- Professor, Ecology and Evolutionary Biology
- Professor, Statistics-GIDP
- Professor, Applied Mathematics - GIDP
- Professor, BIO5 Institute
- Professor, Genetics - GIDP
- Professor, Psychology
- Wissenschaftskolleg zu Berlin, Fall 2013
- Honorable Mention, Outstanding Faculty Mentor
- University of Arizona Undergraduate Biology Research Program, Spring 2011
No activities entered.
DissertationMCB 920 (Spring 2018)
Evidence-based MedicineECOL 379 (Spring 2018)
Lab Presentations & DiscussionMCB 696A (Spring 2018)
ResearchECOL 900 (Spring 2018)
Directed RsrchMCB 492 (Fall 2017)
DissertationMATH 920 (Fall 2017)
DissertationMCB 920 (Fall 2017)
Intro to Modeling in BiologyECOL 419 (Fall 2017)
Intro to Modeling in BiologyECOL 519 (Fall 2017)
Lab Presentations & DiscussionMCB 696A (Fall 2017)
Population BiologyECOL 596B (Fall 2017)
ResearchECOL 900 (Fall 2017)
DissertationMCB 920 (Spring 2017)
Evidence-based MedicineECOL 379 (Spring 2017)
Lab Presentations & DiscussionMCB 696A (Spring 2017)
ResearchECOL 900 (Spring 2017)
Directed ResearchPHYS 492 (Fall 2016)
DissertationMCB 920 (Fall 2016)
Honors Independent StudyECOL 399H (Fall 2016)
Honors Independent StudyECOL 499H (Fall 2016)
Intro to Modeling in BiologyECOL 419 (Fall 2016)
Intro to Modeling in BiologyECOL 519 (Fall 2016)
Lab Presentations & DiscussionMCB 696A (Fall 2016)
ResearchECOL 900 (Fall 2016)
- Masel, J. (2016). Bypass Wall Street: A Biologist's Guide to the Rat Race. Perforce Publishing, LLC.
- Andreatta, M. E., Levine, J. A., Foy, S. G., Guzman, L. D., Kosinski, L. J., Cordes, M. H., & Masel, J. (2015). The Recent De Novo Origin of Protein C-Termini. GENOME BIOLOGY AND EVOLUTION, 7(6), 1686-1701.
- Masel, J., Humphrey, P. T., Blackburn, B., & Levine, J. A. (2015). Evidence-Based Medicine as a Tool for Undergraduate Probability and Statistics Education. CBE life sciences education, 14(4), ar42.More infoMost students have difficulty reasoning about chance events, and misconceptions regarding probability can persist or even strengthen following traditional instruction. Many biostatistics classes sidestep this problem by prioritizing exploratory data analysis over probability. However, probability itself, in addition to statistics, is essential both to the biology curriculum and to informed decision making in daily life. One area in which probability is particularly important is medicine. Given the preponderance of pre health students, in addition to more general interest in medicine, we capitalized on students' intrinsic motivation in this area to teach both probability and statistics. We use the randomized controlled trial as the centerpiece of the course, because it exemplifies the most salient features of the scientific method, and the application of critical thinking to medicine. The other two pillars of the course are biomedical applications of Bayes' theorem and science and society content. Backward design from these three overarching aims was used to select appropriate probability and statistics content, with a focus on eliciting and countering previously documented misconceptions in their medical context. Pretest/posttest assessments using the Quantitative Reasoning Quotient and Attitudes Toward Statistics instruments are positive, bucking several negative trends previously reported in statistics education.
- Teufel, A. I., Masel, J., & Liberles, D. A. (2015). What Fraction of Duplicates Observed in Recently Sequenced Genomes Is Segregating and Destined to Fail to Fix?. GENOME BIOLOGY AND EVOLUTION, 7(8), 2258-2264.
- Mix, L. J., & Masel, J. (2014). CHANCE, PURPOSE, AND PROGRESS IN EVOLUTION AND CHRISTIANITY. Evolution, 68(8), 2441-2451.More infoEvolutionary biology has a complex relationship with ideas of chance, purpose, and progress. Probability plays a subtle role; strikingly, founding figures in statistics were motivated by evolutionary questions. The findings of evolutionary biology have been used both in support of narratives of progress, and in their deconstruction. Likewise, professional biologists bring to their scientific work a set of preconceptions about chance and progress, grounded in their philosophical, religious, and/or political views. From the religious side, questions of purpose are ever-present. We explore this interplay in five broad categories: chance, progress, intelligence, eugenics, and the evolution of religious practices, each the subject of a semester long symposium. The intellectual influence of evolutionary biology has had a broad societal impact in these areas. Based on our experience, we draw attention to a number of relevant facts that, while accepted by experts in their respective fields, may be unfamiliar outside them. We list common areas of miscommunication, including specific examples and discussing causes: sometimes semantics and sometimes more substantive knowledge barriers. We also make recommendations for those attempting similar dialogue.
- Trotter, M. V., Weissman, D. B., Peterson, G. I., Peck, K. M., & Masel, J. (2014). Cryptic genetic variation can make "irreducible complexity" a common mode of adaptation in sexual populations. Evolution, 68(12), 3357-3367.More infoThe existence of complex (multiple-step) genetic adaptations that are irreducible (i.e., all partial combinations are less fit than the original genotype) is one of the longest standing problems in evolutionary biology. In standard genetics parlance, these adaptations require the crossing of a wide adaptive valley of deleterious intermediate stages. Here, we demonstrate, using a simple model, that evolution can cross wide valleys to produce irreducibly complex adaptations by making use of previously cryptic mutations. When revealed by an evolutionary capacitor, previously cryptic mutants have higher initial frequencies than do new mutations, bringing them closer to a valley-crossing saddle in allele frequency space. Moreover, simple combinatorics implies an enormous number of candidate combinations exist within available cryptic genetic variation. We model the dynamics of crossing of a wide adaptive valley after a capacitance event using both numerical simulations and analytical approximations. Although individual valley crossing events become less likely as valleys widen, by taking the combinatorics of genotype space into account, we see that revealing cryptic variation can cause the frequent evolution of complex adaptations.
- Masel, J. (2013). Q&A: Evolutionary capacitance. BMC Biology, 11.More infoPMID: 24228631;PMCID: PMC3849687;
- Rajon, E., & Masel, J. (2013). Compensatory evolution and the origins of innovations. Genetics, 193(4), 1209-1220.More infoPMID: 23335336;PMCID: PMC3606098;Abstract: Cryptic genetic sequences have attenuated effects on phenotypes. In the classic view, relaxed selection allows cryptic genetic diversity to build up across individuals in a population, providing alleles that may later contribute to adaptation when coopted- e.g., following a mutation increasing expression from a low, attenuated baseline. This view is described, for example, by the metaphor of the spread of a population across a neutral network in genotype space. As an alternative view, consider the fact that most phenotypic traits are affected by multiple sequences, including cryptic ones. Even in a strictly clonal population, the co-option of cryptic sequences at different loci may have different phenotypic effects and offer the population multiple adaptive possibilities. Here, we model the evolution of quantitative phenotypic characters encoded by cryptic sequences and compare the relative contributions of genetic diversity and of variation across sites to the phenotypic potential of a population. We show that most of the phenotypic variation accessible through co-option would exist even in populations with no polymorphism. This is made possible by a history of compensatory evolution, whereby the phenotypic effect of a cryptic mutation at one site was balanced by mutations elsewhere in the genome, leading to a diversity of cryptic effect sizes across sites rather than across individuals. Cryptic sequences might accelerate adaptation and facilitate large phenotypic changes even in the absence of genetic diversity, as traditionally defined in terms of alternative alleles. © 2013 by the Genetics Society of America.
- Brettner, L. M., & Masel, J. (2012). Protein stickiness, rather than number of functional protein-protein interactions, predicts expression noise and plasticity in yeast. BMC Systems Biology, 6.More infoPMID: 23017156;PMCID: PMC3527306;Abstract: Background: A hub protein is one that interacts with many functional partners. The annotation of hub proteins, or more generally the protein-protein interaction " degree" of each gene, requires quality genome-wide data. Data obtained using yeast two-hybrid methods contain many false positive interactions between proteins that rarely encounter each other in living cells, and such data have fallen out of favor.Results: We find that protein " stickiness" , measured as network degree in ostensibly low quality yeast two-hybrid data, is a more predictive genomic metric than the number of functional protein-protein interactions, as assessed by supposedly higher quality high throughput affinity capture mass spectrometry data. In the yeast Saccharomyces cerevisiae, a protein's high stickiness, but not its high number of functional interactions, predicts low stochastic noise in gene expression, low plasticity of gene expression across different environments, and high probability of forming a homo-oligomer. Our results are robust to a multiple regression analysis correcting for other known predictors including protein abundance, presence of a TATA box and whether a gene is essential. Once the higher stickiness of homo-oligomers is controlled for, we find that homo-oligomers have noisier and more plastic gene expression than other proteins, consistent with a role for homo-oligomerization in mediating robustness.Conclusions: Our work validates use of the number of yeast two-hybrid interactions as a metric for protein stickiness. Sticky proteins exhibit low stochastic noise in gene expression, and low plasticity in expression across different environments. © 2012 Brettner and Masel; licensee BioMed Central Ltd.
- Masel, J. (2012). Rethinking Hardy-Weinberg and genetic drift in undergraduate biology. BioEssays, 34(8), 701-710.More infoPMID: 22576789;Abstract: Population genetics is often taught in introductory biology classes, starting with the Hardy-Weinberg principle (HWP) and genetic drift. Here I argue that teaching these two topics first aligns neither with current expert knowledge, nor with good pedagogy. Student difficulties with mathematics in general, and probability in particular, make population genetics difficult to teach and learn. I recommend an alternative, historically inspired ordering of population genetics topics, based on progressively increasing mathematical difficulty. This progression can facilitate just-in-time math instruction. This alternative ordering includes, but does not privilege, the HWP and genetic drift. Stochastic events whose consequences are felt within a single generation, and the deterministic accumulation of the effects of selection across multiple generations, are both taught before tackling the stochastic accumulation of the effects of accidents of sampling. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
- Siegal, M. L., & Masel, J. (2012). Hsp90 depletion goes wild. BMC Biology, 10.More infoAbstract: Hsp90 reveals phenotypic variation in the laboratory, but is Hsp90 depletion important in the wild? Recent work from Chen and Wagner in BMC Evolutionary Biology has discovered a naturally occurring Drosophila allele that downregulates Hsp90, creating sensitivity to cryptic genetic variation. Laboratory studies suggest that the exact magnitude of Hsp90 downregulation is important. Extreme Hsp90 depletion might reactivate transposable elements and/or induce aneuploidy, in addition to revealing cryptic genetic variation.See research article http://wwww.biomedcentral.com/1471-2148/12/25. © 2012 Siegal and Masel; licensee BioMed Central Ltd.
- Masel, J. (2011). Genetic drift. Current Biology, 21(20), R837-R838.More infoPMID: 22032182;
- Masel, J., & Lyttle, D. N. (2011). The consequences of rare sexual reproduction by means of selfing in an otherwise clonally reproducing species. Theoretical Population Biology, 80(4), 317-322.More infoPMID: 21888925;PMCID: PMC3218209;Abstract: Clonal reproduction of diploids leads to an increase in heterozygosity over time. A single round of selfing will then create new homozygotic genotypes. Given the same allele frequencies, heritable genetic variation is larger when there are more extreme, i.e. homozygotic genotypes. So after a long clonal expansion, one round of selfing increases heritable genetic variation, but any fully or partially recessive deleterious alleles simultaneously impose a fitness cost. Here we calculate that the cost of selfing in the yeast Saccharomyces is experienced only by a minority of zygotes. This allows a round of selfing to act as an evolutionary capacitor to unlock genetic variation previously found in a cryptic heterozygous form. We calculate the evolutionary consequences rather than the evolutionary causes of sex. We explore a range of parameter values describing sexual frequencies, focusing especially on the parameter values known for wild Saccharomyces. Our results are largely robust to many other parameter value choices, so long as meiosis is rare relative to the strength of selection on heterozygotes. Results may also be limited to organisms with a small number of genes. We therefore expect the same phenomenon in some other species with similar reproductive strategies. © 2011 Elsevier Inc.
- Rajon, E., & Masel, J. (2011). Evolution of molecular error rates and the consequences for evolvability. Proceedings of the National Academy of Sciences of the United States of America, 108(3), 1082-1087.More infoPMID: 21199946;PMCID: PMC3024668;Abstract: Making genes into gene products is subject to predictable errors, each with a phenotypic effect that depends on a normally cryptic sequence. Many cryptic sequences have strongly deleterious effects, for example when they cause protein misfolding. Strongly deleterious effects can be avoided globally by avoiding making errors (e.g., via proofreading machinery) or locally by ensuring that each error has a relatively benign effect. The local solution requires powerful selection acting on every cryptic site and so evolves only in large populations. Small populations with less effective selection evolve global solutions. Here we show that for a large range of realistic intermediate population sizes, the evolutionary dynamics are bistable and either solution may result. The local solution facilitates the genetic assimilation of cryptic genetic variation and therefore substantially increases evolvability.
- Wilson, B. A., & Masel, J. (2011). Putatively noncoding transcripts show extensive association with ribosomes. Genome Biology and Evolution, 3(1), 1245-1252.More infoPMID: 21948395;PMCID: PMC3209793;Abstract: There have been recent surprising reports that whole genes can evolve de novo from noncoding sequences. This would be extraordinary if the noncoding sequences were random with respect to amino acid identity. However, if the noncoding sequences were previously translated at low rates, with the most strongly deleterious cryptic polypeptides purged by selection, then de novo gene origination would be more plausible. Here we analyze Saccharomyces cerevisiae data on noncoding transcripts found in association with ribosomes. We find many such transcripts. Although their average ribosomal densities are lower than those of protein-coding genes, a significant proportion of noncoding transcripts nevertheless have ribosomal densities comparable to those of coding genes. Most show increased ribosomal association in response to starvation, as has been previously reported for other noncoding sequences such as untranslated regions and introns. In rich media, ribosomal association is correlated with start codons but is not usually consistent and contiguous beyond that, suggesting that translation occurs only at low rates. One transcript contains a 28-codon open reading frame, which we name RDT1, which shows evidence of translation, and may be a new protein-coding gene that originated de novo from noncoding sequence. But the bulk of the ribosomal association cannot be attributed to unannotated protein-coding genes. Our primary finding of extensive ribosome association shows that a necessary precondition for selective purging is met, making de novo gene evolution more plausible. Our analysis is also proof of principle of the utility of ribosomal profiling data for the purpose of gene annotation. © The Author(s) 2010.
- Lancaster, A. K., Bardill, J. P., True, H. L., & Masel, J. (2010). The spontaneous appearance rate of the yeast prion [PSI+] and its implications for the evolution of the evolvability properties of the [PSI+] system. Genetics, 184(2), 393-400.More infoPMID: 19917766;PMCID: PMC2828720;Abstract: Epigenetically inherited aggregates of the yeast prion [PSI+] cause genomewide readthrough translation that sometimes increases evolvability in certain harsh environments. The effects of natural selection on modifiers of [PSI+] appearance have been the subject of much debate. It seems likely that [PSI+] would be at least mildly deleterious in most environments, but this may be counteracted by its evolvability properties on rare occasions. Indirect selection on modifiers of [PSI+] is predicted to depend primarily on the spontaneous [PSI+] appearance rate, but this critical parameter has not previously been adequately measured. Here we measure this epimutation rate accurately and precisely as 5.8 × 10-7 per generation, using a fluctuation test. We also determine that genetic "mimics" of [PSI1] account for up to 80% of all phenotypes involving general nonsense suppression. Using previously developed mathematical models, we can now infer that even in the absence of opportunities for adaptation, modifiers of [PSI+] are only weakly deleterious relative to genetic drift. If we assume that the spontaneous [PSI+] appearance rate is at its evolutionary optimum, then opportunities for adaptation are inferred to be rare, such that the [PSI+] system is favored only very weakly overall. But when we account for the observed increase in the [PSI+] appearance rate in response to stress, we infer much higher overall selection in favor of [PSI+] modifiers, suggesting that [PSI+]-forming ability may be a consequence of selection for evolvability. Copyright © 2010 by the Genetics Society of America.
- Masel, J., & Trotter, M. V. (2010). Robustness and evolvability. Trends in Genetics, 26(9), 406-414.More infoPMID: 20598394;PMCID: PMC3198833;Abstract: Why isn't random variation always deleterious? Are there factors that sometimes make adaptation easier? Biological systems are extraordinarily robust to perturbation by mutations, recombination and the environment. It has been proposed that this robustness might make them more evolvable. Robustness to mutation allows genetic variation to accumulate in a cryptic state. Switching mechanisms known as evolutionary capacitors mean that the amount of heritable phenotypic variation available can be correlated to the degree of stress and hence to the novelty of the environment and remaining potential for adaptation. There have been two somewhat separate literatures relating robustness to evolvability. One has focused on molecular phenotypes and new mutations, the other on morphology and cryptic genetic variation. Here, we review both literatures, and show that the true distinction is whether recombination rates are high or low. In both cases, the evidence supports the claim that robustness promotes evolvability. © 2010 Elsevier Ltd.
- Griswold, C. K., & Masel, J. (2009). Complex adaptations can drive the evolution of the capacitor [PSI +], even with realistic rates of yeast sex. PLoS Genetics, 5(6).More infoPMID: 19521499;PMCID: PMC2686163;Abstract: The [PSI+] prion may enhance evolvability by revealing previously cryptic genetic variation, but it is unclear whether such evolvability properties could be favored by natural selection. Sex inhibits the evolution of other putative evolvability mechanisms, such as mutator alleles. This paper explores whether sex also prevents natural selection from favoring modifier alleles that facilitate [PSI+] formation. Sex may permit the spread of "cheater" alleles that acquire the benefits of [PSI +] through mating without incurring the cost of producing [PSI+] at times when it is not adaptive. Using recent quantitative estimates of the frequency of sex in Saccharomyces paradoxus, we calculate that natural selection for evolvability can drive the evolution of the [PSI+] system, so long as yeast populations occasionally require complex adaptations involving synergistic epistasis between two loci. If adaptations are always simple and require substitution at only a single locus, then the [PSI+] system is not favored by natural selection. Obligate sex might inhibit the evolution of [PSI+]-like systems in other species. © 2009 Griswold, Masel.
- Lancaster, A. K., & Masel, J. (2009). The evolution of reversible switches in the presence of irreversible mimics. Evolution, 63(9), 2350-2362.More infoPMID: 19486147;PMCID: PMC2770902;Abstract: Reversible phenotypic switching can be caused by a number of different mechanisms including epigenetic inheritance systems and DNA-based contingency loci. Previous work has shown that reversible switching systems may be favored by natural selection. Many switches can be characterized as "on/off" where the "off" state constitutes a temporary and reversible loss of function. Loss-of-function phenotypes corresponding to the "off" state can be produced in many different ways, all yielding identical fitness in the short term. In the long term, however, a switch-induced loss of function can be reversed, whereas many loss-of-function mutations, especially deletions, cannot. We refer to these loss-of-function mutations as "irreversible mimics" of the reversible switch. Here, we develop a model in which a reversible switch evolves in the presence of both irreversible mimics and metapopulation structure. We calculate that when the rate of appearance of irreversible mimics exceeds the migration rate, the evolved reversible switching rate will exceed the bet-hedging rate predicted by panmictic models. © 2009 The Society for the Study of Evolution.
- Masel, J., & Griswold, C. K. (2009). The strength of selection against the yeast prion [PSI +]. Genetics, 181(3), 1057-1063.More infoPMID: 19153253;PMCID: PMC2651042;Abstract: The [PSI +] prion causes widespread readthrough translation and is rare in natural populations of Saccharomyces, despite the fact that sex is expected to cause it to spread. Using the recently estimated rate of Saccharomyces outcrossing, we calculate the strength of selection necessary to maintain [PSI +] at levels low enough to be compatible with data. Using the best available parameter estimates, we find selection against [PSI +] to be significant. Inference regarding selection on modifiers of [PSI +] appearance depends on obtaining more precise and accurate estimates of the product of yeast effective population size N e and the spontaneous rate of [PSI +] appearance m. The ability to form [PSI +] has persisted in yeast over a long period of evolutionary time, despite a diversity of modifiers that could abolish it. If mN e < 1, this may be explained by insufficiently strong selection. If mN e gt; 1, then selection should favor the spread of [PSI +] resistance modifiers. In this case, rare conditions where [PSI +] is adaptive may permit its persistence in the face of negative selection. Copyright © 2009 by the Genetics Society of America.
- Masel, J., & Siegal, M. L. (2009). Robustness: mechanisms and consequences. Trends in Genetics, 25(9), 395-403.More infoPMID: 19717203;PMCID: PMC2770586;Abstract: Biological systems are robust to perturbation by mutations and environmental fluctuations. New data are shedding light on the biochemical and network-level mechanisms responsible for robustness. Robustness to mutation might have evolved as an adaptation to reduce the effect of mutations, as a congruent byproduct of adaptive robustness to environmental variation, or as an intrinsic property of biological systems selected for their primary functions. Whatever its mechanism or origin, robustness to mutation results in the accumulation of phenotypically cryptic genetic variation. Partial robustness can lead to pre-adaptation, and thereby might contribute to evolvability. The identification and characterization of phenotypic capacitors - which act as switches of the degree of robustness - are critical to understanding the mechanisms and consequences of robustness. © 2009 Elsevier Ltd. All rights reserved.
- Peterson, G. I., & Masel, J. (2009). Quantitative prediction of molecular clock and Ka/Ks at short timescales. Molecular Biology and Evolution, 26(11), 2595-2603.More infoPMID: 19661199;PMCID: PMC2912466;Abstract: Recent empirical studies of taxa including humans, fish, and birds have shown elevated rates of molecular evolution between species that diverged recently. Using the Moran model, we calculate expected divergence as a function of time. Our findings suggest that the observed phenomenon of elevated rates at short timescales is consistent with standard population genetics theory. The apparent acceleration of the molecular clock at short timescales can be explained by segregating polymorphisms present at the time of the ancestral population, both neutral and slightly deleterious, and not newly arising slightly deleterious mutations as has been previously hypothesized. Our work also suggests that the duration of the rate elevation depends on the effective population size, providing a method to correct time estimates of recent divergence events. Our model concords with estimates of divergence obtained from African cichlid fish and humans. As an additional application of our model, we calculate that Ka/Ks is elevated within a population before decaying slowly to its long-term value. Similar to the molecular clock, the duration and magnitude of Ka/Ks elevation depend on the effective population size. Unlike the molecular clock, however, Ka/Ks elevation is caused by newly arising slightly deleterious mutations. This elevation, although not as severe in magnitude as had been previously predicted in models neglecting ancestral polymorphism, persists slightly longer.
- Giacomelli, M. G., Hancock, A. S., & Masel, J. (2007). The conversion of 3′ UTRs into coding regions. Molecular Biology and Evolution, 24(2), 457-464.More infoPMID: 17099057;PMCID: PMC1808353;Abstract: A possible origin of novel coding sequences is the removal of stop codons, leading to the inclusion of 3′ untranslated regions (3′ UTRs) within genes. We classified changes in the position of stop codons in closely related Saccharomyces species and in a mouse/rat comparison as either additions to or subtractions from coding regions. In both cases, the position of stop codons is highly labile, with more subtractions than additions found. The subtraction bias may be balanced by the input of new coding regions through gene duplication. Saccharomyces shows less stop codon lability than rodents, probably due to greater selective constraint. A higher proportion of 3′ UTR incorporation events preserve frame in Saccharomyces. This higher proportion is consistent with the action of the [PSI+] prion as an evolutionary capacitor to facilitate 3′ UTR incorporation in yeast. © 2006 The Authors.
- King, O. D., & Masel, J. (2007). The evolution of bet-hedging adaptations to rare scenarios. Theoretical Population Biology, 72(4), 560-575.More infoPMID: 17915273;PMCID: PMC2118055;Abstract: When faced with a variable environment, organisms may switch between different strategies according to some probabilistic rule. In an infinite population, evolution is expected to favor the rule that maximizes geometric mean fitness. If some environments are encountered only rarely, selection may not be strong enough for optimal switching probabilities to evolve. Here we calculate the evolution of switching probabilities in a finite population by analyzing fixation probabilities of alleles specifying switching rules. We calculate the conditions required for the evolution of phenotypic switching as a form of bet-hedging as a function of the population size N, the rate θ at which a rare environment is encountered, and the selective advantage s associated with switching in the rare environment. We consider a simplified model in which environmental switching and phenotypic switching are one-way processes, and mutation is symmetric and rare with respect to the timescale of fixation events. In this case, the approximate requirements for bet-hedging to be favored by a ratio of at least R are that sN>log(R) and θ N > sqrt(R) . © 2007 Elsevier Inc. All rights reserved.
- Masel, J. (2007). A Bayesian model of quasi-magical thinking can explain observed cooperation in the public good game. Journal of Economic Behavior and Organization, 64(2), 216-231.More infoAbstract: Models of learning, reciprocity and altruism cannot explain all aspects of observed contributions in the public good game. Here a new model is described in which players recognize a correlation between their own contribution and the likely contributions of other players. The correlation is calculated by treating a player's own conjectured contribution just like any other data point within a learning model. Although players recognize that this correlation is not causal, they nevertheless choose to maximize expected utility conditional on their own action rather than standard expected utility. Results from the model explain previously puzzling quantitative trends in the data. © 2006 Elsevier B.V. All rights reserved.
- Masel, J., & Maughan, H. (2007). Mutations leading to loss of sporulation ability in Bacillus subtilis are sufficiently frequent to favor genetic canalization. Genetics, 175(1), 453-457.More infoPMID: 17110488;PMCID: PMC1775008;Abstract: We measured the rate of mutations impairing sporulation ability in Bacillus subtilis as 0.003 in a mutator population, following 6000 generations of strong selection for sporulation that have previously been described. This means that the product of the population size and the functional mutation rate is ∼105, well within the parameter range for which genetic canalization of sporulation ability is expected. Copyright © 2007 by the Genetics Society of America.
- Masel, J., King, O. D., & Maughan, H. (2007). The loss of adaptive plasticity during long periods of environmental stasis. American Naturalist, 169(1), 38-46.More infoPMID: 17206583;PMCID: PMC1766558;Abstract: Adaptive plasticity allows populations to adjust rapidly to environmental change. If this is useful only rarely, plasticity may undergo mutational degradation and be lost from a population. We consider a population of constant size N undergoing loss of plasticity at functional mutation rate m and with selective advantage s associated with loss. Environmental change events occur at rate θ per generation, killing all individuals that lack plasticity. The expected time until loss of plasticity in a fluctuating environment is always at least τ, the expected time until loss of plasticity in a static environment. When mN > 1 and Nθ ≫ 1, we find that plasticity will be maintained for an average of at least 108 generations in a single population, provided τ > 18/θ. In a metapopulation, plasticity is retained under the more lenient condition τ > 1.3/θ, irrespective of mN, for a modest number of demes. We calculate both exact and approximate solutions for τ and find that it is linearly dependent only on the logarithm of N, and so, surprisingly, both the population size and the number of demes in the metapopulation make little difference to the retention of plasticity. Instead, τ is dominated by the term 1/(m + s/2). © 2007 by The University of Chicago.
- Maughan, H., Masel, J., Birky Jr., C. W., & Nicholson, W. L. (2007). The roles of mutation accumulation and selection in loss of sporulation in experimental populations of Bacillus subtilis. Genetics, 177(2), 937-948.More infoPMID: 17720926;PMCID: PMC2034656;Abstract: Phenotypic loss is an important evolutionary force in nature but the mechanism(s) responsible for loss remains unclear. We used both simulation and multiple-regression approaches to analyze data on the loss of sporulation, a complex bacterial developmental process, during experimental evolution of Bacillus subtilis. Neutral processes of mutational degradation alone were sufficient to explain loss-of-sporulation ability in four of five populations, while evidence that selection facilitated mutational loss was found for only one population. These results are discussed in the context of the evolution of sporulation in particular and phenotypic loss in general. Copyright © 2007 by the Genetics Society of America.
- Bliss, T. M., Kelly, S., Shah, A. K., Foo, W. C., Kohli, P., Stokes, C., Sun, G. H., Ma, M., Masel, J., Kleppner, S. R., Schallert, T., Palmer, T., & Steinberg, G. K. (2006). Transplantation of hNT neurons into the ischemic cortex: Cell survival and effect on sensorimotor behavior. Journal of Neuroscience Research, 83(6), 1004-1014.More infoPMID: 16496370;Abstract: Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a model of stroke in which the striatum remains intact and damage is restricted to the cortex. hNT cells were transplanted into the ischemic cortex 1 week after stroke induced by distal middle cerebral artery occlusion (dMCAo). The cells exhibited robust survival at 4 weeks posttransplant even at the lesion border. hNT cells did not migrate, but they did extend long neurites into the surrounding parenchyma mainly through the white matter. Neurite extension was predominantly toward the lesion in ischemic animals but was bidirectional in uninjured animals. Extension of neurites through the cortex toward the lesion was also seen when there was some surviving cortical tissue between the graft and the infarct. Prolonged deficits were obtained in four tests of sensory-motor function. hNT-transplanted animals showed a significant improvement in functional recovery on one motor test, but there was no effect on the other three tests relative to control animals. Thus, despite clear evidence of graft survival and neurite extension, the functional benefit of hNT cells after ischemia is not guaranteed. Functional benefit could depend on other variables, such as infarct location, whether the cells mature, the behavioral tests employed, rehabilitation training, or as yet unidentified factors. © 2006 Wiley-Liss, Inc.
- Masel, J. (2006). Cryptic genetic variation is enriched for potential adaptations. Genetics, 172(3), 1985-1991.More infoPMID: 16387877;PMCID: PMC1456269;Abstract: Cryptic genetic variation accumulates under weakened selection and has been proposed as a source of evolutionary innovations. Weakened selection may, however, also lead to the accumulation of strongly deleterious or lethal alleles, swamping the effect of any potentially adaptive alleles when they are revealed. Here I model variation that is partially shielded from selection, assuming that unconditionally deleterious variation is more strongly deleterious than variation that is potentially adaptive in a future environment. I find that cryptic genetic variation can be substantially enriched for potential adaptations under a broad range of realistic parameter values, including those applicable to alternative splices and readthrough products generated by the yeast prion [PSI+]. This enrichment is dramatically stronger when multiple simultaneous changes are required to generate a potentially adaptive phenotype. Cryptic genetic variation is likely to be an effective source of useful adaptations at a time of environmental change, relative to an equivalent source of variation that has not spent time in a hidden state. Copyright © 2006 by the Genetics Society of America.
- Maughan, H., Callicotte, V., Hancock, A., Birky Jr., C. W., Nicholson, W. L., & Masel, J. (2006). The population genetics of phenotypic deterioration in experimental populations of Bacillus subtilis. Evolution, 60(4), 686-695.More infoPMID: 16739451;Abstract: Although many examples of trait loss exist in nature, the underlying population genetic mechanism responsible for the loss is usually unknown. Selective or neutral processes can result in the deterioration of a trait, and often one of these is inferred based on indirect evidence. Furthermore, selective pressures that are unique to particular environments and the effect these might have on the population genetic cause of trait loss are not well understood. Here we describe an experimental evolution system where two different environments were used for addressing the population genetic cause of trait loss throughout evolutionary time. We found that growth in minimal medium (i.e., prototrophy) was lost in all populations regardless of the experimental environment and that the pattern of trait loss in one environment was due to selection, whereas in the other environment the cause remains inconclusive. © 2006 The Society for the Study of Evolution. All rights reserved.
- Masel, J. (2005). Evolutionary capacitance may be favored by natural selection. Genetics, 170(3), 1359-1371.More infoPMID: 15911577;PMCID: PMC1451192;Abstract: Evolutionary capacitors phenotypically reveal a stock of cryptic genetic variation in a reversible fashion. The sudden and reversible revelation of a range of variation is fundamentally different from the gradual introduction of variation by mutation. Here I study the invasion dynamics of modifiers of revelation. A modifier with the optimal rate of revelation mopt has a higher probability of invading any other population than of being counterinvaded. mopt varies with the population size N and the rate θ at which environmental change makes revelation adaptive. For small populations less than a minimum cutoff Nmin, all revelation is selected against. Nmin is typically quite small and increases only weakly, with θ-1/2. For large populations with N > 1/θ, mopt is ∼1/N. Selection for the optimum is highly effective and increases in effectiveness with larger N ≫ 1/θ. For intermediate values of N, mopt is typically a little less than θ and is only weakly favored over less frequent revelation. The model is analogous to a two-locus model for the evolution of a mutator allele. It is a fully stochastic model and so is able to show that selection for revelation can be strong enough to overcome random drift. Copyright © 2005 by the Genetics Society of America.
- Masel, J., Genoud, N., & Aguzzi, A. (2005). Efficient inhibition of prion replication by PrP-Fc 2 suggests that the prion is a PrP Sc oligomer. Journal of Molecular Biology, 345(5), 1243-1251.More infoPMID: 15644218;Abstract: Soluble dimeric prion protein (PrP-Fc 2) binds to the disease-associated prion protein PrP Sc, and inhibits prion replication when expressed in transgenic mice. Prion inhibition is effective even if PrP-Fc 2 is expressed at low levels, suggesting that its affinity for PrP Sc is higher than that of monomeric PrP C. Here, we model prion accumulation as an exponential replication cycle of prion elongation and breakage. The exponential growth rate corresponding to this cycle is reflected in the incubation period of the disease. We use a mathematical model to calculate the exponential growth rate, and fit the model to in vivo data on prion incubation times corresponding to different levels of PrP C and PrP-Fc 2. We find an excellent fit of the model to the data. Surprisingly, targeting of PrP Sc can be effective at concentrations of PrP-Fc 2 lower than that of PrP C, even if PrP-Fc 2 and PrP C have the same affinity for PrP Sc. The best fit of our model to data predicts that the replicative prion consists of PrP Sc oligomers with a mean size of four to 15 units. © 2004 Elsevier Ltd. All rights reserved.
- Kelly, S., Bliss, T. M., Shah, A. K., Sun, G. H., Ma, M., Foo, W. C., Masel, J., Yenari, M. A., Weissman, I. L., Uchida, N., Palmer, T., & Steinberg, G. K. (2004). Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America, 101(32), 11839-11844.More infoPMID: 15280535;PMCID: PMC511061;Abstract: We characterize the survival, migration, and differentiation of human neurospheres derived from CNS stem cells transplanted into the ischemic cortex of rats 7 days after distal middle cerebral artery occlusion. Transplanted neurospheres survived robustly in naive and ischemic brains 4 wk posttransplant. Survival was influenced by proximity of the graft to the stroke lesion and was negatively correlated with the number of IB4-positive inflammatory cells. Targeted migration of the human cells was seen in ischemic animals, with many human cells migrating long distances (≈1.2 mm) predominantly toward the lesion; in naive rats, cells migrated radially from the injection site in smaller number and over shorter distances (0.2 mm). The majority of migrating cells in ischemic rats had a neuronal phenotype. Migrating cells between the graft and the lesion expressed the neuroblast marker doublecortin, whereas human cells at the lesion border expressed the immature neuronal marker β-tubulin, although a small percentage of cells at the lesion border also expressed glial fibrillary acid protein (GFAP). Thus, transplanted human CNS (hCNS)-derived neurospheres survived robustly in naive and ischemic brains, and the microenvironment influenced their migration and fate.
- Masel, J. (2004). Genetic assimilation can occur in the absence of selection for the assimilating phenotype, suggesting a role for the canalization heuristic. Journal of Evolutionary Biology, 17(5), 1106-1110.More infoPMID: 15312082;Abstract: Genetic assimilation occurs when an acquired trait loses dependency on its environmental trigger and becomes an inherited trait. According to the standard quantitative genetic model for genetic assimilation, the trait is determined by the contributions of multiple genes. Trait expression occurs at a lower threshold with the trigger. Selection for the trait in the presence of the trigger increases the frequency of the trait-determining alleles. Eventually these alleles become frequent enough to breach the higher threshold for expression in the absence of the trigger. This loss of dependence on the trigger signifies genetic assimilation. Here I show that genetic assimilation can occur in the absence of selection for the trait in an evolutionary simulation of a gene network model. This contradicts the prediction of the standard quantitative genetic model, but is consistent with an explanation in terms of the canalization heuristic.
- Masel, J., A., V., Pöschel, T., Brilliantov, N. V., & Frömmel, C. (2004). Prion Kinetics (multiple letters). Biophysical Journal, 87(1), 728-729.More infoPMID: 15240505;PMCID: PMC1304395;
- Masel, J., & Bergman, A. (2003). The evolution of the evolvability properties of the yeast prion [PSI+]. Evolution, 57(7), 1498-1512.More infoPMID: 12940355;Abstract: Saccharomyces cerevisiae's ability to form the prion [PSI+] may increase the rate of evolvability, defined as the rate of appearance of heritable and potentially adaptive phenotypic variants. The increase in evolvability occurs when the appearance of the prion causes read-through translation and reveals hidden variation in untranslated regions. Eventually the portion of the phenotypic variation that is adaptive loses its dependence on the revealing mechanism. The mechanism is reversible, so the restoration of normal translation termination conceals the revealed deleterious variation, leaving the yeast without a permanent handicap. Given that the ability to form [PSI+] is known to be fixed and conserved in yeast, we construct a mathematical model to calculate whether this ability is more likely to have become fixed due to chance alone or due to its evolvability characteristics. We find that evolvability is a more likely explanation, as long as environmental change makes partial read-through of stop codons adaptive at a frequency of at least once every million years.
- Clarke, A. R., Jackson, G. S., Collinge, J., Pepys, M. B., Barron, L. D., Masel, J., Tahari-Alaoui, A., Lansbury, P., Dobson, C. M., Exley, C., & Feizi, T. (2001). The molecular biology of prion propagation. Philosophical Transactions of the Royal Society B: Biological Sciences, 356(1406), 185-195.More infoPMID: 11260799;PMCID: PMC1088424;Abstract: Prion diseases such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals are associated with the accumulation in affected brains of a conformational isomer (PrPSc) of host-derived prion protein (PrPC). According to the protein-only hypothesis, PrPSc is the principal or sole component of transmissible prions. The conformational change known to be central to prion propagation, from a predominantly α-helical fold to one predominantly comprising β structure, can now be reproduced in vitro, and the ability of β-PrP to form fibrillar aggregates provides a plausible molecular mechanism for prion propagation. The existence of multiple prion strains has been difficult to explain in terms of a protein-only infectious agent but recent studies of human prion diseases suggest that strain-specific phenotypes can be encoded by different PrP conformations and glycosylation patterns. The experimental confirmation that a novel form of human prion disease, variant CJD, is caused by the same prion strain as cattle BSE, has highlighted the pressing need to understand the molecular basis of prion propagation and the transmission barriers that limit their passage between mammalian species. These and other advances in the fundamental biology of prion propagation are leading to strategies for the development of rational therapeutics.
- Masel, J., & Jansen, V. A. (2001). The measured level of prion infectivity varies in a predictable way according to the aggregation state of the infectious agent. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1535(2), 164-173.More infoPMID: 11342005;Abstract: Transmissible spongiform encephalopathies are believed to be caused by an infectious form of the prion protein, designated PrPSc. The concentration of PrPSc is often poorly correlated to the level of infectivity. Infectivity can be measured in two ways, namely endpoint titration and the incubation time assay, but patterns of infectivity vary depending on which method is used. These discrepancies can be explained by variation in the aggregation state of PrPSc. Both methods of measuring infectivity are modelled mathematically, and the theoretical results are in agreement with published data. It was found to be theoretically impossible to characterise prion infectivity by a multiple of a single quantity representing 'one prion', no matter how it is measured. Infectivity is instead characterised by both the number and sizes of the PrPSc aggregates. Apparent discrepancies arise when these complexities are reduced to a single number. © 2001 Elsevier Science B.V.
- Masel, J., & Jansen, V. A. (2000). Designing drugs to stop the formation of prion aggregates and other amyloids. Biophysical Chemistry, 88(1-3), 47-59.More infoPMID: 11152275;Abstract: Amyloid protein aggregates are implicated in many neurodegenerative diseases, including Alzheimer's disease and the prion diseases. Therapeutics to block amyloid formation are often tested in vitro, but it is not clear how to extrapolate from these experiments to a clinical setting, where the effective drug dose may be much lower. Here we address this question using a theoretical kinetic model to calculate the growth rate of protein aggregates as a function of the dose of each of three categories of drug. We find that therapeutics which block the growing ends of amyloids are the most promising, as alternative strategies may be ineffective or even accelerate amyloid formation at low drug concentrations. Our mathematical model can be used to identify and optimise an end-blocking drug in vitro. Our model also suggests an alternative explanation for data previously thought to prove the existence of an entity known as protein X. (C) 2000 Elsevier Science B.V.
- Masel, J., Arnaout, R. A., O'Brien, T. R., Goedert, J. J., & Lloyd, A. L. (2000). Fluctuations in HIV-1 viral load are correlated to CD4+ T-lymphocyte count during the natural course of infection. Journal of Acquired Immune Deficiency Syndromes, 23(5), 375-379.More infoPMID: 10866229;Abstract: Viral load fluctuates during the natural course of asymptomatic HIV-1 infection. It is often assumed that these fluctuations are random around a set point or underlying growth trend. Using longitudinal data, we tested whether fluctuations in viral load can be better explained by changes in CD4+ T-cell count than by a set point or trend of exponential growth. The correspondence between viral load and CD4+ T-cell count could be described by a simple mathematical relation. Using a bootstrapping approach, the hypothesis that viral load fluctuations are random around a set point was rejected with p < .00005. The hypothesis that viral load fluctuations are random around a trend of exponential growth was rejected with p < .005. Viral load data was explained better by changes in CD4+ T-cell counts than by a set point or by a trend of exponential growth. The implications of this finding for improved prognostication discussed.
- Masel, J., & Jansen, V. A. (1999). The kinetics of proteinase K digestion of linear prion polymers. Proceedings of the Royal Society B: Biological Sciences, 266(1431), 1927-1931.More infoPMID: 10535107;PMCID: PMC1690213;Abstract: Transmissible spongiform encephalopathies such as scrapie are caused by a protein-only infectious agent, known as a prion. It is not clear how a protein can be capable of replicating itself, and the mechanism remains controversial. One influential model hypothesizes that prions are nucleated, macroscopically linear polymers. We investigated the theoretical kinetics of this model and derived predictions which could be used to test the model. In the model, the polymerization and depolymerization rates are independent of polymer size. This leads to an exponential size distribution at equilibrium. In agreement with a prediction stemming from this size distribution, the average size of PrP-res polymers was proportional to the square root of the concentration of PrP-res in a published study of in vitro conversion. Prion digestion by proteinase K (PK) is predicted to be biphasic. The second phase of digestion should be virtually independent of the PK concentration and should depend on the initial size distribution of prion polymers. For initially equilibrated polymers with an exponential size distribution, phase two digestion is exponential at a predicted rate. This rate varies in a defined way with the concentration used for equilibration and with other parameters which affect the average polymer size.
- Masel, J., Jansen, V. A., & Nowak, M. A. (1999). Quantifying the kinetic parameters of prion replication. Biophysical Chemistry, 77(2-3), 139-152.More infoPMID: 10326247;Abstract: The mechanism of protein-only prion replication is controversial. A detailed mathematical model of prion replication by nucleated polymerisation is developed, and its parameters are estimated from published data. PrP-res decay is around two orders of magnitude slower than PrP-sen decay, a plausible ratio of two parameters estimated from very different experiments. By varying the polymer breakage rate, we reveal that systems of short polymers grow the fastest. Drugs which break polymers could therefore accelerate disease progression. Growth in PrP-res seems slower than growth in infectious titre. This can be explained either by a novel hypothesis concerning inoculum clearance from a newly infected brain, or by the faster growth of compartments containing smaller polymers. The existence of compartments can also explain why prion growth sometimes reaches a plateau. Published kinetic data are all compatible with our mathematical model, so the nucleated polymerisation hypothesis cannot be ruled out on dynamic grounds. Copyright (C) 1999 Elsevier Science B.V. All rights reserved.
- Hazelton, N. W., Bennett, L. M., & Masel, J. (1992). Topological structures for 4-dimensional geographic information systems. Computers, Environment and Urban Systems, 16(3), 227-237.More infoAbstract: The purpose of this paper is to extend the framework for binary topological interactions to spaces up to 4-D. It includes descriptions of the various interactions between objects of various dimensions in various spaces, covering all interactions between all types of objects up to 4-D, in spaces up to 4-D. The need for topology in GIS is briefly discussed, in the instance of a vector-based 4-D GIS. The requirements for spatio-temporal indexing of data in a 4-D GIS are discussed briefly, together with the current dearth of information on query types and temporal analysis needs. This absence limits how well system designers can optimize the indexing, and consequently performance, of a 4-D GIS. This information will become available only after systems are in regular use and their modes of use analyzed. © 1992.
- Murren, C. J., Auld, J. R., Callahan, H., Ghalambor, C. K., Handelsman, C. A., Heskel, M. A., Kingsolver, J. G., Maclean, H. J., Masel, J., Maughan, H., Pfennig, D. W., Relyea, R. A., Seiter, S., Snell-Rood, E., Steiner, U. K., & Schlichting, C. D. (2015. Constraints on the evolution of phenotypic plasticity: limits and costs of phenotype and plasticity(pp 293-301).