Theoretical Immunology
      Albuquerque, NM, United States
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 2007
    • Santa Fe Institute
      Santa Fe, New Mexico, United States
    • University of Montana
      • Division of Biological Sciences
      Missoula, MT, United States
  • 1997–1998
    • State Research Institute of Genetics and Selection of Industrial Microorganisms
      Moskva, Moscow, Russia
  • 1994–1995
    • Michigan State University
      • Center for Microbial Ecology
      East Lansing, MI, United States
    • University of Chicago
      • Department of Ecology & Evolution
      Chicago, Illinois, United States
  • 1993–1994
    • University of Illinois at Chicago
      Chicago, Illinois, United States