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Epistasis
Selected AbstractsGenetic and non-genetic influences on the development of co-occurring alcohol problem use and internalizing symptomatology in adolescence: a reviewADDICTION, Issue 7 2009Luca Saraceno ABSTRACT Aims Alcohol problem use during adolescence has been linked to a variety of adverse consequences, including cigarette and illicit drug use, delinquency, adverse effects on pubertal brain development and increased risk of morbidity and mortality. In addition, heavy alcohol-drinking adolescents are at increased risk of comorbid psychopathology, including internalizing symptomatology (especially depression and anxiety). A range of genetic and non-genetic factors have been implicated in both alcohol problem use as well as internalizing symptomatology. However, to what extent shared risk factors contribute to their comorbidity in adolescence is poorly understood. Design We conducted a systematic review on Medline, PsycINFO, Embase and Web of Science to identify epidemiological and molecular genetic studies published between November 1997 and November 2007 that examined risk factors that may be shared in common between alcohol problem use and internalizing symptomatology in adolescence. Findings Externalizing disorders, family alcohol problems and stress, as well as the serotonin transporter (5-HTT) S-allele, the monoamine oxidase A (MAOA) low-activity alleles and the dopamine D2 receptor (DDR2) Taq A1 allele have been associated most frequently with both traits. An increasing number of papers are focusing upon the role of gene,gene (epistasis) and gene,environment interactions in the development of comorbid alcohol problem use and internalizing symptomatology. Conclusions Further research in adolescents is warranted; the increasing availability of large longitudinal genetically informative studies will provide the evidence base from which effective prevention and intervention strategies for comorbid alcohol problems and internalizing symptomatology can be developed. [source] Effects of dopamine-related gene,gene interactions on working memory component processesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2009Christine Stelzel Abstract Dopamine modulates complex cognitive functions like working memory and cognitive control. It is widely accepted that an optimal level of prefrontal dopamine supports working memory performance. In the present study we used a molecular genetic approach to test whether the optimal activity of the dopamine system for different component processes of working memory is additionally related to the availability of dopamine D2 receptors. We sought evidence for this assumption by investigating the interaction effect (epistasis) of variations in two dopaminergic candidate genes: the catechol- O -methyltransferase (COMT) Val158Met polymorphism, which has been shown to influence prefrontal dopamine concentration, and the DRD2/ANKK1-Taq-Ia polymorphism, which has been related to the density of D2 receptors. Our results show that COMT effects on working memory performance are modulated by the DRD2/ANKK1-TAQ-Ia polymorphism and the specific working memory component process under investigation. Val, participants , supposedly characterized by increased prefrontal dopamine concentrations , outperformed Val+ participants in the manipulation of working memory contents, but only when D2 receptor density could be considered to be high. No such effect was present for passive maintenance of working memory contents or for maintenance in the face of distracting information. This beneficial effect of a balance between prefrontal dopamine availability and D2 receptor density reveals the importance of considering epistasis effects and different working memory subprocesses in genetic association studies. [source] CYTONUCLEAR INTERACTIONS CAN FAVOR THE EVOLUTION OF GENOMIC IMPRINTINGEVOLUTION, Issue 5 2009Jason B. Wolf Interactions between cytoplasmic (generally organelle) and nuclear genomes may be relatively common and could potentially have major fitness consequences. As in the case of within-genome epistasis, this cytonuclear epistasis can favor the evolutionary coadaptation of high-fitness combinations of nuclear and cytoplasmic alleles. Because cytoplasmic factors are generally uniparentally inherited, the cytoplasmic genome is inherited along with only one of the nuclear haplotypes, and therefore, coadaptation is expected to evolve through the interaction of these coinherited (usually maternally inherited) genomes. Here I show that, as a result of this coinheritance of the two genomes, cytonuclear epistasis can favor the evolution of genomic imprinting such that, when the cytoplasmic factor is maternally inherited, selection favors maternal expression of the nuclear locus and when the factor is paternally inherited selection favors paternal expression. Genomic imprinting evolves in this model because it leads to a pattern of gene expression in the nuclear haplotype that is coadapted with (i.e., adaptively coordinated with) gene expression in the coinherited cytoplasmic genome. [source] POPULATION DIFFERENTIATION IN THE BEETLE TRIBOLIUM CASTANEUM.EVOLUTION, Issue 3 2007We used joint-scaling analyses in conjunction with rearing temperature variation to investigate the contributions of additive, non-additive, and environmental effects to genetic divergence and incipient speciation among 12 populations of the red flour beetle, Tribolium castaneum, with small levels of pairwise nuclear genetic divergence (0.033 < Nei's D < 0.125). For 15 population pairs we created a full spectrum of line crosses (two parental, two reciprocal F1's, four F2's, and eight backcrosses), reared them at multiple temperatures, and analyzed the numbers and developmental defects of offspring. We assayed a total of 219,388 offspring from 5147 families. Failed crosses occurred predominately in F2's, giving evidence of F2 breakdown within this species. In all cases where a significant model could be fit to the data on offspring number, we observed at least one type of digenic epistasis. We also found maternal and cytoplasmic effects to be common components of divergence among T. castaneum populations. In some cases, the most complex model tested (additive, dominance, epistatic, maternal, and cytoplasmic effects) did not provide a significant fit to the data, suggesting that linkage or higher order epistasis is involved in differentiation between some populations. For the limb deformity data, we observed significant genotype-by-environment interaction in most crosses and pure parent crosses tended to have fewer deformities than hybrid crosses. Complexity of genetic architecture was not correlated with either geographic distance or genetic distance. Our results support the view that genetic incompatibilities responsible for postzygotic isolation, an important component of speciation, may be a natural but serendipitous consequence of nonadditive genetic effects and structured populations. [source] THE CHANGE IN QUANTITATIVE GENETIC VARIATION WITH INBREEDINGEVOLUTION, Issue 12 2006Josh Van Buskirk Abstract Inbreeding is known to reduce heterozygosity of neutral genetic markers, but its impact on quantitative genetic variation is debated. Theory predicts a linear decline in additive genetic variance (VA) with increasing inbreeding coefficient (F) when loci underlying the trait act additively, but a nonlinear hump-shaped relationship when dominance and epistasis are important. Predictions for heritability (h2) are similar, although the exact shape depends on the value of h2 in the absence of inbreeding. We located 22 published studies in which the level of genetic variation in [source] EVOLUTION OF GENETIC ARCHITECTURE UNDER DIRECTIONAL SELECTIONEVOLUTION, Issue 8 2006Thomas F. Hansen Abstract We investigate the multilinear epistatic model under mutation-limited directional selection. We confirm previous results that only directional epistasis, in which genes on average reinforce or diminish each other's effects, contribute to the initial evolution of mutational effects. Thus, either canalization or decanalization can occur under directional selection, depending on whether positive or negative epistasis is prevalent. We then focus on the evolution of the epistatic coefficients themselves. In the absence of higher-order epistasis, positive pairwise epistasis will tend to weaken relative to additive effects, while negative pairwise epistasis will tend to become strengthened. Positive third-order epistasis will counteract these effects, while negative third-order epistasis will reinforce them. More generally, gene interactions of all orders have an inherent tendency for negative changes under directional selection, which can only be modified by higher-order directional epistasis. We identify three types of nonadditive quasi-equilibrium architectures that, although not strictly stable, can be maintained for an extended time: (1) nondirectional epistatic architectures; (2) canalized architectures with strong epistasis; and (3) near-additive architectures in which additive effects keep increasing relative to epistasis. [source] AN EXACT FORM OF THE BREEDER'S EQUATION FOR THE EVOLUTION OF A QUANTITATIVE TRAIT UNDER NATURAL SELECTIONEVOLUTION, Issue 11 2005John S. Heywood Abstract Starting with the Price equation, I show that the total evolutionary change in mean phenotype that occurs in the presence of fitness variation can be partitioned exactly into five components representing logically distinct processes. One component is the linear response to selection, as represented by the breeder's equation of quantitative genetics, but with heritability defined as the linear regression coefficient of mean offspring phenotype on parent phenotype. The other components are identified as constitutive transmission bias, two types of induced transmission bias, and a spurious response to selection caused by a covariance between parental fitness and offspring phenotype that cannot be predicted from parental phenotypes. The partitioning can be accomplished in two ways, one with heritability measured before (in the absence of) selection, and the other with heritability measured after (in the presence of) selection. Measuring heritability after selection, though unconventional, yields a representation for the linear response to selection that is most consistent with Darwinian evolution by natural selection because the response to selection is determined by the reproductive features of the selected group, not of the parent population as a whole. The analysis of an explicitly Mendelian model shows that the relative contributions of the five terms to the total evolutionary change depends on the level of organization (gene, individual, or mated pair) at which the parent population is divided into phenotypes, with each frame of reference providing unique insight. It is shown that all five components of phenotypic evolution will generally have nonzero values as a result of various combinations of the normal features of Mendelian populations, including biparental sex, allelic dominance, inbreeding, epistasis, linkage disequilibrium, and environmental covariances between traits. Additive genetic variance can be a poor predictor of the adaptive response to selection in these models. The narrow-sense heritability s,2A/s,2P should be viewed as an approximation to the offspring-parent linear regression rather than the other way around. [source] PERSPECTIVE: SIGN EPISTASIS AND GENETIC COSTRAINT ON EVOLUTIONARY TRAJECTORIESEVOLUTION, Issue 6 2005Daniel M. Weinreich Abstract Epistasis for fitness means that the selective effect of a mutation is conditional on the genetic background in which it appears. Although epistasis is widely observed in nature, our understanding of its consequences for evolution by natural selection remains incomplete. In particular, much attention focuses only on its influence on the instantaneous rate of changes in frequency of selected alleles via epistatic contribution to the additive genetic variance for fitness. Thus, in this framework epistasis only has evolutionary importance if the interacting loci are simultaneously segregating in the population. However, the selective accessibility of mutational trajectories to high fitness genotypes may depend on the genetic background in which novel mutations appear, and this effect is independent of population polymorphism at other loci. Here we explore this second influence of epistasis on evolution by natural selection. We show that it is the consequence of a particular form of epistasis, which we designate sign epistasis. Sign epistasis means that the sign of the fitness effect of a mutation is under epistatic control; thus, such a mutation is beneficial on some genetic backgrounds and deleterious on others. Recent experimental innovations in microbial systems now permit assessment of the fitness effects of individual mutations on multiple genetic backgrounds. We review this literature and identify many examples of sign epistasis, and we suggest that the implications of these results may generalize to other organisms. These theoretical and empirical considerations imply that strong genetic constraint on the selective accessibility of trajectories to high fitness genotypes may exist and suggest specific areas of investigation for future research. [source] RAPID EVOLUTIONARY ESCAPE BY LARGE POPULATIONS FROM LOCAL FITNESS PEAKS IS LIKELY IN NATUREEVOLUTION, Issue 6 2005Daniel M. Weinreich Abstract Fitness interactions between loci in the genome, or epistasis, can result in mutations that are individually deleterious but jointly beneficial. Such epistasis gives rise to multiple peaks on the genotypic fitness landscape. The problem of evolutionary escape from such local peaks has been a central problem of evolutionary genetics for at least 75 years. Much attention has focused on models of small populations, in which the sequential fixation of valley genotypes carrying individually deleterious mutations operates most quickly owing to genetic drift. However, valley genotypes can also be subject to mutation while transiently segregating, giving rise to copies of the high fitness escape genotype carrying the jointly beneficial mutations. In the absence of genetic recombination, these mutations may then fix simultaneously. The time for this process declines sharply with increasing population size, and it eventually comes to dominate evolutionary behavior. Here we develop an analytic expression for Ncrit, the critical population size that defines the boundary between these regimes, which shows that both are likely to operate in nature. Frequent recombination may disrupt high-fitness escape genotypes produced in populations larger than Ncrit before they reach fixation, defining a third regime whose rate again slows with increasing population size. We develop a novel expression for this critical recombination rate, which shows that in large populations the simultaneous fixation of mutations that are beneficial only jointly is unlikely to be disrupted by genetic recombination if their map distance is on the order of the size of single genes. Thus, counterintuitively, mass selection alone offers a biologically realistic resolution to the problem of evolutionary escape from local fitness peaks in natural populations. [source] SEXUAL SELECTION, GENETIC ARCHITECTURE, AND THE CONDITION DEPENDENCE OF BODY SHAPE IN THE SEXUALLY DIMORPHIC FLY PROCHYLIZA XANTHOSTOMA (PIOPHILIDAE)EVOLUTION, Issue 1 2005Russell Bonduriansky Abstract The hypothesis that sexual selection drives the evolution of condition dependence is not firmly supported by empirical evidence, and the process remains poorly understood. First, even though sexual competition typically involves multiple traits, studies usually compare a single sexual trait with a single "control" trait, ignoring variation among sexual traits and raising the possibility of sampling bias. Second, few studies have addressed the genetic basis of condition dependence. Third, even though condition dependence is thought to result from a form of sex-specific epistasis, the evolution of condition dependence has never been considered in relation to intralocus sexual conflict. We argue that condition dependence may weaken intersexual genetic correlations and facilitate the evolution of sexual dimorphism. To address these questions, we manipulated an environmental factor affecting condition (larval diet) and examined its effects on four sexual and four nonsexual traits in Prochyliza xanthostoma adults. As predicted by theory, the strength of condition dependence increased with degree of exaggeration among male traits. Body shape was more condition dependent in males than in females and, perhaps as a result, genetic and environmental effects on body shape were congruent in males, but not in females. However, of the four male sexual traits, only head length was significantly larger in high-condition males after controlling for body size. Strong condition dependence was associated with reduced intersexual genetic correlation. However, homologous male and female traits exhibited correlated responses to condition, suggesting an intersexual genetic correlation for condition dependence itself. Our findings support the role of sexual selection in the evolution of condition dependence, but reveal considerable variation in condition dependence among sexual traits. It is not clear whether the evolution of condition dependence has mitigated or exacerbated intralocus sexual conflict in this species. [source] EFFECTS OF GENETIC DRIFT ON VARIANCE COMPONENTS UNDER A GENERAL MODEL OF EPISTASISEVOLUTION, Issue 10 2004N.H. Barton Abstract We analyze the changes in the mean and variance components of a quantitative trait caused by changes in allele frequencies, concentrating on the effects of genetic drift. We use a general representation of epistasis and dominance that allows an arbitrary relation between genotype and phenotype for any number of diallelic loci. We assume initial and final Hardy-Weinberg and linkage equilibrium in our analyses of drift-induced changes. Random drift generates transient linkage disequilibria that cause correlations between allele frequency fluctuations at different loci. However, we show that these have negligible effects, at least for interactions among small numbers of loci. Our analyses are based on diffusion approximations that summarize the effects of drift in terms of F, the inbreeding coefficient, interpreted as the expected proportional decrease in heterozygosity at each locus. For haploids, the variance of the trait mean after a population bottleneck is var(,z,) =where n is the number of loci contributing to the trait variance, VA(1)=VA is the additive genetic variance, and VA(k) is the kth-order additive epistatic variance. The expected additive genetic variance after the bottleneck, denoted (V*A), is closely related to var(,z,); (V*A) (1 ,F)Thus, epistasis inflates the expected additive variance above VA(1 ,F), the expectation under additivity. For haploids (and diploids without dominance), the expected value of every variance component is inflated by the existence of higher order interactions (e.g., third-order epistasis inflates (V*AA)). This is not true in general with diploidy, because dominance alone can reduce (V*A) below VA(1 ,F) (e.g., when dominant alleles are rare). Without dominance, diploidy produces simple expressions: var(,z,)==1 (2F) kVA(k) and (V*A) = (1 ,F)k(2F)k-1VA(k) With dominance (and even without epistasis), var(,z,)and (V*A) no longer depend solely on the variance components in the base population. For small F, the expected additive variance simplifies to (V*A)(1 ,F) VA+ 4FVAA+2FVD+2FCAD, where CAD is a sum of two terms describing covariances between additive effects and dominance and additive × dominance interactions. Whether population bottlenecks lead to expected increases in additive variance depends primarily on the ratio of nonadditive to additive genetic variance in the base population, but dominance precludes simple predictions based solely on variance components. We illustrate these results using a model in which genotypic values are drawn at random, allowing extreme and erratic epistatic interactions. Although our analyses clarify the conditions under which drift is expected to increase VA, we question the evolutionary importance of such increases. [source] EPISTASIS AND THE TEMPORAL CHANGE IN THE ADDITIVE VARIANCE-COVARIANCE MATRIX INDUCED BY DRIFTEVOLUTION, Issue 8 2004Carlos López-Fanjul Abstract The effect of population bottlenecks on the components of the genetic covariance generated by two neutral independent epistatic loci has been studied theoretically (additive, covA; dominance, covD; additive-by-additive, covAA; additive-by-dominance, covAD; and dominance-by-dominance, covDD). The additive-by-additive model and a more general model covering all possible types of marginal gene action at the single-locus level (additive/dominance epistatic model) were considered. The covariance components in an infinitely large panmictic population (ancestral components) were compared with their expected values at equilibrium over replicates randomly derived from the base population, after t consecutive bottlenecks of equal size N (derived components). Formulae were obtained in terms of the allele frequencies and effects at each locus, the corresponding epistatic effects and the inbreeding coefficient Ft. These expressions show that the contribution of nonadditive loci to the derived additive covariance (covAt) does not linearly decrease with inbreeding, as in the pure additive case, and may initially increase or even change sign in specific situations. Numerical examples were also analyzed, restricted for simplicity to the case of all covariance components being positive. For additive-by-additive epistasis, the condition covAt > covA only holds for high frequencies of the allele decreasing the metric traits at each locus (negative allele) if epistasis is weak, or for intermediate allele frequencies if it is strong. For the additive/dominance epistatic model, however, covAt > covA applies for low frequencies of the negative alleles at one or both loci and mild epistasis, but this result can be progressively extended to intermediate frequencies as epistasis becomes stronger. Without epistasis the same qualitative results were found, indicating that marginal dominance induced by epistasis can be considered as the primary cause of an increase of the additive covariance after bottlenecks. For all models, the magnitude of the ratio covAt/covA was inversely related to N and t. [source] THE ADDITIVE GENETIC VARIANCE AFTER BOTTLENECKS IS AFFECTED BY THE NUMBER OF LOCI INVOLVED IN EPISTATIC INTERACTIONSEVOLUTION, Issue 4 2003Yamama Naciri-Graven Abstract We investigated the role of the number of loci coding for a neutral trait on the release of additive variance for this trait after population bottlenecks. Different bottleneck sizes and durations were tested for various matrices of genotypic values, with initial conditions covering the allele frequency space. We used three different types of matrices. First, we extended Cheverud and Routman's model by defining matrices of "pure" epistasis for three and four independent loci; second, we used genotypic values drawn randomly from uniform, normal, and exponential distributions; and third we used two models of simple metabolic pathways leading to physiological epistasis. For all these matrices of genotypic values except the dominant metabolic pathway, we find that, as the number of loci increases from two to three and four, an increase in the release of additive variance is occurring. The amount of additive variance released for a given set of genotypic values is a function of the inbreeding coefficient, independently of the size and duration of the bottleneck. The level of inbreeding necessary to achieve maximum release in additive variance increases with the number of loci. We find that additive-by-additive epistasis is the type of epistasis most easily converted into additive variance. For a wide range of models, our results show that epistasis, rather than dominance, plays a significant role in the increase of additive variance following bottlenecks. [source] THE EFFECT OF EPISTASIS ON THE EXCESS OF THE ADDITIVE AND NONADDITIVE VARIANCES AFTER POPULATION BOTTLENECKSEVOLUTION, Issue 5 2002Carlos López-Fanjul Abstract The effect of population bottlenecks on the components of the genetic variance generated by two neutral independent epistatic loci has been studied theoretically (VA, additive; VD, dominant; VAA, additive × additive; VAD, additive × dominant; VDD; dominant × dominant components of variance). Nonoverdominance and overdominance models were considered, covering all possible types of marginal gene action at the single locus level. The variance components in an infinitely large panmictic population (ancestral components) were compared with their expected values at equilibrium, after t consecutive bottlenecks of equal size N (derived components). Formulae were obtained in terms of allele frequencies and effects at each locus and the corresponding epistatic value. An excess of VA after bottlenecks can be assigned to two sources: (1) the spatiotemporal changes in the marginal average effects of gene substitution ai, which are equal to zero only for additive gene action within and between loci; and (2) the covariance between a2i and the heterozygosity at the loci involved, which is generated by dominance, with or without epistasis. Numerical examples were analyzed, indicating that an increase in VA after bottlenecks will only occur if its ancestral value is minimal or very small. For the nonoverdominance model with weak reinforcing epistasis, that increase has been detected only for extreme frequencies of the negative allele at one or both loci. With strong epistasis, however, this result can be extended to a broad range of intermediate frequencies. With no epistasis, the same qualitative results were found, indicating that dominance can be considered as the primary cause of an increase in VA following bottlenecks. In parallel, the derived total nonadditive variance exceeded its ancestral value (VNA= VD+ VAA+VAD+ VDD) for a range of combinations of allele frequencies covering those for an excess of VA and for very large frequencies of the negative allele at both loci. For the overdominance model, an increase in VA and VNA was respectively observed for equilibrium (intermediate) frequencies at one or both loci or for extreme frequencies at both loci. For all models, the magnitude of the change of VA and VNA was inversely related to N and t. At low levels of inbreeding, the between-line variance was not affected by the type of gene action. For the models considered, the results indicate that it is unlikely that the rate of evolution may be accelerated after population bottlenecks, in spite of occasional increments of the derived VA over its ancestral value. [source] HETEROSIS AND OUTBREEDING DEPRESSION IN DESCENDANTS OF NATURAL IMMIGRANTS TO AN INBRED POPULATION OF SONG SPARROWS (MELOSPIZA MELODIA)EVOLUTION, Issue 1 2002Amy B. Marr Abstract We studied heterosis and outbreeding depression among immigrants and their descendants in a population of song sparrows on Mandarte Island, Canada. Using data spanning 19 generations, we compared survival, seasonal reproductive success, and lifetime reproductive success of immigrants, natives (birds with resident-hatched parents and grandparents), and their offspring (F1s, birds with an immigrant and a native parent, and F2s, birds with an immigrant grandparent and resident-hatched grandparent in each of their maternal and paternal lines). Lifetime reproductive success of immigrants was no worse than that of natives, but other measures of performance differed in several ways. Immigrant females laid later and showed a tendency to lay fewer clutches, but had relatively high success raising offspring per egg produced. The few immigrant males survived well but were less likely to breed than native males of the same age that were alive in the same year. Female F1s laid earlier than expected based on the average for immigrant and native females, and adult male F1s were more likely to breed than expected based on the average for immigrant and native males. The performance differences between immigrant and native females and between F1s and the average of immigrants and natives are consistent with the hypothesis that immigrants were disadvantaged by a lack of site experience and that immigrant offspring benefited from heterosis. However, we could not exclude the possibility that immigrants had a different strategy for optimizing reproductive success or that they experienced ecological compensation for life-history parameters. For example, the offspring of immigrants may have survived well because immigrants laid later and produced fewer clutches, thereby raising offspring during a period of milder climatic conditions. Although sample sizes were small, we found large performance differences between F1s and F2s, which suggested that either heterosis was associated with epistasis in F1s, that F2s experienced outbreeding depression, or that both phenomena occurred. These findings indicate that the performance of dispersers may be affected more by fine-scale genetic differentiation than previously assumed in this and comparable systems. [source] Genetic association tests in the presence of epistasis or gene-environment interactionGENETIC EPIDEMIOLOGY, Issue 7 2008Kai WangArticle first published online: 24 APR 200 Abstract A genetic variant is very likely to manifest its effect on disease through its main effect as well as through its interaction with other genetic variants or environmental factors. Power to detect genetic variants can be greatly improved by modeling their main effects and their interaction effects through a common set of parameters or "generalized association parameters" (Chatterjee et al. [2006] Am. J. Hum. Genet. 79:1002,1016) because of the reduced number of degrees of freedom. Following this idea, I propose two models that extend the work by Chatterjee and colleagues. Particularly, I consider not only the case of relatively weak interaction effect compared to the main effect but also the case of relatively weak main effect. This latter case is perhaps more relevant to genetic association studies. The proposed methods are invariant to the choice of the allele for scoring genotypes or the choice of the reference genotype score. For each model, the asymptotic distribution of the likelihood ratio statistic is derived. Simulation studies suggest that the proposed methods are more powerful than existing ones under certain circumstances. Genet. Epidemiol. 2008. © 2008 Wiley-Liss, Inc. [source] Quantitative trait association in parent offspring trios: Extension of case/pseudocontrol method and comparison of prospective and retrospective approachesGENETIC EPIDEMIOLOGY, Issue 8 2007Eleanor Wheeler Abstract The case/pseudocontrol method provides a convenient framework for family-based association analysis of case-parent trios, incorporating several previously proposed methods such as the transmission/disequilibrium test and log-linear modelling of parent-of-origin effects. The method allows genotype and haplotype analysis at an arbitrary number of linked and unlinked multiallelic loci, as well as modelling of more complex effects such as epistasis, parent-of-origin effects, maternal genotype and mother-child interaction effects, and gene-environment interactions. Here we extend the method for analysis of quantitative as opposed to dichotomous (e.g. disease) traits. The resulting method can be thought of as a retrospective approach, modelling genotype given trait value, in contrast to prospective approaches that model trait given genotype. Through simulations and analytical derivations, we examine the power and properties of our proposed approach, and compare it to several previously proposed single-locus methods for quantitative trait association analysis. We investigate the performance of the different methods when extended to allow analysis of haplotype, maternal genotype and parent-of-origin effects. With randomly ascertained families, with or without population stratification, the prospective approach (modeling trait value given genotype) is found to be generally most effective, although the retrospective approach has some advantages with regard to estimation and interpretability of parameter estimates when applied to selected samples. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc. [source] Runt-related transcription factor 3 is associated with ulcerative colitis and shows epistasis with solute carrier family 22, members 4 and 5INFLAMMATORY BOWEL DISEASES, Issue 12 2008Rinse K. Weersma MD Abstract Background: Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are intestinal inflammatory disorders with a complex genetic background. Mice deficient for the runt-domain-transcription-factor3 (Runx3) develop spontaneous colitis. Human RUNX3 resides in an IBD-susceptibility locus. We studied the association of RUNX3 in a cohort of IBD patients and analyzed the interaction with SLC22A4/5. RUNX3 and OCTN1 mRNA expression was assessed in inflamed and noninflamed mucosa from patients and controls. Methods: 543 IBD patients (309 CD / 234 UC) and 296 controls were included. Four single nucleotide polymorphisms (SNPs) and 4 microsatellite markers were studied for RUNX3. Five SNPs (including SNP-207G,C and SNP1672C,T) were analyzed for SLC22A4/5. RUNX3, and OCTN1 expression in mucosal tissue from 30 patients (14 UC / 16 CD) and 6 controls were determined by quantitative polymerase chain reaction. Results: A significant association between RUNX3 -SNP rs2236851 and UC (OR 1.61; 95% confidence interval [CI] 1.11,2.32, P = 0.020) was found. Carriership is associated with pancolitis (odds ratio [OR] 1.86; 95% CI 1.08,3.21). SLC22A4/5 -SNPs rs272893 and rs273900 are associated with CD (OR 2.16; 95% CI 1.21,3.59 and OR 2.40; 95% CI 1.43,4.05). We found epistasis for carriership of a risk-associated allele in RUNX3 and SLC22A4/5 for UC patients versus CD patients (OR 3.83; 95% CI 1.26,11.67). RUNX3 mRNA expression is increased (P = 0.01) in inflamed colonic mucosa of UC patients compared to noninflamed mucosa and controls. Conclusions: We provide evidence for the genetic association of RUNX3 with UC and for CD with the IBD5 locus including SLC22A4/5. An epistatic effect of RUNX3 and SLC22A4 was associated with an increased risk for UC. Our data suggest a role for RUNX3 in UC susceptibility. (Inflamm Bowel Dis 2008) [source] Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): Upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBDINFLAMMATORY BOWEL DISEASES, Issue 4 2008Julia Seiderer MD Abstract Background: Interleukin (IL)-17F, produced in IL-23R-expressing Th17 cells, is a novel member of the IL-17 cytokine family. Given the association of IL23R with inflammatory bowel disease (IBD), we characterized the role of IL-17F in IBD including its intestinal gene expression and the effect of the IL17F p.His161Arg polymorphism on disease susceptibility and phenotype of Crohn's disease (CD) and ulcerative colitis (UC). In addition, we analyzed the IL17F p.His161Arg polymorphism for potential epistasis with IL23R and NOD2/CARD15 variants. Methods: Intestinal IL-17F mRNA expression was measured by quantitative polymerase chain reaction (PCR). Genomic DNA from 1682 individuals (CD: n = 499; UC: n = 216; controls: n = 967) was analyzed for the presence of the IL17F p.His161Arg polymorphism, the 3 NOD2 variants, p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008, and 10 CD-associated IL23R variants. Results: Intestinal IL-17F mRNA expression was 4.4-fold increased in inflamed colonic lesions compared to uninflamed biopsies in CD (P = 0.016) but not in UC. However, the mean intestinal IL-17F mRNA expression was higher in UC than in CD (P < 0.0001). The IL17F p.His161Arg substitution was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype, but weakly associated with a low body mass index (BMI; P = 0.009) and an earlier age of disease onset (P = 0.039) in UC. There was no evidence for epistasis between the IL17F p.His161Arg polymorphism and IBD-associated single nucleotide polymorphisms within the IL23R gene. Conclusions: Intestinal IL17F gene expression is increased in active CD. The IL17F p.His161Arg polymorphism is not associated with IBD susceptibility and has no epistatic interaction with CD-associated IL23R variants. (Inclamm Bowel Dis 2007) [source] Contribution of the novel inflammatory bowel disease gene IL23R to disease susceptibility and phenotypeINFLAMMATORY BOWEL DISEASES, Issue 9 2007J.R. Fraser Cummings MRCP(UK) Abstract Background: A North American genome-wide single nucleotide polymorphism (SNP) association study identified IL23R as a novel inflammatory bowel disease (IBD) susceptibility gene. Association was reported with multiple risk variants in the centromeric portion of IL23R in 3 large independent cohorts. The aims of this study were to replicate the association of IL23R with Crohn's disease (CD), examine subphenotype relationships, and look for evidence of epistasis with the known CD susceptibility gene CARD15 and susceptibility haplotype IBD5 in a large collection of CD patients. We further investigated the relationship between IL23R and ulcerative colitis (UC). Methods: In all, 604 CD and 647 UC patients who had been rigorously phenotyped and who had been recruited from a single UK center were used in this study. Controls were either spouses of patients (141) or were recruited from well-person clinics (993). Eight SNPs were genotyped using MassArray (Sequenom). All 8 SNPs genotyped were significantly associated with CD. Results: The association with the nonsynonymous SNP rs11209026 was confirmed (P = 6.65 × 10,6, odds ratio [OR], 0.43, 95% confidence interval [CI]: 0.29-0.64). The most significant SNP in our study was rs7517847 (P = 4.9 × 10,9, OR 0.65, 0.56,0.75), which is statistically independent of rs11209026. Preliminary evidence suggests an epistatic interaction with the IBD5 risk haplotype. The effects of mutations in this IL23R appear weaker in UC (P = 0.008, OR 0.63, 0.45,0.89 and 0.005 OR, 0.81, 0.71,0.94, respectively). No subphenotype associations were identified. Conclusions: We confirmed the findings that IL23R is a susceptibility gene for IBD with suggestive epistasis with the IBD5 locus in the CD population. (Inflamm Bowel Dis 2007) [source] Genetic association analysis: a primer on how it works, its strengths and its weaknessesINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 6 2008Laura Rodriguez-Murillo Summary Currently, the most used approach to mapping disease genes is the genome wide association study, using large samples of cases and controls and hundreds of thousands of markers spread throughout the genome. This review focuses in explaining how an association study works, its strengths and its weaknesses, and the methods available to analyse the data. Issues related to sample size, genetic effect sizes, epistasis, replication and population stratification are specifically addressed, issues that an investigator must take into account when planning an association study of any complex disease. Finally, we include some special features concerning association studies in the Y chromosome, and we contrast the analysis characteristics of linkage and association. [source] Human MHC architecture and evolution: implications for disease association studiesINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2008J. A. Traherne Summary Major histocompatibility complex (MHC) variation is a key determinant of susceptibility and resistance to a large number of infectious, autoimmune and other diseases. Identification of the MHC variants conferring susceptibility to disease is problematic, due to high levels of variation and linkage disequilibrium. Recent cataloguing and analysis of variation over the complete MHC has facilitated localization of susceptibility loci for autoimmune diseases, and provided insight into the MHC's evolution. This review considers how the unusual genetic characteristics of the MHC impact on strategies to identify variants causing, or contributing to, disease phenotypes. It also considers the MHC in relation to novel mechanisms influencing gene function and regulation, such as epistasis, epigenetics and microRNAs. These developments, along with recent technological advances, shed light on genetic association in complex disease. [source] Parasites and deleterious mutations: interactions influencing the evolutionary maintenance of sexJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 5 2010A. W. PARK Abstract The restrictive assumptions associated with purely genetic and purely ecological mechanisms suggest that neither of the two forces, in isolation, can offer a general explanation for the evolutionary maintenance of sex. Consequently, attention has turned to pluralistic models (i.e. models that apply both ecological and genetic mechanisms). Existing research has shown that combining mutation accumulation and parasitism allows restrictive assumptions about genetic and parasite parameter values to be relaxed while still predicting the maintenance of sex. However, several empirical studies have shown that deleterious mutations and parasitism can reduce fitness to a greater extent than would be expected if the two acted independently. We show how interactions between these genetic and ecological forces can completely reverse predictions about the evolution of reproductive modes. Moreover, we demonstrate that synergistic interactions between infection and deleterious mutations can render sex evolutionarily stable even when there is antagonistic epistasis among deleterious mutations, thereby widening the conditions for the evolutionary maintenance of sex. [source] Synergistic epistasis and alternative hypothesesJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 6 2004S. Trouve Abstract Inbreeding generally results in deleterious shifts in mean fitness. If the fitness response to increasing inbreeding coefficient is non-linear, this suggests a contribution of epistasis to inbreeding depression. In a cross-breeding experiment, Salathé & Ebert (2003. J. Evol. Biol. 16: 976,985) tested and found the presence of this non-linearity in Daphnia magna. They argue that epistatic interactions cause this non-linearity. We argue here that their experimental protocol does not allow disentangling the effect of synergistic epistasis from two alternative hypotheses, namely hybrid vigour and statistical non-independence of data. [source] Genetic architecture of population differences in oviposition behaviour of the seed beetle Callosobruchus maculatusJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 5 2004C. W. Fox Abstract Few studies have examined the genetic architecture of population differences in behaviour and its implications for population differentiation and adaptation. Even fewer have examined whether differences in genetic architecture depend on the environment in which organisms are reared or tested. We examined the genetic basis of differences in oviposition preference and egg dispersion between Asian (SI) and African (BF) populations of the seed beetle, Callosobruchus maculatus. We reared and tested females on each of two host legumes (cowpea and mung bean). The two populations differed in mean oviposition preference (BF females preferred cowpea seeds more strongly than did SI females) and egg dispersion (SI females distributed eggs more uniformly among seeds than did BF females). Observations of hybrid and backcross individuals indicated that only the population difference in oviposition preference could be explained by complete additivity, whereas substantial dominance and epistasis contributed to the differences in egg dispersion. Both rearing host and test host affected the relative magnitude of population differences in egg dispersion and the composite genetic effects. Our results thus demonstrate that the relative influence of epistasis and dominance on the behaviour of hybrids depends on the behaviour measured and that different aspects of insect oviposition are under different genetic control. In addition, the observed effect of rearing host and oviposition host on the relative importance of dominance and epistasis indicates that the genetic basis of population differences depends on the environment in which genes are expressed. [source] A gene's eye view of epistasis, selection and speciationJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 3 2002M. J. Wade In this mini-review, I discuss the effects of gene interaction or epistasis from a `gene's eye view.' By a `gene's eye view' of epistasis, I mean that I will consider a single, bi-allelic locus, A, whose effects on fitness result only from its interactions with alleles of another, unknown locus, X. I will show how changes in the frequencies of alleles at the background locus affect the relationship of alleles at the A -locus to fitness. Changing the genetic background changes the fundamental characteristics of the A -locus, such as the magnitude and sign of allelic effects on fitness, and, consequently, it changes the strength and pattern of selection. I consider each of the four kinds of pair,wise interactions between two loci and show that some kinds of epistasis are more sensitive than others to population genetic subdivision. Lastly, I show that some kinds of epistasis are more likely than others to affect the process of speciation and contribute to or be responsible for general genetic features of interspecific hybrids, such as Haldane's rule. [source] The genic view of the process of speciationJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 6 2001Chung-I Wu The unit of adaptation is usually thought to be a gene or set of interacting genes, rather than the whole genome, and this may be true of species differentiation. Defining species on the basis of reproductive isolation (RI), on the other hand, is a concept best applied to the entire genome. The biological species concept (BSC; Mayr, 1963) stresses the isolation aspect of speciation on the basis of two fundamental genetic assumptions , the number of loci underlying species differentiation is large and the whole genome behaves as a cohesive, or coadapted genetic unit. Under these tenets, the exchange of any part of the genomes between diverging groups is thought to destroy their integrity. Hence, the maintenance of each species' genome cohesiveness by isolating mechanisms has become the central concept of species. In contrast, the Darwinian view of speciation is about differential adaptation to different natural or sexual environments. RI is viewed as an important by product of differential adaptation and complete RI across the whole genome need not be considered as the most central criterion of speciation. The emphasis on natural and sexual selection thus makes the Darwinian view compatible with the modern genic concept of evolution. Genetic and molecular analyses of speciation in the last decade have yielded surprisingly strong support for the neo-Darwinian view of extensive genetic differentiation and epistasis during speciation. However, the extent falls short of what BSC requires in order to achieve whole-genome ,cohesiveness'. Empirical observations suggest that the gene is the unit of species differentiation. Significantly, the genetic architecture underlying RI, the patterns of species hybridization and the molecular signature of speciation genes all appear to support the view that RI is one of the manifestations of differential adaptation, as Darwin (1859, Chap. 8) suggested. The nature of this adaptation may be as much the result of sexual selection as natural selection. In the light of studies since its early days, BSC may now need a major revision by shifting the emphasis from isolation at the level of whole genome to differential adaptation at the genic level. With this revision, BSC would in fact be close to Darwin's original concept of speciation. [source] Shuttle craft: a candidate quantitative trait gene for Drosophila lifespanAGING CELL, Issue 5 2004Elena G. Pasyukova Summary Variation in longevity in natural populations is attributable to the segregation of multiple interacting loci, whose effects are sensitive to the environment. Although there has been considerable recent progress towards understanding the environmental factors and genetic pathways that regulate lifespan, little is known about the genes causing naturally occurring variation in longevity. Previously, we used deficiency complementation mapping to map two closely linked quantitative trait loci (QTL) causing female-specific variation in longevity between the Oregon (Ore) and 2b strains of Drosophila melanogaster to 35B9,C3 and 35C3 on the second chromosome. The 35B9,C3 QTL encompasses a 50-kb region including four genes, for one of which, shuttle craft (stc), mutations have been generated. The 35C3 QTL localizes to a 200-kb interval with 15 genes, including three genes for which mutations exist (reduced (rd), guftagu (gft) and ms(2)35Ci). Here, we report quantitative complementation tests to mutations at these four positional candidate genes, and show that ms(2)35Ci and stc are novel candidate quantitative trait genes affecting variation in Drosophila longevity. Complementation tests with stc alleles reveal sex- and allele-specific failure to complement, and complementation effects are dependent on the genetic background, indicating considerable epistasis for lifespan. In addition, a homozygous viable stc allele has a sex-specific effect on lifespan. stc encodes an RNA polymerase II transcription factor, and is an attractive candidate gene for the regulation of longevity and variation in longevity, because it is required for motoneuron development and is expressed throughout development. Quantitative genetic analysis of naturally occurring variants with subtle effects on lifespan can identify novel candidate genes and pathways important in the regulation of longevity. [source] Sequence diversity and haplotype associations with phenotypic responses to crowding: GIGANTEA affects fruit set in Arabidopsis thalianaMOLECULAR ECOLOGY, Issue 14 2007MARCUS T. BROCK Abstract Identifying the molecular genetic basis of intraspecific variation in quantitative traits promises to provide novel insight into their evolutionary history as well as genetic mechanisms of adaptation. In an attempt to identify genes responsible for natural variation in competitive responses in Arabidopsis thaliana, we examined DNA sequence diversity at seven loci previously identified as members of the phytochrome B signalling network. For one gene, GIGANTEA (GI), we detected significant haplotype structure. To test for GI haplogroup,phenotype associations, we genotyped 161 A. thaliana accessions at GI and censused the same accessions for total fruit set and the expression of three phenotypic traits (days to flowering, petiole length, and inflorescence height) in a greenhouse experiment where plants were grown in crowded and uncrowded environments. We detected a significant association between GI and total fruit set that resulted in a 14% difference in average fruit set among GI haplogroups. Given that fruit set is an important component of fitness in this species and given the magnitude of the effect, the question arises as to how variation at this locus is maintained. Our observation of frequent and significant epistasis between GI and background single nucleotide polymorphisms (SNP), where the fitness ranking of the GI allele either reverses or does not differ depending on the allele at the interacting SNP, suggests that epistatic selection may actively maintain or at least slow the loss of variation at GI. This result is particularly noteworthy in the light of the ongoing debate regarding the genetic underpinnings of phenotypic evolution and recent observations that epistasis for phenotypic traits and components of fitness is common in A. thaliana. [source] The role of hybridization in evolutionMOLECULAR ECOLOGY, Issue 3 2001N. H. Barton Abstract Hybridization may influence evolution in a variety of ways. If hybrids are less fit, the geographical range of ecologically divergent populations may be limited, and prezygotic reproductive isolation may be reinforced. If some hybrid genotypes are fitter than one or both parents, at least in some environments, then hybridization could make a positive contribution. Single alleles that are at an advantage in the alternative environment and genetic background will introgress readily, although such introgression may be hard to detect. ,Hybrid speciation', in which fit combinations of alleles are established, is more problematic; its likelihood depends on how divergent populations meet, and on the structure of epistasis. These issues are illustrated using Fisher's model of stabilizing selection on multiple traits, under which reproductive isolation evolves as a side-effect of adaptation in allopatry. This confirms a priori arguments that while recombinant hybrids are less fit on average, some gene combinations may be fitter than the parents, even in the parental environment. Fisher's model does predict heterosis in diploid F1s, asymmetric incompatibility in reciprocal backcrosses, and (when dominance is included) Haldane's Rule. However, heterosis arises only when traits are additive, whereas the latter two patterns require dominance. Moreover, because adaptation is via substitutions of small effect, Fisher's model does not generate the strong effects of single chromosome regions often observed in species crosses. [source] | ||||||||||||||||||||||||||||