Genomic imprinting, where an allele's expression pattern depends on its parental origin, is t... more Genomic imprinting, where an allele's expression pattern depends on its parental origin, is thought to result primarily from an intragenomic evolutionary conflict. Imprinted genes are widely expressed in the brain and have been linked to various phenotypes, including behaviours related to risk tolerance. In this paper, we analyse a model of evolutionary bet-hedging in a system with imprinted gene expression. Previous analyses of bet-hedging have shown that natural selection may favour alleles and traits that reduce reproductive variance, even at the expense of reducing mean reproductive success, with the trade-off between mean and variance depending on the population size. In species where the sexes have different reproductive variances, this bet-hedging trade-off differs between maternally and paternally inherited alleles. Where males have the higher reproductive variance, alleles are more strongly selected to reduce variance when paternally inherited than when maternally inher...
A bacterial biosensor for benzene, toluene, and similar compounds has been constructed, character... more A bacterial biosensor for benzene, toluene, and similar compounds has been constructed, characterized, and field tested on contaminated water and soil. The biosensor is based on a plasmid incorporating the transcriptional activator xylR from the TOL plasmid of Pseudomonas putida mt-2. The XylR protein binds a subset of toluene-like compounds and activates transcription at its promoter, P u . A reporter plasmid was constructed by placing the luc gene for firefly luciferase under the control of XylR and P u . When Escherichia coli cells were transformed with this plasmid vector, luminescence from the cells was induced in the presence of benzene, toluene, xylenes, and similar molecules. Accurate concentration dependencies of luminescence were obtained and exhibited K 1/2 values ranging from 39.0 ± 3.8 μM for 3-xylene to 2,690 ± 160 μM for 3-methylbenzylalcohol (means ± standard deviations). The luminescence response was specific for only toluene-like molecules that bind to and activate...
Philosophical Transactions of the Royal Society B: Biological Sciences, 2019
Genomic imprinting, where an allele’s expression pattern depends on its parental origin, is thoug... more Genomic imprinting, where an allele’s expression pattern depends on its parental origin, is thought to result primarily from an intragenomic evolutionary conflict. Imprinted genes are widely expressed in the brain and have been linked to various phenotypes, including behaviours related to risk tolerance. In this paper, we analyse a model of evolutionary bet-hedging in a system with imprinted gene expression. Previous analyses of bet-hedging have shown that natural selection may favour alleles and traits that reduce reproductive variance, even at the expense of reducing mean reproductive success, with the trade-off between mean and variance depending on the population size. In species where the sexes have different reproductive variances, this bet-hedging trade-off differs between maternally and paternally inherited alleles. Where males have the higher reproductive variance, alleles are more strongly selected to reduce variance when paternally inherited than when maternally inherited...
Currently, drug development efforts and clinical trials to test them are often prioritized by tar... more Currently, drug development efforts and clinical trials to test them are often prioritized by targeting genes with high frequencies of somatic variants among tumors. However, differences in oncogenic mutation rate-not necessarily the effect the variant has on tumor growth-contribute enormously to somatic variant frequency. We argue that decoupling the contributions of mutation and cancer lineage selection to the frequency of somatic variants among tumors is critical to understanding-and predicting-the therapeutic potential of different interventions. To provide an indicator of that strength of selection and therapeutic potential, the frequency at which we observe a given variant across patients must be modulated by our expectation given the mutation rate and target size to provide an indicator of that strength of selection and therapeutic potential. Additionally, antagonistic and synergistic epistasis among mutations also impacts the potential therapeutic benefit of targeted drug de...
Imprinted genes are expressed from one parental allele only as a consequence of epigenetic events... more Imprinted genes are expressed from one parental allele only as a consequence of epigenetic events that take place in the mammalian germ line and are thought to have evolved through intra-genomic conflict between parental alleles. We demonstrate, for the first time, oppositional effects of imprinted genes on brain and behavior. Specifically, here we show that mice lacking paternalmake fewer impulsive choices, with no dissociable effects on a separate measure of impulsive action. Taken together with previous work showing that mice lacking maternal Nesp55 make more impulsive choices this suggests that impulsive choice behavior is a substrate for the action of genomic imprinting. Moreover, the contrasting effect of these two genes suggests impulsive choices are subject to intra-genomic conflict and that maternal and paternal interests pull this behavior in opposite directions. Finally, these data may also indicate that an imbalance in expression of imprinted genes contributes to patholo...
We develop inference methods for generalized coalescent models, such as the Λ- and Ξ-coalescents,... more We develop inference methods for generalized coalescent models, such as the Λ- and Ξ-coalescents, which have recently been proposed for populations with broad offspring distributions, repeated selective sweeps, or strong selection. These are all populations that may not be adequately described by the usual Kingman coalescent. A roadblock to the application of such models has been the lack of effective tools for inferring an appropriate model, which stems from difficulties in evaluating the associated likelihoods. We overcome these difficulties by introducing estimators that are both computationally tractable and statistically efficient. We use these estimators to obtain point estimates and confidence intervals for the parameters of the coalescent models, and p-values for the hypothesis that the population is described by the Kingman coalescent. Our approach is based on the theory of unbiased estimating equations, which is more general than composite likelihood and may be applicable ...
BioEssays : news and reviews in molecular, cellular and developmental biology, Jan 18, 2016
Three recent genome-wide studies in mice and humans have produced the most definitive map to date... more Three recent genome-wide studies in mice and humans have produced the most definitive map to date of genomic imprinting (gene expression that depends on parental origin) by incorporating multiple tissue types and developmental stages. Here, we explore the results of these studies in light of the kinship theory of genomic imprinting, which predicts that imprinting evolves due to differential genetic relatedness between maternal and paternal relatives. The studies produce a list of imprinted genes with around 120-180 in mice and ∼100 in humans. The studies agree on broad patterns across mice and humans including the complex patterns of imprinted expression at loci like Igf2 and Grb10. We discuss how the kinship theory provides a powerful framework for hypotheses that can explain these patterns. Finally, since imprinting is rare in the genome despite predictions from the kinship theory that it might be common, we discuss evolutionary factors that could favor biallelic expression.
Proceedings of the National Academy of Sciences of the United States of America, 2016
How universal is human conceptual structure? The way concepts are organized in the human brain ma... more How universal is human conceptual structure? The way concepts are organized in the human brain may reflect distinct features of cultural, historical, and environmental background in addition to properties universal to human cognition. Semantics, or meaning expressed through language, provides indirect access to the underlying conceptual structure, but meaning is notoriously difficult to measure, let alone parameterize. Here, we provide an empirical measure of semantic proximity between concepts using cross-linguistic dictionaries to translate words to and from languages carefully selected to be representative of worldwide diversity. These translations reveal cases where a particular language uses a single "polysemous" word to express multiple concepts that another language represents using distinct words. We use the frequency of such polysemies linking two concepts as a measure of their semantic proximity and represent the pattern of these linkages by a weighted network. T...
Philosophical transactions of the Royal Society of London. Series B, Biological sciences, Jan 29, 2000
Genomic imprinting has been proposed to evolve when a gene's expression has fitness consequen... more Genomic imprinting has been proposed to evolve when a gene's expression has fitness consequences for individuals with different coefficients of matrilineal and patrilineal relatedness, especially in the context of competition between offspring for maternal resources. Previous models have focused on pre-emptive hierarchies, where conflict arises with respect to resource allocation between present and future offspring. Here we present a model in which imprinting arises from scramble competition within litters. The model predicts paternal-specific expression of a gene that increases an offspring's fractional share of resources but reduces the size of the resource pool, and maternal-specific expression of a gene with opposite effects. These predictions parallel the observation in economic models that individuals tend to underprovide public goods, and that the magnitude of this shortfall increases with the number of individuals in the group. Maternally derived alleles are more wi...
Concerted evolution is normally used to describe parallel changes at different sites in a genome,... more Concerted evolution is normally used to describe parallel changes at different sites in a genome, but it is also observed in languages where a specific phoneme changes to the same other phoneme in many words in the lexicon—a phenomenon known as regular sound change. We develop a general statistical model that can detect concerted changes in aligned sequence data and apply it to study regular sound changes in the Turkic language family. Linguistic evolution, unlike the genetic substitutional process, is dominated by events of concerted evolutionary change. Our model identified more than 70 historical events of regular sound change that occurred throughout the evolution of the Turkic language family, while simultaneously inferring a dated phylogenetic tree. Including regular sound changes yielded an approximately 4-fold improvement in the characterization of linguistic change over a simpler model of sporadic change, improved phylogenetic inference, and returned more reliable and plaus...
Proceedings of the National Academy of Sciences, 1996
The phosphoprotein phosducin (Pd) regulates many guanine nucleotide binding protein (G protein)-l... more The phosphoprotein phosducin (Pd) regulates many guanine nucleotide binding protein (G protein)-linked signaling pathways. In visual signal transduction, unphosphorylated Pd blocks the interaction of light-activated rhodopsin with its G protein (Gt) by binding to the beta gamma subunits of Gt and preventing their association with the Gt alpha subunit. When Pd is phosphorylated by cAMP-dependent protein kinase, it no longer inhibits Gt subunit interactions. Thus, factors that determine the phosphorylation state of Pd in rod outer segments are important in controlling the number of Gts available for activation by rhodopsin. The cyclic nucleotide dependencies of the rate of Pd phosphorylation by endogenous cAMP-dependent protein kinase suggest that cAMP, and not cGMP, controls Pd phosphorylation. The synthesis of cAMP by adenylyl cyclase in rod outer segment preparations was found to be dependent on Ca2+ and calmodulin. The Ca2+ dependence was within the physiological range of Ca2+ con...
Genomic imprinting, where an allele's expression pattern depends on its parental origin, is t... more Genomic imprinting, where an allele's expression pattern depends on its parental origin, is thought to result primarily from an intragenomic evolutionary conflict. Imprinted genes are widely expressed in the brain and have been linked to various phenotypes, including behaviours related to risk tolerance. In this paper, we analyse a model of evolutionary bet-hedging in a system with imprinted gene expression. Previous analyses of bet-hedging have shown that natural selection may favour alleles and traits that reduce reproductive variance, even at the expense of reducing mean reproductive success, with the trade-off between mean and variance depending on the population size. In species where the sexes have different reproductive variances, this bet-hedging trade-off differs between maternally and paternally inherited alleles. Where males have the higher reproductive variance, alleles are more strongly selected to reduce variance when paternally inherited than when maternally inher...
A bacterial biosensor for benzene, toluene, and similar compounds has been constructed, character... more A bacterial biosensor for benzene, toluene, and similar compounds has been constructed, characterized, and field tested on contaminated water and soil. The biosensor is based on a plasmid incorporating the transcriptional activator xylR from the TOL plasmid of Pseudomonas putida mt-2. The XylR protein binds a subset of toluene-like compounds and activates transcription at its promoter, P u . A reporter plasmid was constructed by placing the luc gene for firefly luciferase under the control of XylR and P u . When Escherichia coli cells were transformed with this plasmid vector, luminescence from the cells was induced in the presence of benzene, toluene, xylenes, and similar molecules. Accurate concentration dependencies of luminescence were obtained and exhibited K 1/2 values ranging from 39.0 ± 3.8 μM for 3-xylene to 2,690 ± 160 μM for 3-methylbenzylalcohol (means ± standard deviations). The luminescence response was specific for only toluene-like molecules that bind to and activate...
Philosophical Transactions of the Royal Society B: Biological Sciences, 2019
Genomic imprinting, where an allele’s expression pattern depends on its parental origin, is thoug... more Genomic imprinting, where an allele’s expression pattern depends on its parental origin, is thought to result primarily from an intragenomic evolutionary conflict. Imprinted genes are widely expressed in the brain and have been linked to various phenotypes, including behaviours related to risk tolerance. In this paper, we analyse a model of evolutionary bet-hedging in a system with imprinted gene expression. Previous analyses of bet-hedging have shown that natural selection may favour alleles and traits that reduce reproductive variance, even at the expense of reducing mean reproductive success, with the trade-off between mean and variance depending on the population size. In species where the sexes have different reproductive variances, this bet-hedging trade-off differs between maternally and paternally inherited alleles. Where males have the higher reproductive variance, alleles are more strongly selected to reduce variance when paternally inherited than when maternally inherited...
Currently, drug development efforts and clinical trials to test them are often prioritized by tar... more Currently, drug development efforts and clinical trials to test them are often prioritized by targeting genes with high frequencies of somatic variants among tumors. However, differences in oncogenic mutation rate-not necessarily the effect the variant has on tumor growth-contribute enormously to somatic variant frequency. We argue that decoupling the contributions of mutation and cancer lineage selection to the frequency of somatic variants among tumors is critical to understanding-and predicting-the therapeutic potential of different interventions. To provide an indicator of that strength of selection and therapeutic potential, the frequency at which we observe a given variant across patients must be modulated by our expectation given the mutation rate and target size to provide an indicator of that strength of selection and therapeutic potential. Additionally, antagonistic and synergistic epistasis among mutations also impacts the potential therapeutic benefit of targeted drug de...
Imprinted genes are expressed from one parental allele only as a consequence of epigenetic events... more Imprinted genes are expressed from one parental allele only as a consequence of epigenetic events that take place in the mammalian germ line and are thought to have evolved through intra-genomic conflict between parental alleles. We demonstrate, for the first time, oppositional effects of imprinted genes on brain and behavior. Specifically, here we show that mice lacking paternalmake fewer impulsive choices, with no dissociable effects on a separate measure of impulsive action. Taken together with previous work showing that mice lacking maternal Nesp55 make more impulsive choices this suggests that impulsive choice behavior is a substrate for the action of genomic imprinting. Moreover, the contrasting effect of these two genes suggests impulsive choices are subject to intra-genomic conflict and that maternal and paternal interests pull this behavior in opposite directions. Finally, these data may also indicate that an imbalance in expression of imprinted genes contributes to patholo...
We develop inference methods for generalized coalescent models, such as the Λ- and Ξ-coalescents,... more We develop inference methods for generalized coalescent models, such as the Λ- and Ξ-coalescents, which have recently been proposed for populations with broad offspring distributions, repeated selective sweeps, or strong selection. These are all populations that may not be adequately described by the usual Kingman coalescent. A roadblock to the application of such models has been the lack of effective tools for inferring an appropriate model, which stems from difficulties in evaluating the associated likelihoods. We overcome these difficulties by introducing estimators that are both computationally tractable and statistically efficient. We use these estimators to obtain point estimates and confidence intervals for the parameters of the coalescent models, and p-values for the hypothesis that the population is described by the Kingman coalescent. Our approach is based on the theory of unbiased estimating equations, which is more general than composite likelihood and may be applicable ...
BioEssays : news and reviews in molecular, cellular and developmental biology, Jan 18, 2016
Three recent genome-wide studies in mice and humans have produced the most definitive map to date... more Three recent genome-wide studies in mice and humans have produced the most definitive map to date of genomic imprinting (gene expression that depends on parental origin) by incorporating multiple tissue types and developmental stages. Here, we explore the results of these studies in light of the kinship theory of genomic imprinting, which predicts that imprinting evolves due to differential genetic relatedness between maternal and paternal relatives. The studies produce a list of imprinted genes with around 120-180 in mice and ∼100 in humans. The studies agree on broad patterns across mice and humans including the complex patterns of imprinted expression at loci like Igf2 and Grb10. We discuss how the kinship theory provides a powerful framework for hypotheses that can explain these patterns. Finally, since imprinting is rare in the genome despite predictions from the kinship theory that it might be common, we discuss evolutionary factors that could favor biallelic expression.
Proceedings of the National Academy of Sciences of the United States of America, 2016
How universal is human conceptual structure? The way concepts are organized in the human brain ma... more How universal is human conceptual structure? The way concepts are organized in the human brain may reflect distinct features of cultural, historical, and environmental background in addition to properties universal to human cognition. Semantics, or meaning expressed through language, provides indirect access to the underlying conceptual structure, but meaning is notoriously difficult to measure, let alone parameterize. Here, we provide an empirical measure of semantic proximity between concepts using cross-linguistic dictionaries to translate words to and from languages carefully selected to be representative of worldwide diversity. These translations reveal cases where a particular language uses a single "polysemous" word to express multiple concepts that another language represents using distinct words. We use the frequency of such polysemies linking two concepts as a measure of their semantic proximity and represent the pattern of these linkages by a weighted network. T...
Philosophical transactions of the Royal Society of London. Series B, Biological sciences, Jan 29, 2000
Genomic imprinting has been proposed to evolve when a gene's expression has fitness consequen... more Genomic imprinting has been proposed to evolve when a gene's expression has fitness consequences for individuals with different coefficients of matrilineal and patrilineal relatedness, especially in the context of competition between offspring for maternal resources. Previous models have focused on pre-emptive hierarchies, where conflict arises with respect to resource allocation between present and future offspring. Here we present a model in which imprinting arises from scramble competition within litters. The model predicts paternal-specific expression of a gene that increases an offspring's fractional share of resources but reduces the size of the resource pool, and maternal-specific expression of a gene with opposite effects. These predictions parallel the observation in economic models that individuals tend to underprovide public goods, and that the magnitude of this shortfall increases with the number of individuals in the group. Maternally derived alleles are more wi...
Concerted evolution is normally used to describe parallel changes at different sites in a genome,... more Concerted evolution is normally used to describe parallel changes at different sites in a genome, but it is also observed in languages where a specific phoneme changes to the same other phoneme in many words in the lexicon—a phenomenon known as regular sound change. We develop a general statistical model that can detect concerted changes in aligned sequence data and apply it to study regular sound changes in the Turkic language family. Linguistic evolution, unlike the genetic substitutional process, is dominated by events of concerted evolutionary change. Our model identified more than 70 historical events of regular sound change that occurred throughout the evolution of the Turkic language family, while simultaneously inferring a dated phylogenetic tree. Including regular sound changes yielded an approximately 4-fold improvement in the characterization of linguistic change over a simpler model of sporadic change, improved phylogenetic inference, and returned more reliable and plaus...
Proceedings of the National Academy of Sciences, 1996
The phosphoprotein phosducin (Pd) regulates many guanine nucleotide binding protein (G protein)-l... more The phosphoprotein phosducin (Pd) regulates many guanine nucleotide binding protein (G protein)-linked signaling pathways. In visual signal transduction, unphosphorylated Pd blocks the interaction of light-activated rhodopsin with its G protein (Gt) by binding to the beta gamma subunits of Gt and preventing their association with the Gt alpha subunit. When Pd is phosphorylated by cAMP-dependent protein kinase, it no longer inhibits Gt subunit interactions. Thus, factors that determine the phosphorylation state of Pd in rod outer segments are important in controlling the number of Gts available for activation by rhodopsin. The cyclic nucleotide dependencies of the rate of Pd phosphorylation by endogenous cAMP-dependent protein kinase suggest that cAMP, and not cGMP, controls Pd phosphorylation. The synthesis of cAMP by adenylyl cyclase in rod outer segment preparations was found to be dependent on Ca2+ and calmodulin. The Ca2+ dependence was within the physiological range of Ca2+ con...
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Papers by Jon Wilkins