Large-effect Mutations Research Articles

ADAPTATION TO DIFFERENT RATES OF ENVIRONMENTAL CHANGE INCHLAMYDOMONAS

We investigate how different rates of environmental change affect adaptive outcomes and dynamics by selecting Chlamydomonas populations for over 200 generations in environments where the rate of change varies. We find that slower rates of environmental change result in end populations that grow faster and pay a lower cost of adaptation than populations that adapt to a sudden change of the same magnitude. We detected partial selective sweeps in adapting populations by monitoring changes in marker frequency in each population. Although populations adapting to a sudden environmental change showed evidence of mutations of large effect segregating early on, populations adapting to slow rates of change showed patterns that were consistent with mutations of relatively small effect occurring at less predictable times. This work suggests that rates of environmental change may fundamentally alter adaptive dynamics and outcomes of adaptation by changing the size and timing of fitness increases. We suggest that using mutations of smaller effect during adaptation may result in lower levels of pleiotropy and historical constraints, which could in turn result in higher fitness by the end of the experiment.

Variants in the LRP5 gene influence BMD both through common variants of small effect and rare mutations of large effect in osteoporotic families

Variants in the LRP5 gene influence BMD both through common variants of small effect and rare mutations of large effect in osteoporotic families

Cis-regulatory Variation Is Typically Polyallelic in Drosophila

Gene expression levels vary heritably, with approximately 25-35% of the loci affecting expression acting in cis. We characterized standing cis-regulatory variation among 16 wild-derived strains of Drosophila melanogaster. Our experiment's robust biological and technical replication enabled precise estimates of variation in allelic expression on a high-throughput SNP genotyping platform. We observed concordant, significant differential allelic expression (DAE) in 7/10 genes queried with multiple SNPs, and every member of a set of eight additional, one-assay genes suggest significant DAE. Four of the high-confidence, multiple-assay genes harbor three or more statistically distinguishable allelic classes, often at intermediate frequency. Numerous intermediate-frequency, detectable regulatory polymorphisms cast doubt on a model in which cis-acting variation is a product of deleterious mutations of large effect. Comparing our data to predictions of population genetics theory using coalescent simulations, we estimate that a typical gene harbors 7-15 cis-regulatory sites (nucleotides) at which a selectively neutral mutation would elicit an observable expression phenotype. If standing cis-regulatory variation is actually slightly deleterious, the true mutational target size is larger.

Clonal Interference, Multiple Mutations and Adaptation in Large Asexual Populations

Two important problems affect the ability of asexual populations to accumulate beneficial mutations and hence to adapt. First, clonal interference causes some beneficial mutations to be outcompeted by more-fit mutations that occur in the same genetic background. Second, multiple mutations occur in some individuals, so even mutations of large effect can be outcompeted unless they occur in a good genetic background that contains other beneficial mutations. In this article, we use a Monte Carlo simulation to study how these two factors influence the adaptation of asexual populations. We find that the results depend qualitatively on the shape of the distribution of the fitness effects of possible beneficial mutations. When this distribution falls off slower than exponentially, clonal interference alone reasonably describes which mutations dominate the adaptation, although it gives a misleading picture of the evolutionary dynamics. When the distribution falls off faster than exponentially, an analysis based on multiple mutations is more appropriate. Using our simulations, we are able to explore the limits of validity of both of these approaches, and we explore the complex dynamics in the regimes where neither one is fully applicable.

Analysis and implications of mutational variation

Variation from new mutations is important for several questions in quantitative genetics. Key parameters are the genomic mutation rate and the distribution of effects of mutations (DEM), which determine the amount of new quantitative variation that arises per generation from mutation (V(M)). Here, we review methods and empirical results concerning mutation accumulation (MA) experiments that have shed light on properties of mutations affecting quantitative traits. Surprisingly, most data on fitness traits from laboratory assays of MA lines indicate that the DEM is platykurtic in form (i.e., substantially less leptokurtic than an exponential distribution), and imply that most variation is produced by mutations of moderate to large effect. This finding contrasts with results from MA or mutagenesis experiments in which mutational changes to the DNA can be assayed directly, which imply that the vast majority of mutations have very small phenotypic effects, and that the distribution has a leptokurtic form. We compare these findings with recent approaches that attempt to infer the DEM for fitness based on comparing the frequency spectra of segregating nucleotide polymorphisms at putatively neutral and selected sites in population samples. When applied to data for humans and Drosophila, these analyses also indicate that the DEM is strongly leptokurtic. However, by combining the resultant estimates of parameters of the DEM with estimates of the mutation rate per nucleotide, the predicted V(M) for fitness is only a tiny fraction of V(M) observed in MA experiments. This discrepancy can be explained if we postulate that a few deleterious mutations of large effect contribute most of the mutational variation observed in MA experiments and that such mutations segregate at very low frequencies in natural populations, and effectively are never seen in population samples.

Effect of Mutations on Developmental Stability and Canalization in Morphological Traits in Drosophila ananassae

The present study was designed to determine the effects of visible mutations of large effect on developmental stability and canalization in different morphological traits, namely, sternopleural bristle number, wing length, wing to thorax ratio, ovariole number, and sex comb tooth number (SCTN) in Drosophila ananassae. We have compared the mean trait size, fluctuating asymmetry (FA) (as an index of developmental stability), and morphological variation (as an index of canalization) of different mutant strains (yellow body color, y; claret eye color, ca; plexus wing, px; spread wing, spr; ebony body and sepia eye color, e se; yellow body and claret eye color, y ca; and cardinal eye color, curled wing, and ebony body color, cd cu e) with wild-type strain. The mean trait size of all morphological traits differs significantly among the wild-type and mutant strains. The wild-type and mutant strains vary significantly for the morphological variation and also for the levels of the FA in different morphological traits. However, we have found no increase in either the variance or in the degree of FA with the increase of the mutations (except in SCTN in y mutant). The plausible reasons for the variation in wild-type and mutant strains with particular reference to developmental stability and canalization have been discussed.

Anticipation and the genetics of psychosis

A theoretical model should explain all of the observed facts. Both the model of schizophrenia which proposes many genes of small effect ([McClellan et al , 2007][1]) and that which proposes few gene mutations of large effect ([Craddock et al , 2007][2]) explain many of the observed facts. In

The combined effect of two mutations that alter serially homologous color pattern elements on the fore and hindwings of a butterfly

BackgroundThe ability for serially homologous structures to acquire a separate identity has been primarily investigated for structures dependent on Hox gene input but is still incompletely understood in other systems. The fore and hindwings of butterflies are serially homologous structures as are the serially homologous eyespots that can decorate each of these wings. Eyespots can vary in number between fore and hindwings of the same individual and mutations of large effect can control the total number of eyespots that each of the wings displays. Here we investigate the genetics of a new spontaneous color pattern mutation, Missing, that alters eyespot number in the nymphalid butterfly, Bicyclus anynana. We further test the interaction of Missing with a previously described mutation, Spotty, describe the developmental stage affected by Missing, and test whether Missing is a mutant variant of the gene Distal-less via a linkage association study.ResultsMissing removes or greatly reduces the size of two of the hindwing eyespots from the row of seven eyespots, with no detectable effect on the rest of the wing pattern. Offspring carrying a single Missing allele display intermediate sized eyespots at these positions. Spotty has the opposite effect of Missing, i.e., it introduces two extra eyespots in homologous wing positions to those affected by Missing, but on the forewing. When Missing is combined with Spotty the size of the two forewing eyespots decreases but the size of the hindwing spots stays the same, suggesting that these two mutations have a combined effect on the forewing such that Missing reduces eyespot size when in the presence of a Spotty mutant allele, but that Spotty has no effect on the hindwing. Missing prevents the complete differentiation of two of the eyespot foci on the hindwing. We found no evidence for any linkage between the Distal-less and Missing genes.ConclusionThe spontaneous mutation Missing controls the differentiation of the signaling centers of a subset of the serial homologous eyespots present on both the fore and the hindwing in a dose-dependent fashion. The effect of Missing on the forewing, however, is only observed when the mutation Spotty introduces additional eyespots on this wing. Spotty, on the other hand, controls the differentiation of eyespot centers only on the forewing. Spotty, unlike Missing, may be under Ubx gene regulation, since it affects a subset of eyespots on only one of the serially homologous wings.

VARIATION IN PLEIOTROPY AND THE MUTATIONAL UNDERPINNINGS OF THE G-MATRIX

Abstract The pattern and extent of pleiotropic gene action can contribute substantially to the internal structure and shape of the additive genetic variance-covariance matrix (G)–a key determinant of evolutionary trajectories. We use data from our study (Estes et al. 2004) on the univariate effects of mutation in a mismatch-repair-defective strain, msh-2, of Caenorhabditis elegans to address the impact of increasing levels of selection on the magnitude and pattern of genetic covariance due to new mutations. Mutational covariances between three life-history traits are shown to exhibit a weak pattern of decline with increasing population size (increasing selection), while the orientation of mutational matrices remains reasonably constant. This suggests that mutations with smaller effects on fitness may tend to be slightly more confined in their influence than large-effect mutations (i.e., small-effect mutations reduce the magnitude of covariation between characters), but do not change the direction of this covariation.

Evolution of an obligate social cheater to a superior cooperator

Obligate relationships have evolved many times and can be parasitic or mutualistic. Obligate organisms rely on others to survive and thus coevolve with their host or partner. An important but little explored question is whether obligate status is an evolutionarily terminal condition or whether obligate lineages can evolve back to an autonomous lifestyle. The bacterium Myxococcus xanthus survives starvation by the social development of spore-bearing fruiting bodies. Some M. xanthus genotypes defective at fruiting body development in isolation can nonetheless exploit proficient genotypes in chimaeric groups. Here we report an evolutionary transition from obligate dependence on an altruistic host to an autonomous mode of social cooperation. This restoration of social independence was caused by a single mutation of large effect that confers fitness superiority over both ancestral genotypes, including immunity from exploitation by the ancestral cheater. Thus, a temporary state of obligate cheating served as an evolutionary stepping-stone to a novel state of autonomous social dominance.

VARIATION IN PLEIOTROPY AND THE MUTATIONAL UNDERPINNINGS OF THE G-MATRIX

The pattern and extent of pleiotropic gene action can contribute substantially to the internal structure and shape of the additive genetic variance-covariance matrix (G)--a key determinant of evolutionary trajectories. We use data from our study (Estes et al. 2004) on the univariate effects of mutation in a mismatch-repair-defective strain, msh-2, of Caenorhabditis elegans to address the impact of increasing levels of selection on the magnitude and pattern of genetic covariance due to new mutations. Mutational covariances between three life-history traits are shown to exhibit a weak pattern of decline with increasing population size (increasing selection), while the orientation of mutational matrices remains reasonably constant. This suggests that mutations with smaller effects on fitness may tend to be slightly more confined in their influence than large-effect mutations (i.e., small-effect mutations reduce the magnitude of covariation between characters), but do not change the direction of this covariation.

PLEIOTROPIC EFFECTS OF BENEFICIAL MUTATIONS IN ESCHERICHIA COLI

Micromutational models of adaptation have placed considerable weight on antagonistic pleiotropy as a mechanism that prevents mutations of large effect from achieving fixation. However, there are few empirical studies of the distribution of pleiotropic effects, and no studies that have examined this distribution for a large number of adaptive mutations. Here we examine the form and extent of pleiotropy associated with beneficial mutations in Escherichia coli. To do so, we used a collection of independently evolved genotypes, each of which contains a beneficial mutation that confers increased fitness in a glucose-limited environment. To determine the pleiotropic effects of these mutations, we examined the fitnesses of the mutants in five novel resource environments. Our results show that the majority of mutations had significant fitness effects in alternative resources, such that pleiotropy was common. The predominant form of this pleiotropy was positive--that is, most mutations that conferred increased fitness in glucose also conferred increased fitness in novel resources. We did detect some deleterious pleiotropic effects, but they were primarily limited to one of the five resources, and within this resource, to only a subset of mutants. Although pleiotropic effects were generally positive, fitness levels were lower and more variable on resources that differed most in their mechanisms of uptake and catabolism from that of glucose. Positive pleiotropic effects were strongly correlated in magnitude with their direct effects, but no such correlation was found among mutants with deleterious pleiotropic effects. Whereas previous studies of populations evolved on glucose for longer periods of time showed consistent declines on some of the resources used here, our results suggest that deleterious pleiotropic effects were limited to only a subset of the beneficial mutations available.

Susceptibility genes for complex epilepsy

Common idiopathic epilepsies are, clinically and genetically, a heterogeneous group of complex seizure disorders. Seizures arise from periodic neuronal hyperexcitability of unknown cause. The genetic component is mostly polygenic, where each susceptibility gene in any given individual is likely to represent a small component of the total heritability. Two susceptibility genes have been so far identified, where genetic variation is associated with experimentally demonstrated changes in ion channel properties, consistent with seizure susceptibility. Rare variants and a polymorphic allele of the T-type calcium channel CACNA1H and a polymorphic allele and a rare variant of the GABA(A) receptor delta subunit gene have differential functional effects. We speculate that these and other as yet undiscovered susceptibility genes for complex epilepsy could act as 'modifier' loci, affecting penetrance and expressivity of the mutations of large effect in those 'monogenic' epilepsies with simple inheritance that segregate through large families. Discovery of epilepsy-associated ion channel defects in these rare families has opened the door to the discovery of the first two susceptibility genes in epilepsies with complex genetics. The susceptibility genes so far detected are not commonly involved in complex epilepsy suggesting the likelihood of considerable underlying polygenic heterogeneity.

Widespread correlations between dominance and homozygous effects of mutations: implications for theories of dominance.

The dominance of deleterious mutations has important consequences for phenomena such as inbreeding depression, the evolution of diploidy, and levels of natural genetic variation. Kacser and Burns' metabolic theory provides a paradigmatic explanation for why most large-effect mutations are recessive. According to the metabolic theory, the recessivity of large-effect mutations is a consequence of a diminishing-returns relationship between flux through a metabolic pathway and enzymatic activity at any step in the pathway, which in turn is an inevitable consequence of long metabolic pathways. A major line of support for this theory was the demonstration of a negative correlation between homozygous effects and dominance of mutations in Drosophila, consistent with a central prediction of the metabolic theory. Using data on gene deletions in yeast, we show that a negative correlation between homozygous effects and dominance of mutations exists for all major categories of genes analyzed, not just those encoding enzymes. The relationship between dominance and homozygous effects is similar for duplicated and single-copy genes and for genes whose products are members of protein complexes and those that are not. A complete explanation of dominance therefore requires either a generalization of Kacser and Burns' theory to nonenzyme genes or a new theory.

PLEIOTROPIC EFFECTS OF BENEFICIAL MUTATIONS IN ESCHERICHIA COLI

Micromutational models of adaptation have placed considerable weight on antagonistic pleiotropy as a mechanism that prevents mutations of large effect from achieving fixation. However, there are few empirical studies of the distribution of pleiotropic effects, and no studies that have examined this distribution for a large number of adaptive mutations. Here we examine the form and extent of pleiotropy associated with beneficial mutations in Escherichia coli. To do so, we used a collection of independently evolved genotypes, each of which contains a beneficial mutation that confers increased fitness in a glucose-limited environment. To determine the pleiotropic effects of these mutations, we examined the fitnesses of the mutants in five novel resource environments. Our results show that the majority of mutations had significant fitness effects in alternative resources, such that pleiotropy was common. The predominant form of this pleiotropy was positive—that is, most mutations that conferred increased fitness in glucose also conferred increased fitness in novel resources. We did detect some deleterious pleiotropic effects, but they were primarily limited to one of the five resources, and within this resource, to only a subset of mutants. Although pleiotropic effects were generally positive, fitness levels were lower and more variable on resources that differed most in their mechanisms of uptake and catabolism from that of glucose. Positive pleiotropic effects were strongly correlated in magnitude with their direct effects, but no such correlation was found among mutants with deleterious pleiotropic effects. Whereas previous studies of populations evolved on glucose for longer periods of time showed consistent declines on some of the resources used here, our results suggest that deleterious pleiotropic effects were limited to only a subset of the beneficial mutations available.

Paucimorphic Alleles versus Polymorphic Alleles and Rare Mutations in Disease Causation: Theory, Observation and Detection

Definitions of polymorphism in a gene include occurrence of a rarer allele of at least 1% frequency; or occurrence of the commonest allele at less than 95% frequency. Many alleles of single nucleotide polymorphisms (SNPs) in genes occur at much higher frequency (up to 50%). Many common diseases have a substantial genetic component. The prevailing hypothesis for the molecular basis of common diseases is that it involves the combinatoric action of common polymorphic alleles of minor effect (common disease / common variant, CD / CV hypothesis). The ready development of genome-wide databases of high frequency SNPs is enabling the testing of this hypothesis. A contrasting approach has been the study of very highly selected cases and families by linkage and mutation detection techniques to identify rare mutations of large effect on a gene, often private to a single family (rare disease / rare variant, RD / RV hypothesis. These approaches have formed the mainstay of disease gene discovery, the latter having been feasible for a decade, the former just now becoming feasible. However, an intermediate possibility exists. Sequence changes at an intermediate frequency (herewith, “paucimorphisms”, arbitrarily 0.0005<q<0.05) may exist and may have a moderate effect. A number of different loci may predispose to the same disease, although only one paucimorphic allele of one particular gene will be found in any one individual. Exploring the “paucimorphisms hypothesis” will require mutation detection applied both at the level of large numbers of relatively unselected cases and at the population level. In this review we consider the foundations of this hypothesis, relevant available technologies and possible future approaches to systematically explore this hypothesis.

Mutational effects on the clonal interference phenomenon.

We study the process of fixation of beneficial mutations in an asexual population by means of a theoretical model. Particularly, we wish to investigate how the supply of deleterious and beneficial mutations influences the dynamics of the adaptive process of an evolving population. It is well known that the deleterious mutations drastically affect the fate of beneficial mutations. In addition, an increasing supply of favorable mutations, to compensate the decay of the fitness due to the accumulation of deleterious mutations, produces the clonal interference phenomenon where advantageous mutations in distinct lineages compete to reach fixation. This competition imposes a limit to the speed of adaptation of the population. Intuitively, we would expect that the interplay of the two mechanisms would conspire to ensure fixation of only large-effect beneficial mutations. Our results, however, show that beneficial mutations of small effect have an increased probability of fixation when both beneficial and deleterious mutations rates are increased.

Evolution restricts the coexistence of specialists and generalists: the role of trade-off structure.

Environmental variability and adaptive foraging behavior have been shown to favor coexistence of specialists and generalists on an ecological timescale. This leaves unaddressed the question of whether such coexistence can also be expected on an evolutionary timescale. In this article, we study the attainability, through gradual evolution, of specialist-generalist coexistence, as well as the evolutionary stability of such communities when allowing for immigration. Our analysis shows that the potential for specialist-generalist coexistence is much more restricted than originally thought and strongly depends on the trade-off structure assumed. We establish that ecological coexistence is less likely for species facing a trade-off between per capita reproduction in different habitats than when the trade-off acts on carrying capacities alone. We also demonstrate that coexistence is evolutionarily stable whenever it is ecologically stable but that in most cases, such coexistence cannot be reached through gradual evolution. We conclude that an evolutionarily stable community of specialists and generalists may be created only through immigration from elsewhere or through mutations of large effect. Our results highlight that trade-offs in fitness-determining traits can have counterintuitive effects on the evolution of specialization.

MUTATIONAL EFFECTS ON THE CLONAL INTERFERENCE PHENOMENON

We study the process of fixation of beneficial mutations in an asexual population by means of a theoretical model. Particularly, we wish to investigate how the supply of deleterious and beneficial mutations influences the dynamics of the adaptive process of an evolving population. It is well known that the deleterious mutations drastically affect the fate of beneficial mutations. In addition, an increasing supply of favorable mutations, to compensate the decay of the fitness due to the accumulation of deleterious mutations, produces the clonal interference phenomenon where advantageous mutations in distinct lineages compete to reach fixation. This competition imposes a limit to the speed of adaptation of the population. Intuitively, we would expect that the interplay of the two mechanisms would conspire to ensure fixation of only large-effect beneficial mutations. Our results, however, show that beneficial mutations of small effect have an increased probability of fixation when both beneficial and deleterious mutations rates are increased.

Estimating numbers of EMS-induced mutations affecting life history traits in Caenorhabditis elegans in crosses between inbred sublines

Inbred lines of the nematode Caenorhabditis elegans containing independent EMS-induced mutations were crossed to the ancestral wild-type strain (N2). Replicated inbred sublines were generated from the F1 offspring under conditions of minimal selection and, along with the N2 and mutant progenitor lines, were assayed for several fitness correlates including relative fitness (w). A modification of the Castle-Wright estimator and a maximum-likelihood (ML) method were used to estimate the numbers and effects of detectable mutations affecting these characters. The ML method allows for variation in mutational effects by fitting either one or two classes of mutational effect, and uses a Box-Cox power transformation of residual values to account for a skewed distribution of residuals. Both the Castle-Wright and the ML analyses suggest that most of the variation among sublines was due to a few (approximately 1.5-2.5 on average) large-effect mutations. Under ML, a model with two classes of mutational effects, including a class with small effects, fitted better than a single mutation class model, although not significantly better. Nonetheless, given that we expect there to be many mutations induced per line, our results support the hypothesis that mutations vary widely in their effects.