Mice lacking paternal expression of imprinted Grb10 are risk-takers.

The imprinted genes Grb10 and Nesp influence impulsive behavior on a delay discounting task in an opposite manner. A recently developed theory suggests that this pattern of behavior may be representative of predicted effects of imprinted genes on tolerance to risk. Here we examine whether mice lacking paternal expression of Grb10 show abnormal behavior across a number of measures indicative of risk-taking.

Intragenomic conflict over bet-hedging.

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.

Analysis of mutation, selection, and epistasis: an informed approach to cancer clinical trials.

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.

Impulsive Choice in Mice Lacking Paternal Expression of Suggests Intragenomic Conflict in Behavior.

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 intragenomic conflict between parental alleles. We demonstrate, for the first time, oppositional effects of imprinted genes on brain and behavior. Specifically, we show that mice lacking paternal make fewer impulsive choices, with no dissociable effects on a separate measure of impulsive action.

Survival of the Curviest: Noise-Driven Selection for Synergistic Epistasis.

A major goal of human genetics is to elucidate the genetic architecture of human disease, with the goal of fueling improvements in diagnosis and the understanding of disease pathogenesis. The degree to which epistasis, or non-additive effects of risk alleles at different loci, accounts for common disease traits is hotly debated, in part because the conditions under which epistasis evolves are not well understood. Using both theory and evolutionary simulation, we show that the occurrence of common diseases (i.

The evolving landscape of imprinted genes in humans and mice: Conflict among alleles, genes, tissues, and kin.

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.

On the universal structure of human lexical semantics.

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.

Genomic imprinting of Grb10: coadaptation or conflict?

Mammalian development involves significant interactions between offspring and mother. But is this interaction a carefully coordinated effort by two individuals with a common goal--offspring survival? Or is it an evolutionary battleground (a central idea in our understanding of reproduction). The conflict between parents and offspring extends to an offspring's genes, where paternally inherited genes favor demanding more from the mother, while maternally inherited genes favor restraint.

Demography, kinship, and the evolving theory of genomic imprinting.

Genomic imprinting is the differential expression of an allele based on the parent of origin. Recent transcriptome-wide evaluations of the number of imprinted genes reveal complex patterns of imprinted expression among developmental stages and cell types. Such data demand a comprehensive evolutionary framework in which to understand the effect of natural selection on imprinted gene expression.

Diseases associated with genomic imprinting.

Genomic imprinting is the phenomenon where the expression of a locus differs between the maternally and paternally inherited alleles. Typically, this manifests as transcriptional silencing of one of the alleles, although many genes are imprinted in a tissue- or isoform-specific manner. Diseases associated with imprinted genes include various cancers, disorders of growth and metabolism, and disorders in neurodevelopment, cognition, and behavior, including certain major psychiatric disorders.

Genomic imprinting and conflict-induced decanalization.

Genomic imprinting is the phenomenon in which the expression pattern of an allele depends on its parental origin. When maternally expressed and paternally expressed imprinted loci affect the same trait, the result is an arms race, with each locus under selection to increase its level of expression. This article develops a model of the deleterious consequences of this escalation, deriving from an increase in the variance in gene expression level, and resulting increase in phenotypic variance in the population.

Antagonistic coevolution of two imprinted loci with pleiotropic effects.

At a locus subject to genomic imprinting, the expression pattern of an allele depends on its parent of origin. Typically, one allele is expressed while the other is transcriptionally silent, and natural selection at the locus will be driven by the inclusive fitness of the active allele. For some aspects of phenotype, the relevant fitness function differs between maternally and paternally derived alleles, so that maternally and paternally expressed imprinted loci become involved in an intragenomic, interlocus conflict.

Imprinted genes and human disease: an evolutionary perspective.

Imprinted genes have been associated with a wide range of diseases. Many of these diseases have symptoms that can be understood in the context of the evolutionary forces that favored imprinted expression at these loci. Modulation of perinatal growth and resource acquisition has played a central role in the evolution of imprinting and many of the diseases associated with imprinted genes involve some sort of growth or feeding disorder.

Unraveling male and female histories from human genetic data.

The increasing availability of large-scale genetic datasets has made it possible to ask detailed questions about the structure of human genetic diversity, and what that structure can teach us about human demographic history. Global, multi-locus analyses have suggested that human genetic diversity may fall into clusters that correspond approximately to continental origin. Detailed comparisons of mitochondrial DNA and the Y chromosome have revealed a history of sex-biased migration patterns that can vary widely across human populations.

Competitive signal discrimination, methylation reprogramming and genomic imprinting.

Genomic imprinting (parent-of-origin-dependent gene regulation) is associated with intra-genomic evolutionary conflict over the optimal pattern of gene expression. Most theoretical models of imprinting focus on the conflict between the maternally and paternally derived alleles at an imprinted locus. Recently, however, more attention has been focused on multi-directional conflicts involving not only the imprinted gene itself, but also the genes that encode the regulatory machinery responsible for establishing and maintaining imprinted gene expression.

Sex-biased migration in humans: what should we expect from genetic data?

Different patterns of mitochondrial and Y-chromosome diversity have been cited as evidence of long-term patrilocality in human populations. However, what patterns are expected depends on the nature of the sampling scheme. Samples from a local region reveal only the recent demographic history of that region, whereas sampling over larger geographic scales accesses older demographic processes.

Tissue-specific reactivation of gene expression at an imprinted locus.

Genomic imprinting is the phenomenon where the expression pattern of an allele at a locus differs depending on the allele's parent of origin. In most cases, one of the two alleles is transcriptionally silent. Recent empirical work has shown some genes to be imprinted in a tissue-specific manner, where the silenced allele becomes reactivated in particular cell lineages during development.

Genomic imprinting and methylation: epigenetic canalization and conflict.

Imprinted genes have patterns of expression that depend on the parent of origin of their alleles. Establishment of imprinting at a locus requires that the two alleles be differentially marked in oogenesis and spermatogenesis, that these marks escape reprogramming after fertilization, and that they are reliably transmitted through development. Recent work on the mammalian DNA methyltransferases involved in these processes suggests mechanisms of epigenetic canalization, which might contribute to the stability of epigenetic inheritance.

A separation-of-timescales approach to the coalescent in a continuous population.

This article presents an analysis of a model of isolation by distance in a continuous, two-dimensional habitat. An approximate expression is derived for the distribution of coalescence times for a pair of sequences sampled from specific locations in a rectangular habitat. Results are qualitatively similar to previous analyses of isolation by distance, but account explicitly for the location of samples relative to the habitat boundaries.

What good is genomic imprinting: the function of parent-specific gene expression.

Parent-specific gene expression (genomic imprinting) is an evolutionary puzzle because it forgoes an important advantage of diploidy--protection against the effects of deleterious recessive mutations. Three hypotheses claim to have found a countervailing selective advantage of parent-specific expression. Imprinting is proposed to have evolved because it enhances evolvability in a changing environment, protects females against the ravages of invasive trophoblast, or because natural selection acts differently on genes of maternal and paternal origin in interactions among kin.

Inbreeding, maternal care and genomic imprinting.

Inactivation of expression of the paternal allele at two maternally silent imprinted loci has recently been reported to diminish the quality of care that female mice lavish on their offspring. This suggests that there can be disagreement between the maternally and paternally derived genomes of mothers over how much care for offspring is appropriate, with the paternally derived genome favoring greater care. The reason for such disagreement is not obvious because the maternally and paternally derived alleles at a locus have equal probabilities of being transmitted to each of the mother's ova and, therefore, would appear to have equal interests in a mother's offspring.

Parental modifiers, antisense transcripts and loss of imprinting.

The kinship theory of genomic imprinting has explained parent-specific gene expression as the outcome of an evolutionary conflict between the two alleles at a diploid locus of an offspring over how much to demand from parents. Previous models have predicted that maternally derived (madumnal) alleles will be silent at demand-enhancing loci, while paternally derived (padumnal) alleles will be silent at demand-suppressing loci, but these models have not considered the evolution of trans-acting modifiers that are expressed in parents and influence imprinted expression in offspring. We show that such modifiers will sometimes be selected to reactivate the silent padumnal allele at a demand-suppressing locus but will not be selected to reactivate the silent madumnal allele at a demand-enhancing locus.

The coalescent in a continuous, finite, linear population.

In this article we present a model for analyzing patterns of genetic diversity in a continuous, finite, linear habitat with restricted gene flow. The distribution of coalescent times and locations is derived for a pair of sequences sampled from arbitrary locations along the habitat. The results for mean time to coalescence are compared to simulated data.