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Natural hybrid zones offer a powerful framework for understanding the genetic basis of speciation in progress because ongoing hybridization continually creates unfavorable gene combinations. Evidence indicates that postzygotic reproductive isolation is often caused by epistatic interactions between mutations in different genes that evolved independently of one another (hybrid incompatibilities). We examined the potential to detect epistatic selection against incompatibilities from genome sequence data using the site frequency spectrum (SFS) of polymorphisms by conducting individual-based simulations in SLiM. We found that the genome-wide SFS in hybrid populations assumes a diagnostic shape, with the continual input of fixed differences between source populations via migration inducing a mass at intermediate allele frequency. Epistatic selection locally distorts the SFS as non-incompatibility alleles rise in frequency in a manner analogous to a selective sweep. Building on these results, we present a statistical method to identify genomic regions containing incompatibility loci that locates departures in the local SFS compared with the genome-wide SFS. Cross-validation studies demonstrate that our method detects recessive and codominant incompatibilities across a range of scenarios varying in the strength of epistatic selection, migration rate, and hybrid zone age. Our approach takes advantage of whole genome sequence data, does not require knowledge of demographic history, and can be applied to any pair of nascent species that forms a hybrid zone. [ABSTRACT FROM AUTHOR]

A plausible explanation for statistical epistasis revealed in genome wide association analyses is the presence of high order linkage disequilibrium (LD) between the genotyped markers tested for interactions and unobserved functional polymorphisms. Based on findings in experimental data, it has been suggested that high order LD might be a common explanation for statistical epistasis inferred between local polymorphisms in the same genomic region. Here, we empirically evaluate how prevalent high order LD is between local, as well as distal, polymorphisms in the genome. This could provide insights into whether we should account for this when interpreting results from genome wide scans for statistical epistasis. An extensive and strong genome wide high order LD was revealed between pairs of markers on the high density 250k SNP-chip and individual markers revealed by whole genome sequencing in the Arabidopsis thaliana 1001-genomes collection. The high order LD was found to be more prevalent in smaller populations, but present also in samples including several hundred individuals. An empirical example illustrates that high order LD might be an even greater challenge in cases when the genetic architecture is more complex than the common assumption of bi-allelic loci. The example shows how significant statistical epistasis is detected for a pair of markers in high order LD with a complex multi allelic locus. Overall, our study illustrates the importance of considering also other explanations than functional genetic interactions when genome wide statistical epistasis is detected, in particular when the results are obtained in small populations of inbred individuals. [ABSTRACT FROM AUTHOR]

Abstract: Theory on indirect genetic effects (IGEs) indicates that variation in the genetic composition of social groups can generate GxG epistasis that may promote the evolution of stable polymorphisms. Using a livebearing fish with a genetic polymorphism in coloration and associated behavioral differences, we tested whether genotypes of social partners interacted with focal individual genotypes to influence growth and condition over 16 weeks of development. We found that IGEs had a significant influence on patterns of feeding, regardless of focal fish genotype. There was no influence of social environment on juvenile length, but there was significant GxG epistasis for body condition. Each focal juvenile was in better condition when its own genotype was not present in adult social partners. These data are consistent with negative frequency‐dependent selection in which each morph performs better when it is rare. Neither variation in feeding nor activity‐related behaviors explained variation in body condition, suggesting that GxG epistasis for condition was caused by physiological differences between the two genotypes. These findings indicate that GxG epistasis in a given polymorphism can generate fitness landscapes that contribute to the maintenance of that polymorphism and to maintenance of genetic variation for additional fitness‐related traits. [ABSTRACT FROM AUTHOR]

The impact of epistasis on the evolution of multi-locus traits depends on recombination. While sexually reproducing eukaryotes recombine so frequently that epistasis between polymorphisms is not considered to play a large role in short-term adaptation, many bacteria also recombine, some to the degree that their populations are described as "panmictic" or "freely recombining." However, whether this recombination is sufficient to limit the ability of selection to act on epistatic contributions to fitness is unknown. We quantify homologous recombination in five bacterial pathogens and use these parameter estimates in a multilocus model of bacterial evolution with additive and epistatic effects. We find that even for highly recombining species (e.g., Streptococcus pneumoniae or Helicobacter pylori), selection on weak interactions between distant mutations is nearly as efficient as for an asexual species, likely because homologous recombination typically transfers only short segments. However, for strong epistasis, bacterial recombination accelerates selection, with the dynamics dependent on the amount of recombination and the number of loci. Epistasis may thus play an important role in both the short- and long-term adaptive evolution of bacteria, and, unlike in eukaryotes, is not limited to strong effect sizes, closely linked loci, or other conditions that limit the impact of recombination. [ABSTRACT FROM AUTHOR]

Two-locus two-allele models are among the most studied models in population genetics. The reason is that they are the simplest models to explore the role of epistasis for a variety of important evolutionary problems, including the maintenance of polymorphism and the evolution of genetic incompatibilities. Many specific types of models have been explored. However, due to the mathematical complexity arising from the fact that epistasis generates linkage disequilibrium, few general insights have emerged. Here, we study a simpler problem by assuming that linkage disequilibrium can be ignored. This is a valid approximation if selection is sufficiently weak relative to recombination. The goal of our paper is to characterize all possible equilibrium structures, or more precisely and general, all robust phase portraits or evolutionary flows arising from this weak-selection dynamics. For general fitness matrices, we have not fully accomplished this goal, because some cases remain undecided. However, for many specific classes of fitness schemes, including additive fitnesses, purely additive-by-additive epistasis, haploid selection, multilinear epistasis, marginal overdominance or underdominance, and the symmetric viability model, we obtain complete characterizations of the possible equilibrium structures and, in several cases, even of all possible phase portraits. A central point in our analysis is the inference of the number and stability of fully polymorphic equilibria from the boundary flow, i.e., from the dynamics at the four marginal single-locus subsystems. The key mathematical ingredient for this is index theory. The specific form of epistasis has both a big influence on the possible boundary flows as well as on the internal equilibrium structure admitted by a given boundary flow. [ABSTRACT FROM AUTHOR]

Frequency-independent selection is generally considered as a force that acts to reduce the genetic variation in evolving populations, yet rigorous arguments for this idea are scarce. When selection fluctuates in time, it is unclear whether frequencyindependent selection may maintain genetic polymorphism without invoking additional mechanisms. We show that constant frequency-independent selection with arbitrary epistasis on a well-mixed haploid population eliminates genetic variation if we assume linkage equilibrium between alleles. To this end, we introduce the notion of frequency-independent selection at the level of alleles, which is sufficient to prove our claim and contains the notion of frequency-independent selection on haploids. When selection and recombination are weak but of the same order, there may be strong linkage disequilibrium; numerical calculations show that stable equilibria are highly unlikely. Using the example of a diallelic two-locus model, we then demonstrate that frequency-independent selection that fluctuates in time can maintain stable polymorphism if linkage disequilibrium changes its sign periodically. We put our findings in the context of results from the existing literature and point out those scenarios in which the possible role of frequencyindependent selection in maintaining genetic variation remains unclear. [ABSTRACT FROM AUTHOR]

For over a decade functional gene-to-gene interaction (epistasis) has been suspected to be a determinant in the "missing heritability" of complex traits. However, searching for epistasis on the genome-wide scale has been challenging due to the prohibitively large number of tests which result in a serious loss of statistical power as well as computational challenges. In this article, we propose a two-stage method applicable to existing case-control data sets, which aims to lessen both of these problems by pre-assessing whether a candidate pair of genetic loci is involved in epistasis before it is actually tested for interaction with respect to a complex phenotype. The pre-assessment is based on a two-locus genotype independence test performed in the sample of cases. Only the pairs of loci that exhibit non-equilibrium frequencies are analyzed via a logistic regression score test, thereby reducing the multiple testing burden. Since only the computationally simple independence tests are performed for all pairs of loci while the more demanding score tests are restricted to the most promising pairs, genome-wide association study (GWAS) for epistasis becomes feasible. By design our method provides strong control of the type I error. Its favourable power properties especially under the practically relevant misspecification of the interaction model are illustrated. Ready-to-use software is available. Using the method we analyzed Parkinson's disease in four cohorts and identified possible interactions within several SNP pairs in multiple cohorts. [ABSTRACT FROM AUTHOR]

A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap10, is associated with the autoinflammatory disorder Behçet's disease (BD) in epistasis with HLA-B*51, which is the main risk factor for this disorder. The role of Hap10 in BD pathogenesis is unknown. We sought to define the effects of Hap10 on the HLA-B*51 peptidome and to distinguish these effects from those due to HLA-B*51 polymorphisms unrelated to disease. The peptidome of the BD-associated HLA-B*51:08 subtype expressed in a Hap10-positive cell line was isolated, characterized by mass spectrometry, and compared with the HLA-B*51:01 peptidome from cells expressing more active ERAP1 allotypes. We additionally performed synthetic peptide digestions with recombinant ERAP1 variants and estimated peptide-binding affinity with standard algorithms. In the BD-associated ERAP1 context of B*51:08, longer peptides were generated; of the two major HLA-B*51 subpeptidomes with Pro-2 and Ala-2, the former one was significantly reduced, and the latter was increased and showed more ERAP1-susceptible N-terminal residues. These effects were readily explained by the low activity of Hap10 and the differential susceptibility of X-Pro and X-Ala bonds to ERAP1 trimming and together resulted in a significantly altered peptidome with lower affinity. The differences due to ERAP1 were clearly distinguished from those due to HLA-B*51 subtype polymorphism, which affected residue frequencies at internal positions of the peptide ligands. The alterations in the nature and affinity of HLA-B*51·peptide complexes probably affect T-cell and natural killer cell recognition, providing a sound basis for the joint association of ERAP1 and HLA-B*51 with BD. [ABSTRACT FROM AUTHOR]

The relative role of drift versus selection underlying the evolution of bacterial species within the gut microbiota remains poorly understood. The large sizes of bacterial populations in this environment suggest that even adaptive mutations with weak effects, thought to be the most frequently occurring, could substantially contribute to a rapid pace of evolutionary change in the gut. We followed the emergence of intra-species diversity in a commensal Escherichia coli strain that previously acquired an adaptive mutation with strong effect during one week of colonization of the mouse gut. Following this first step, which consisted of inactivating a metabolic operon, one third of the subsequent adaptive mutations were found to have a selective effect as high as the first. Nevertheless, the order of the adaptive steps was strongly affected by a mutational hotspot with an exceptionally high mutation rate of 10−5. The pattern of polymorphism emerging in the populations evolving within different hosts was characterized by periodic selection, which reduced diversity, but also frequency-dependent selection, actively maintaining genetic diversity. Furthermore, the continuous emergence of similar phenotypes due to distinct mutations, known as clonal interference, was pervasive. Evolutionary change within the gut is therefore highly repeatable within and across hosts, with adaptive mutations of selection coefficients as strong as 12% accumulating without strong constraints on genetic background. In vivo competitive assays showed that one of the second steps (focA) exhibited positive epistasis with the first, while another (dcuB) exhibited negative epistasis. The data shows that strong effect adaptive mutations continuously recur in gut commensal bacterial species. [ABSTRACT FROM AUTHOR]

Poor inhibitory processing of negative emotional content is central to many psychiatric disorders, including depression and anxiety. Moreover, increasing evidence suggests that core aspects of emotion-inhibitory processing are largely inherited and as such may represent a key intermediate or risk-related phenotype for common affective diseases (e.g., unipolar depressive, anxiety disorders). The current study employed a candidate-gene approach in order to most effectively examine this complex behavioral phenotype. We examined the novel interaction between BDNF (Val66Met) and TPH2 (rs4570625) polymorphisms and their influence on behavioral inhibition of negative emotion in two independent investigations of healthy adults. BDNF Met carriers consistently report greater symptoms of affective disease and display corresponding behavioral rigidity, while TPH2 T carriers display poor inhibitory processing. These genotypes are traditionally perceived as ‘risk’ genotypes when compared to their respective major Val and G homozygous genotypes, but evidence is mixed. Recent studies in humans and mutant mouse models suggest biological epistasis between BDNF and genes involved in serotonin regulation. Moreover, polymorphisms in the TPH2 gene may have greater influence on serotonergic function than other more commonly studied polymorphisms (e.g., 5-HTTLPR). We observed consistent evidence across two different emotion-inhibition paradigms, one with high internal validity (Study 1, n = 119) and one with high ecological validity (Study 2, n = 115) that the combination of Val/Val and G/G genotypes was clearly associated with impaired inhibition of negative emotional content. This was followed by individuals carrying the BDNF—Met allele (including Met/Val and Met/Met) when combined with the TPH2—T allele (including T/G and T/T combinations). The consistency of these results across tasks and studies suggests that these two groups may be particularly vulnerable to the most common psychiatric disorders and should be targets for future clinical investigation. [ABSTRACT FROM AUTHOR]

The inflammatory diseases that are most strongly associated with major histocompatibility Complex class I (MHC-I) alleles are also influenced by endoplasmic reticulum aminopeptidase (ERAP) 1 and/or 2, often in epistasis with the susceptibility MHC-I allele. This review will focus on the four major MHC-I-associated inflammatory disorders: ankylosing spondylitis, birdshot chorioretinopathy, Behçet’s disease and psoriasis. The genetics of ERAP1/ERAP2 association and the alterations induced by polymorphism of these enzymes on the risk MHC-I allotypes will be examined. A pattern emerges of analogous effects on peptide length, sequence and affinity of disparate peptidomes, suggesting that similar peptide-mediated mechanisms underlie the pathogenesis and the joint contribution of ERAP1/ERAP2 and MHC-I to distinct inflammatory diseases. Processing of specific antigens, peptide-dependent changes in global properties of the MHC-I molecules, such as folding and stability, or both may be pathogenic. [ABSTRACT FROM AUTHOR]

Background: In schizophrenia, genetic background may provide a substrate for intrinsic maldevelopment of the brain through environmental influences, by recruiting neurotrophic factors and cytokines, to trigger the changes that lead to impaired neuronal functions. Cytokines being the key regulators of immune/inflammatory reactions are also known to influence the dopaminergic, noradrenergic, and serotonergic neurotransmission. Therefore, functional polymorphisms in cytokine genes may result in imbalances in the pro- and anti-inflammatory cytokine production.Methods: We screened polymorphisms in pro- and anti-inflammatory cytokine genes using a case-control association study in a South Indian population. The role of allele, genotype, haplotype, and diplotypes of these cytokine genes and their epistatic interactions were assessed in contributing to the risk of developing schizophrenia. Meta-analysis for the reported associations was also monitored for global significance.Results: The pro-inflammatory cytokine gene polymorphisms in IL1Ars1800587, IL6rs1800796, TNFArs361525, and IFNGrs2069718 were associated with schizophrenia. The study also provides significant evidence for strong epistatic interactions among pro-inflammatory cytokine genes IL6 and IFNG in the development of schizophrenia. In silico analysis suggested that associated risk variants were indicative of altered transcriptional activity with higher production of IL1α, IL-6, TNF-α, and IFN-ɤ cytokines. Meta-analysis indicated heterogeneity among study population while IL1Ars1800587 was found to be globally significant.Conclusions: It is important to identify the nature of inflammatory response that can be amplified by the environment, to influence either Th1 response or Th2 response. The associated functional variants in the study are involved with increased expression resulting in higher production of the pro-inflammatory cytokines IL-1α, IL-6, TNF-α, and IFN-γ. The interaction of immunological stressors with these high producer alleles of pro-inflammatory cytokines may suggest that even a lower threshold may be sufficient to induce a resultant chronic effect on the psycho-social and environmental stressors that may result in the development and pathogenesis of schizophrenia. Understanding environmental factors that influence the expression of these pro-inflammatory cytokine genes or their interaction can possibly help in dissecting the phenotypic variation and therapeutic response to antipsychotics in schizophrenia. [ABSTRACT FROM AUTHOR]

The extent to which epistasis affects the genetic architecture of complex traits is difficult to quantify, and identifying variants in natural populations with epistatic interactions is challenging. Previous studies in Drosophila implicated extensive epistasis between variants in genes that affect neural connectivity and contribute to natural variation in olfactory response to benzaldehyde. In this study, we implemented a powerful screen to quantify the extent of epistasis as well as identify candidate interacting variants using 203 inbred wild-derived lines with sequenced genomes of the Drosophila melanogaster Genetic Reference Panel ( DGRP). We crossed the DGRP lines to P[ GT1]-element insertion mutants in Sema-5c and neuralized ( neur), two neurodevelopmental loci which affect olfactory behavior, and to their coisogenic wild-type control. We observed significant variation in olfactory responses to benzaldehyde among F1 genotypes and for the DGRP line by mutant genotype interactions for both loci, showing extensive nonadditive genetic variation. We performed genome-wide association analyses to identify the candidate modifier loci. None of these polymorphisms were in or near the focal genes; therefore, epistasis is the cause of the nonadditive genetic variance. Candidate genes could be placed in interaction networks. Several candidate modifiers are associated with neural development. Analyses of mutants of candidate epistatic partners with neur ( merry-go-round ( mgr), prospero ( pros), CG10098, Alhambra ( Alh) and CG12535) and Sema-5c ( CG42540 and bruchpilot ( brp)) showed aberrant olfactory responses compared with coisogenic controls. Thus, integrating genome-wide analyses of natural variants with mutations at defined genomic locations in a common coisogenic background can unmask specific epistatic modifiers of behavioral phenotypes. [ABSTRACT FROM AUTHOR]

Summary The interplay between selection and aspects of the genetic architecture of traits (such as linkage, dominance, and epistasis) can either drive or constrain speciation [ 1–3 ]. Despite accumulating evidence that speciation can progress to “intermediate” stages—with populations evolving only partial reproductive isolation—studies describing selective mechanisms that impose constraints on speciation are more rare than those describing drivers. The stick insect Timema cristinae provides an example of a system in which partial reproductive isolation has evolved between populations adapted to different host plant environments, in part due to divergent selection acting on a pattern polymorphism [ 4, 5 ]. Here, we demonstrate how selection on a green/melanistic color polymorphism counteracts speciation in this system. Specifically, divergent selection between hosts does not occur on color phenotypes because melanistic T. cristinae are cryptic on the stems of both host species, are resistant to a fungal pathogen, and have a mating advantage. Using genetic crosses and genome-wide association mapping, we quantify the genetic architecture of both the pattern and color polymorphism, illustrating their simple genetic control. We use these empirical results to develop an individual-based model that shows how the melanistic phenotype acts as a “genetic bridge” that increases gene flow between populations living on different hosts. Our results demonstrate how variation in the nature of selection acting on traits, and aspects of trait genetic architecture, can impose constraints on both local adaptation and speciation. [ABSTRACT FROM AUTHOR]

Adiponectin appears to play an important role in the development and progression of several obesity-related malignancies. Also, overexpression of survivin, an inhibitor of apoptosis protein, is associated with increased risk of cancers. The aim of this study was to investigate the association between two polymorphisms in the adiponectin gene and endometrial cancer (EC) risk. We also investigated whether epistasis between surviving and adiponectin gene polymorphisms are associated with EC risk in an Iranian population. The samples comprised formalin-fixed, paraffin-embedded tissue sections obtained from the archive of the pathology department, Imam-Khomeini Hospital and Firouzgar hospital. After DNA extraction the genotyping was performed using PCR-RFLP technique. Single nucleotide polymorphisms (SNPs) in adiponectin (rs1063539, rs2241766) and survivin (rs9904341) gene were evaluated in the study. The increased frequency of ADIPOQ rs1063539C allele (CC + CG genotype) was associated with decreased EC risk [OR: 0.39(0.17–0.90)]. Survivin rs9904341C allele (CC + CG genotype) was associated with increased EC risk [crude OR: 2.75(1.27–5.95), adjusted OR: 2.93(1.27–6.76)]. We observed an epistatic interaction between survivin rs9904341 CC + CG genotype and ADIPOQ rs1063539 GG genotype increasing the risk of EC compared to those with other genotypes [OR: 4.86(1.88–12.54), P = 0.001]. Our findings indicate that adiponectin might have a modulatory effect on survivin role and function in EC, which requires further investigation. [ABSTRACT FROM AUTHOR]

Epistasis helps to explain how multiple single-nucleotide polymorphisms (SNPs) interact to cause disease. A variety of tools have been developed to detect epistasis. In this article, we explore the strengths and weaknesses of an information theory approach for detecting epistasis and compare it to the logistic regression approach through simulations. We consider several scenarios to simulate the involvement of SNPs in an epistasis network with respect to linkage disequilibrium patterns among them and the presence or absence of main and interaction effects. We conclude that the information theory approach more efficiently detects interaction effects when main effects are absent, whereas, in general, the logistic regression approach is appropriate in all scenarios but results in higher false positives. We compute epistasis networks for SNPs in the FSD1L gene using a two-phase head and neck cancer genomewide association study involving 2,185 cases and 4,507 controls to demonstrate the practical application of the methods. [ABSTRACT FROM AUTHOR]

Virtually all psychiatric traits are genetically complex. This article discusses the genetics of complex traits in psychiatry. The complexity is accounted for by numerous factors, including multiple risk alleles, epistasis, and epigenetic effects such as methylation. Risk alleles can individually be common or rare, and can include, for example, single nucleotide polymorphisms and copy number variants that are transmitted or are new mutations, and other kinds of variation. Many different kinds of variation can be important for trait risk, either together in various proportions or as different factors in different subjects. Until more recently, approaches to complex traits were limited, and consequently only a few variants, usually of individually minor effect, were identified. At the present time, a much richer armamentarium exists that includes the routine application of genome-wide association studies and next-generation high-throughput sequencing and the combination of this information with other biologically relevant information, such as expression data. We have also seen the emergence of large meta-analysis and mega-analysis consortia. These developments are extremely important for psychiatric genetics, have advanced the field substantially, and promise formidable gains in the years to come as they are applied more widely. [ABSTRACT FROM AUTHOR]

Abnormalities in the enzymatic activity of catechol-O-methyltransferase (COMT) contribute to chronic pain conditions, such as temporomandibular disorders (TMD). Thus, we sought to determine the effects of polymorphisms in COMT and functionally related pain genes in the COMT pathway (estrogen receptor 1 [ESR1], guanosine-5-triphosphate cyclohydrolase 1 [GCH1], methylenetetrahydrofolate reductase [MTHFR]) on COMT enzymatic activity, musculoskeletal pain, and pain-related intermediate phenotypes among TMD cases and healthy control subjects. Results show that the COMT rs4680 ( val 158 met ) polymorphism is most strongly associated with outcome measures, such that individuals with the minor A allele (met) exhibit reduced COMT activity, increased TMD risk, and increased musculoskeletal pain. Epistatic interactions were observed between the COMT rs4680 polymorphism and polymorphisms in GCH1 and ESR1. Among individuals with the COMT met allele, those with 2 copies of the GCH1 rs10483639 minor G allele exhibit normalized COMT activity and increased mechanical pain thresholds. Among individuals with the COMT val allele, those with 2 copies of the ESR1 rs3020377 minor A allele exhibit reduced COMT activity, increased bodily pain, and poorer self-reported health. These data reveal that the GCH1 minor G allele confers a protective advantage among met carriers, whereas the ESR1 minor A allele is disadvantageous among val carriers. Furthermore, these data suggest that the ability to predict the downstream effects of genetic variation on COMT activity is critically important to understanding the molecular basis of chronic pain conditions. [ABSTRACT FROM AUTHOR]

Higher cognitive performance, maintenance of mental health and psychological well-being require adequate prefrontal cortex (PFC) function. “Inverted U-shaped” dopamine model indicates optimal PFC dopamine level is important to attain its function while high or low levels have adverse effects. Catechol-O-methyltransferase ( COMT ) and methylenetetrahydrofolate reductase ( MTHFR ) may be involved in this complex non-linear PFC dopamine regulation. We addressed whether genetic variation reflecting COMT and MTHFR activities can explain the inter-individual mental health differences in healthy Japanese men ( n = 188). The mental health was measured by Mental Health Inventory (MHI)-5 score. The rs4633–rs4818–rs4680 haplotypes were used to represent the multilevel COMT activities, while for MTHFR , the functional single polymorphism, rs1801133 (C677T), was used. We examined the effectiveness of haplotype-based association analysis of COMT on mental health together with studying its interaction with MTHFR -C677T. As a result, the relation between activity-ranked COMT genotype and MHI-5 score showed a tendency to fit into an “inverted U-shaped” quadratic curve ( P = 0.054). This curvilinear correlation was significant in the subjects with MTHFR -CC ( P < 0.001), but not with MTHFR T-allele carriers ( P = 0.793). Our pilot study implies a potential influence of COMT and MTHFR genotypic combination on normal variation of mental health. [ABSTRACT FROM AUTHOR]

A key question in evolutionary genomics is how populations navigate the adaptive landscape in the presence of epistasis, or interactions among loci. This problem can be directly addressed by studying the evolution of RNA secondary structures, for which there is constraint to maintain pairing between Watson-Crick (WC) sites. Replacement of a nucleotide at one site of a WC pair reduces fitness by disrupting binding, which can be restored via a compensatory replacement at the interacting site. Here, I present the first genome-scale analysis of epistasis on the RNA secondary structure of human immunodeficiency virus type 1 (HIV-1). Comparison of polymorphism frequencies at ancestrally conserved sites reveals that selection against replacements is ∼2.7 times stronger at WC than at non-WC sites, such that nearly 50% of constraint can be attributed to epistasis. However, almost all epistatic constraint is due to selection against conversions of WC pairs to unpaired (UP) nucleotides, whereas conversions to GU wobbles are only slightly deleterious. This disparity is also evident in pairs with second-site compensatory replacements; conversions from UP nucleotides to WC pairs increase median fitness by ∼4.2%, whereas conversions from GU wobbles to WC pairs only increase median fitness by ∼0.3%. Moreover, second-site replacements that convert UP nucleotides to GU wobbles also increase median fitness by ∼4%, indicating that such replacements are nearly as compensatory as those that restore WC pairing. Thus, WC peaks of the HIV-1 epistatic adaptive landscape are connected by high GU ridges, enabling the viral population to rapidly explore distant peaks without traversing deep UP valleys. [ABSTRACT FROM AUTHOR]

The genotype-fitness map plays a fundamental role in shaping the dynamics of evolution. However, it is difficult to directly measure a fitness landscape in practice, because the number of possible genotypes is astronomical. One approach is to sample as many genotypes as possible, measure their fitnesses, and fit a statistical model of the landscape that includes additive and pairwise interactive effects between loci. Here, we elucidate the pitfalls of using such regressions by studying artificial but mathematically convenient fitness landscapes. We identify two sources of bias inherent in these regression procedures, each of which tends to underestimate high fitnesses and overestimate low fitnesses. We characterize these biases for random sampling of genotypes as well as samples drawn from a population under selection in the Wright- Fisher model of evolutionary dynamics. We show that common measures of epistasis, such as the number of monotonically increasing paths between ancestral and derived genotypes, the prevalence of sign epistasis, and the number of local fitness maxima, are distorted in the inferred landscape. As a result, the inferred landscape will provide systematically biased predictions for the dynamics of adaptation. We identify the same biases in a computational RNAfolding landscape as well as regulatory sequence binding data treated with the same fitting procedure. Finally, we present a method to ameliorate these biases in some cases. [ABSTRACT FROM AUTHOR]

Background Drought is one of the most important abiotic stresses that cause drastic reduction in rice grain yield (GY) in rainfed environments. The identification and introgression of QTL leading to high GY under drought have been advocated to be the preferred breeding strategy to improve drought tolerance of popular rice varieties. Genetic control of GY under reproductive-stage drought stress (RS) was studied in two BC1F4 mapping populations derived from crosses of Kali Aus, a drought-tolerant aus cultivar, with high-yielding popular varieties MTU1010 and IR64. The aim was to identify QTL for GY under RS that show a large and consistent effect for the trait. Bulk segregant analysis (BSA) was used to identify significant markers putatively linked with high GY under drought. Results QTL analysis revealed major-effect GY QTL: qDTY1.2, qDTY2.2 and qDTY1.3, qDTY2.3(DTY; Drought grain yield) under drought consistently over two seasons in Kali Aus/2*MTU1010 and Kali Aus/2*IR64 populations, respectively. qDTY1.2 and qDTY2.2 explained an additive effect of 288 kg ha-1 and 567 kg ha-1 in Kali Aus/2*MTU1010, whereas qDTY1.3 and qDTY2.3 explained an additive effect of 198 kg ha-1 and 147 kg ha-1 in Kali Aus/2*IR64 populations, respectively. Epistatic interaction was observed for DTF (days to flowering) between regions on chromosome 2 flanked by markers RM154-RM324 and RM263-RM573 and major epistatic QTL for GY showing interaction between genomic locations on chromosome 1 at marker interval RM488-RM315 and chromosome 2 at RM324-RM263 in 2012 DS and 2013 DS RS in Kali Aus/2*IR64 mapping populations. Conclusion The QTL, qDTY1.2, qDTY1.3, qDTY2.2, and qDTY2.3, identified in this study can be used to improve GY of mega varieties MTU1010 and IR64 under different degrees of severity of drought stress through marker-aided backcrossing and provide farmers with improved varieties that effectively combine high yield potential with good yield under drought. The observed epistatic interaction for GY and DTF will contribute to our understanding of the genetic basis of agronomically important traits and enhance predictive ability at an individualized level in agriculture. [ABSTRACT FROM AUTHOR]

Epistasis is the phenomenon whereby one polymorphism's effect on a trait depends on other polymorphisms present in the genome. The extent to which epistasis influences complex traits and contributes to their variation is a fundamental question in evolution and human genetics. Although often demonstrated in artificial gene manipulation studies in model organisms, and some examples have been reported in other species, few examples exist for epistasis among natural polymorphisms in human traits. Its absence from empirical findings may simply be due to low incidence in the genetic control of complex traits, but an alternative view is that it has previously been too technically challenging to detect owing to statistical and computational issues. Here we show, using advanced computation and a gene expression study design, that many instances of epistasis are found between common single nucleotide polymorphisms (SNPs). In a cohort of 846 individuals with 7,339 gene expression levels measured in peripheral blood, we found 501 significant pairwise interactions between common SNPs influencing the expression of 238 genes (P < 2.91 × 10−16). Replication of these interactions in two independent data sets showed both concordance of direction of epistatic effects (P = 5.56 × 10−31) and enrichment of interaction P values, with 30 being significant at a conservative threshold of P < 9.98 × 10−5. Forty-four of the genetic interactions are located within 5 megabases of regions of known physical chromosome interactions (P = 1.8 × 10−10). Epistatic networks of three SNPs or more influence the expression levels of 129 genes, whereby one cis-acting SNP is modulated by several trans-acting SNPs. For example, MBNL1 is influenced by an additive effect at rs13069559, which itself is masked by trans-SNPs on 14 different chromosomes, with nearly identical genotype-phenotype maps for each cis-trans interaction. This study presents the first evidence, to our knowledge, for many instances of segregating common polymorphisms interacting to influence human traits. [ABSTRACT FROM AUTHOR]

Haptoglobin (Hp) scavenges free hemoglobin following malaria-induced hemolysis. Few studies have investigated the relationship between the common Hp variants and the risk of severe malaria, and their results are inconclusive. We conducted a case-control study of 996 children with severe Plasmodium falciparum malaria and 1220 community controls and genotyped for Hp, hemoglobin (Hb) S heterozygotes, and α+thalassemia. Hb S heterozygotes and α+thalassemia homozygotes were protected from severe malaria (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.07-0.1 Sand OR, 0.69; 95% Cl, 0.53-0.91, respectively). The risk of severe malaria also varied by Hp genotype: Hp2-1 was associated with the greatest protection against severe malaria and Hp2-2 with the greatest risk. Meta- analysis of the current and published studies suggests that Hp2-2 is associated with increased risk of severe malaria compared with Hp2-1. We found a significant interaction between Hp genotype and oα+thalassemia in predicting risk of severe malaria: Hp2-1 in combination with heterozygous or homozygous α+thalassemia was associated with protection from severe malaria (OR, 0.73; 95% Cl, 0.54-0.99 and OR, 0.48; 95% Cl, 0.32-0.73, respectively), but α+thalassemia in combination with Hp2-2 was not protective. This epistatic interaction together with varying frequencies of α+thaIassemia across Africa may explain the inconsistent relationship between Hp genotype and malaria reported in previous studies. [ABSTRACT FROM AUTHOR]

Ecological opportunities promote population divergence into coexisting lineages. However, the genetic mechanisms that enable new lineages to exploit these opportunities are poorly understood except in cases of single mutations. We examined how two Escherichia coli lineages diverged from their common ancestor at the outset of a long-term coexistence. By sequencing genomes and reconstructing the genetic history of one lineage, we showed that three mutations together were sufficient to produce the frequency-dependent fitness effects that allowed this lineage to invade and stably coexist with the other. These mutations all affected regulatory genes and collectively caused substantial metabolic changes. Moreover, the particular derived alleles were critical for the initial divergence and invasion, indicating that the establishment of this polymorphism depended on specific epistatic interactions. [ABSTRACT FROM AUTHOR]

The killer cell immunoglobulin-like receptor ( KIR)-human leukocyte antigen ( HLA) interaction represents an example of genetic epistasis, where the concomitant presence of specific genes or alleles encoding receptor-ligand units is necessary for the activity of natural killer ( NK) cells. Although KIR and HLA genes segregate independently, they co-evolved under environmental pressures to maintain particular KIR-HLA functional blocks for species survival. We investigated, in 270 Italian healthy individuals, the distribution of KIR and HLA polymorphisms in three climatic areas (from cold north to warm south), to verify their possible geographical stratification. We analyzed the presence of 13 KIR genes and genotyped KIR ligands belonging to HLA class I: HLA-C, HLA-B and HLA-A. We did not observe any genetic stratification for KIR genes and HLA-C ligands in Italy. By contrast, in a north-to-south direction, we found a decreasing trend for the HLA-A3 and HLA-A11 ligands ( P = 0.012) and an increasing trend for the HLA-B ligands carrying the Bw4 epitope ( P = 0.0003) and the Bw4 Ile80 epitope ( P = 0.0005). The HLA-A and HLA-B KIR ligands were in negative linkage disequilibrium (correlation coefficient −0.1211), possibly as a consequence of their similar function in inhibiting NK cells. The distribution of the KIR-HLA functional blocks was different along Italy, as we observed a north-to-south ascending trend for KIR3DL1, when coupled with HLA-B Bw4 ligands ( P = 0.0067) and with HLA-B Bw4 Ile80 ( P = 0.0027), and a descending trend for KIR3DL2 when coupled with HLA-A3 and HLA-A11 ligands ( P = 0.0044). Overall, people from South Italy preferentially use the KIR3DL1-HLA-B Bw4 functional unit, while those from the North Italy equally use both the KIR3DL2-HLA-A3/ A11 and the KIR3DL1-HLA-B Bw4 functional units to fight infections. Thus, only KIR3DL receptors, which exert the unique role of microbial sensors through the specific D0 domain, and their cognate HLA-A and HLA-B ligands are selectively pressured in Italy according to geographical north-to-south distribution. [ABSTRACT FROM AUTHOR]

One of the central goals of evolutionary biology is to explain and predict the molecular basis of adaptive evolution. We studied the evolution of genetic networks in Saccharomyces cerevisiae (budding yeast) populations propagated for more than 200 generations in different nitrogen-limiting conditions. We find that rapid adaptive evolution in nitrogen-poor environments is dominated by the de novo generation and selection of copy number variants (CNVs), a large fraction of which contain genes encoding specific nitrogen transporters including PUT4, DUR3 and DAL4. The large fitness increases associated with these alleles limits the genetic heterogeneity of adapting populations even in environments with multiple nitrogen sources. Complete identification of acquired point mutations, in individual lineages and entire populations, identified heterogeneity at the level of genetic loci but common themes at the level of functional modules, including genes controlling phosphatidylinositol-3-phosphate metabolism and vacuole biogenesis. Adaptive strategies shared with other nutrient-limited environments point to selection of genetic variation in the TORC1 and Ras/PKA signaling pathways as a general mechanism underlying improved growth in nutrient-limited environments. Within a single population we observed the repeated independent selection of a multi-locus genotype, comprised of the functionally related genes GAT1, MEP2 and LST4. By studying the fitness of individual alleles, and their combination, as well as the evolutionary history of the evolving population, we find that the order in which these mutations are acquired is constrained by epistasis. The identification of repeatedly selected variation at functionally related loci that interact epistatically suggests that gene network polymorphisms (GNPs) may be a frequent outcome of adaptive evolution. Our results provide insight into the mechanistic basis by which cells adapt to nutrient-limited environments and suggest that knowledge of the selective environment and the regulatory mechanisms important for growth and survival in that environment greatly increase the predictability of adaptive evolution. [ABSTRACT FROM AUTHOR]

Mutations in PRPF31 are responsible for autosomal dominant retinitis pigmentosa (adRP, RP11 form) and affected families show nonpenetrance. Differential expression of the wildtype PRPF31 allele is responsible for this phenomenon: coinheritance of a mutation and a higher expressing wildtype allele provide protection against development of disease. It has been suggested that a major modulating factor lies in close proximity to the wildtype PRPF31 gene on Chromosome 19, implying that a cis-acting factor directly alters PRPF31 expression. Variable expression of CNOT3 is one determinant of PRPF31 expression. This study explored the relationship between CNOT3 (a trans-acting factor) and its paradoxical cis-acting nature in relation to RP11. Linkage analysis on Chromosome 19 was performed in mutation-carrying families, and the inheritance of the wildtype PRPF31 allele in symptomatic-asymptomatic sibships was assessed-confirming that differential inheritance of wildtype chromosome 19q13 determines the clinical phenotype ( P < 2.6 × 10−7). A theoretical model was constructed that explains the apparent conflict between the linkage data and the recent demonstration that a trans-acting factor ( CNOT3) is a major nonpenetrance factor: we propose that this apparently cis-acting effect arises due to the intimate linkage of CNOT3 and PRPF31 on Chromosome 19q13-a novel mechanism that we have termed ' linked trans-acting epistasis.' [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do single nucleotide polymorphisms (SNPs) or synergistic interactions between SNPs and diplotypes within the insulin-like growth factor 2 receptor (IGF2R) and ADAM metallopeptidase with thrombospondin type 1 motif, 19 (ADAMTS19), contribute to premature ovarian failure (POF)? SUMMARY ANSWER Synergistic interactions were detected between SNPs, including a non-synonymous SNP, and diplotypes within IGF2R and ADAMTS19 which may contribute to POF; however, there was no correlation with POF in a single SNP model after Bonferroni correction. WHAT IS KNOWN ALREADY IGF2R regulates free IGF2 level, which is involved in steroidogenesis in bovine granulosa cells. ADAMTS19 expression is higher in the murine embryonic ovary than in the embryonic testis during sexual differentiation, and an ADAMTS19 SNP (rs246246) showed a possible association with POF in a genome-wide association study in Caucasian women. STUDY DESIGN, SIZE, DURATION This study analyzed interactions between SNPs and diplotypes within IGF2R and ADAMTS19 as well as SNPs within the two genes. In Stage I, a total of 120 patients with POF and 152 female controls were recruited. All patients were diagnosed with POF at the CHA hospital in Seoul, Korea, and were recruited between 1994 and 2004. The 152 controls were recruited from Chungju, Korea, as part of another study that was conducted from April 2002 to March 2004. For Stage II, we obtained genotype data for an additional 1641 female controls, recruited in Ansung and Ansan from 2001 to 2008, from the Korean Genome Epidemiology Study (KoGES). PARTICIPANTS/MATERIALS, SETTING, METHODS In Stage I, the GoldenGate assay with VeraCode technology was used to genotype SNPs in IGF2R and ADAMTS19. In Stage II, we obtained genotype data for IGF2R and ADAMTS19 using Affymetrix Genome-Wide Human SNP array 5.0 and imputed data by the IMPUTE program from the KoGES. To identify POF-associated SNPs, logistic regression analysis in an additive model was performed using the PLINK tool. Synergistic interactions between SNPs and diplotypes within IGF2R and ADAMTS19 were analyzed by logistic regression analysis in three alternative models. MAIN RESULTS AND THE ROLE OF CHANCE In Stage I, 13 combinations of SNPs showed significant synergistic interactions after Bonferroni correction [the strongest association had odds ratio (OR) = 5.77, 95% confidence interval (CI): 2.26–14.75, P = 0.00025]. In Stage II and combined analyses, two and four combinations, respectively, of the significant results in Stage I showed significant synergistic interactions after Bonferroni correction. For interactions between diplotypes in block 2 of IGF2R and block 3 of ADAMTS19 in Stage I, we found 17 synergistic interactions with P < 0.0001, but there was no significant interaction after Bonferroni correction. In Stage II and combined analyses, we found that three and seven combinations in the same blocks, respectively, showed significant synergistic interactions after Bonferroni correction (strongest association: OR = 4.12, 95% CI: 2.22–7.62, P = 6.74E−06). LIMITATIONS, REASONS FOR CAUTION The sample size for patients with POF in this study was small but, compared with recent reports describing associations between SNPs and POF and considering the low prevalence of POF (1%), the sample size is considered to be reasonable. These results should be confirmed in large-scale studies involving different ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS Our results may ultimately provide predictive markers for women at a high risk of POF. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2009-0093821, ... [ABSTRACT FROM PUBLISHER]

Background: Determining the complex relationship between diseases, polymorphisms in human genes and environmental factors is challenging. Multifactor dimensionality reduction (MDR) has proven capable of effectively detecting statistical patterns of epistasis. However, MDR has its weakness in accurately assigning multi-locus genotypes to either high-risk and low-risk groups, and does generally not provide accurate error rates when the case and control data sets are imbalanced. Consequently, results for classification error rates and odds ratios (OR) may provide surprising values in that the true positive (TP) value is often small. Methodology/Principal Findings: To address this problem, we introduce a classifier function based on the ratio between the percentage of cases in case data and the percentage of controls in control data to improve MDR (MDR-ER) for multi-locus genotypes to be classified correctly into high-risk and low-risk groups. In this study, a real data set with different ratios of cases to controls (1∶4) was obtained from the mitochondrial D-loop of chronic dialysis patients in order to test MDR-ER. The TP and TN values were collected from all tests to analyze to what degree MDR-ER performed better than MDR. Conclusions/Significance: Results showed that MDR-ER can be successfully used to detect the complex associations in imbalanced data sets. [ABSTRACT FROM AUTHOR]

Contemporary genetic studies are revealing the genetic complexity of many traits in humans and model organisms. Two hallmarks of this complexity are epistasis, meaning gene-gene interaction, and pleiotropy, in which one gene affects multiple phenotypes. Understanding the genetic architecture of complex traits requires addressing these phenomena, but interpreting the biological significance of epistasis and pleiotropy is often difficult. While epistasis reveals dependencies between genetic variants, it is often unclear how the activity of one variant is specifically modifying the other. Epistasis found in one phenotypic context may disappear in another context, rendering the genetic interaction ambiguous. Pleiotropy can suggest either redundant phenotype measures or gene variants that affect multiple biological processes. Here we present an R package, R/cape, which addresses these interpretation ambiguities by implementing a novel method to generate predictive and interpretable genetic networks that influence quantitative phenotypes. R/cape integrates information from multiple related phenotypes to constrain models of epistasis, thereby enhancing the detection of interactions that simultaneously describe all phenotypes. The networks inferred by R/cape are readily interpretable in terms of directed influences that indicate suppressive and enhancing effects of individual genetic variants on other variants, which in turn account for the variance in quantitative traits. We demonstrate the utility of R/cape by analyzing a mouse backcross, thereby discovering novel epistatic interactions influencing phenotypes related to obesity and diabetes. R/cape is an easy-to-use, platform-independent R package and can be applied to data from both genetic screens and a variety of segregating populations including backcrosses, intercrosses, and natural populations. The package is freely available under the GPL-3 license at http://cran.r-project.org/web/packages/cape. [ABSTRACT FROM AUTHOR]

Epistatic interactions between mutant sites in the same protein can exert a strong influence on pathways of molecular evolution. We performed protein engineering experiments that revealed pervasive epistasis among segregating amino acid variants that contribute to adaptive functional variation in deer mouse hemoglobin (Hb). Amino acid mutations increased or decreased Hb-O2 affinity depending on the allelic state of other sites. Structural analysis revealed that epistasis for Hb-O2 affinity and allosteric regulatory control is attributable to indirect interactions between structurally remote sites. The prevalence of sign epistasis for fitness-related biochemical phenotypes has important implications for the evolutionary dynamics of protein polymorphism in natural populations. [ABSTRACT FROM AUTHOR]

Background: Applying a statistical method implies identifying underlying (model) assumptions and checking their validity in the particular context. One of these contexts is association modeling for epistasis detection. Here, depending on the technique used, violation of model assumptions may result in increased type I error, power loss, or biased parameter estimates. Remedial measures for violated underlying conditions or assumptions include data transformation or selecting a more relaxed modeling or testing strategy. Model-Based Multifactor Dimensionality Reduction (MB-MDR) for epistasis detection relies on association testing between a trait and a factor consisting of multilocus genotype information. For quantitative traits, the framework is essentially Analysis of Variance (ANOVA) that decomposes the variability in the trait amongst the different factors. In this study, we assess through simulations, the cumulative effect of deviations from normality and homoscedasticity on the overall performance of quantitative Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect 2-locus epistasis signals in the absence of main effects. Methodology: Our simulation study focuses on pure epistasis models with varying degrees of genetic influence on a quantitative trait. Conditional on a multilocus genotype, we consider quantitative trait distributions that are normal, chi-square or Student's t with constant or non-constant phenotypic variances. All data are analyzed with MB-MDR using the built-in Student's t-test for association, as well as a novel MB-MDR implementation based on Welch's t-test. Traits are either left untransformed or are transformed into new traits via logarithmic, standardization or rank-based transformations, prior to MB-MDR modeling. Results: Our simulation results show that MB-MDR controls type I error and false positive rates irrespective of the association test considered. Empirically-based MB-MDR power estimates for MB-MDR with Welch's t-tests are generally lower than those for MB-MDR with Student's t-tests. Trait transformations involving ranks tend to lead to increased power compared to the other considered data transformations. Conclusions: When performing MB-MDR screening for gene-gene interactions with quantitative traits, we recommend to first rank-transform traits to normality and then to apply MB-MDR modeling with Student's t-tests as internal tests for association. [ABSTRACT FROM AUTHOR]

It has increasingly been recognized that adapting populations of microbes contain not one, but many lineages continually arising and competing at once. This process, termed "clonal interference," alters the rate and dynamics of adaptation and biases winning mutations toward those with the largest selective effect. Here we uncovered a dramatic example of clonal interference between multiple similar mutations occurring at the same locus within replicate populations of Methylobacterium extorquens AM1. Because these mutational events involved the transposition of an insertion sequence into a narrow window of a single gene, they were both readily detectable at low frequencies and could be distinguished due to differences in insertion sites. This allowed us to detect up to 17 beneficial alleles of this type coexisting in a single population. Despite conferring a large selective benefit, the majority of these alleles rose and then fell in frequency due to other lineages emerging that were more fit. By comparing allele-frequency dynamics to the trajectories of fitness gains by these populations, we estimated the fitness values of the genotypes that contained these mutations. Collectively across all populations, these alleles arose upon backgrounds with a wide range of fitness values. Within any single population, however, multiple alleles tended to rise and fall synchronously during a single wave of multiple genotypes with nearly identical fitness values. These results suggest that alleles of large benefit arose repeatedly in failed "soft sweeps" during narrow windows of adaptation due to the combined effects of epistasis and clonal interference. [ABSTRACT FROM AUTHOR]

Abstract: We tested human participants on a modified peak procedure in order to investigate the relation between interval timing and reward processing, and examine the interaction of this relation with three different dopamine-related gene polymorphisms. These gene polymorphisms affected the expression of catechol-o-methyltransferase, which catabolizes synaptic dopamine primarily in the prefrontal cortex (COMT Val158Met polymorphism), D2 dopamine receptors primarily in the striatum (DRD2/ANKK1-Taq1a polymorphism), and dopamine transporters, which clear synaptic dopamine in the striatum (DAT 3′ VNTR variant). The inclusion of these polymorphisms allowed us to investigate dissociable aspects of the dopamine system and their interaction with reward magnitude manipulations in shaping timed behavior. These genes were chosen for their roles in reward processing and cortico-striatal information processing that have been implicated for interval timing. Consistent with recent animal studies, human participants initiated their timed anticipatory responding earlier when expecting a larger reward in the absence of any changes in the timing of response termination or perceived time. This effect however was specific to two out of four evaluated COMT and DRD2 polymorphism combinations that lead to high prefrontal dopamine coupled with high D2 density and low prefrontal dopamine coupled with low D2 density. Larger rewards also decreased timing precision indices, some of which interacted with the COMT polymorphism. Furthermore, the COMT polymorphism that leads to higher prefrontal dopamine resulted in weaker manifestation of memory variability (relative to threshold variability) in timed behavior. There was no effect of DAT polymorphisms on any of the core behavioral measures. These results suggest that the reward modulates decision thresholds rather than clock speed, and that these effects are specific to COMT and DRD2 epistasis effects that presumably constitute a balanced prefrontal and striatal dopamine transmission. [Copyright &y& Elsevier]

STUDY QUESTION Does synergism between AR(CAG)n and CYP19(TTTA)n polymorphisms influence the quality of sperm? SUMMARY ANSWER AR(CAG)n and CYP19(TTTA)n polymorphisms had a synergistic effect on sperm concentration and motility. WHAT IS KNOWN ALREADY Androgens exert their action in the testicular tissue by binding to androgen receptor (AR), while their action is mediated by the aromatase P450 enzyme (CYP19). AR(CAG)n alleles are associated with sperm motility and CYP19(TTTA)n allelic variants have implications for sperm concentration and motility. STUDY DESIGN, SIZE, DURATION Two hundred oligozoospermic and 250 normozoospermic men who presented for infertility investigation were examined during a period of 2 years. PARTICIPANTS/MATERIALS, SETTING, METHODS Conventional semen analysis was performed. DNA was extracted from spermatozoa and both polymorphisms were genotyped by polymerase chain reaction. Serum hormone levels were determined. MAIN RESULTS AND THE ROLE OF CHANCE Six combined genotypes were identified between the 18 AR(CAG)n alleles with 12–32 repeats and the 6 CYP19(TTTA)n alleles with 7–12 repeats. A gradual reduction in the sperm concentration (106/ml) and motility (%) from long AR allele–non-CYP19(TTTA)7 allele carriers to long AR allele–CYP19(TTTA)7 homozygotes and from short AR allele–non-CYP19(TTTA)7 carriers to short AR allele–CYP19(TTTA)7 homozygotes was observed in normozoospermic men (means ± SD; concentration: 93 ± 53.1 versus 65 ± 48.6 and 85 ± 60.1 versus 37 ± 17.2l, P < 0.002; motility: 63 ± 10.3 versus 55 ± 14.5 and 52 ± 19.6 versus 41 ± 13.7, P < 0.001, respectively). Similar associations were observed in oligozoospermic men (concentration: 10 ± 4.2 versus 9 ± 5.9 and 10 ± 6.3 versus 6 ± 3.1, P < 0.03; motility: 47 ± 17.1 versus 39 ± 6.2 and 39 ± 22 versus 27 ± 18.3, P < 0.003, respectively). The above associations of the combined genotypes with sperm concentration and motility were confirmed in the total study population (P < 0.006 and P < 0.001, respectively). LIMITATIONS, REASONS FOR CAUTION Our study population was limited to Greek Caucasian adult males, residents of Northwest Greece. WIDER IMPLICATIONS OF THE FINDINGS The confirmation of our findings in other populations would verify the significance of AR and CYP19 genes for spermatogenesis. STUDY FUNDING/COMPETING INTERESTS This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. The authors declare no conflicts of interest. [ABSTRACT FROM PUBLISHER]

Several confirmed genetic susceptibility loci involved in the interferon signaling and Th17/B cell response for SLE in Chinese Han populations have been described. Available data also indicate that sex-specific genetic differences contribute to SLE susceptibility. The aim of this study was to test for gene-gene/gene-sex epistasis (interactions) in these known lupus susceptibility loci. Six single-nucleotide polymorphisms (SNPs) in MiR146a, IRF5, IKZF1, ETS1 and IL21 were genotyped by Sequenom MassArray system. A total of 1,825 subjects (858 SLE patients and 967 controls) were included in the final analysis. Epistasis was tested by additive model, multiplicative model and multifactor dimensionality reduction (MDR) method. Additive interaction analysis revealed interactions between IRF5 and IKZF1 (OR 2.26, 95% CI 1.48-3.44 [P = 1.21×104]). A similar tendency was also observed between IL21 and ETS1 by parametric methods. In addition, multiple high dimensional gene-gene or gene-sex interactions (three-and four-way) were identified by MDR analysis. Our study identified novel gene-gene/gene-sex interactions in lupus. Furthermore, these findings highlight sex, interferon pathway, and Th17/B cells as important contributors to the pathogenesis of SLE. [ABSTRACT FROM AUTHOR]

Psoriasis was until recently regarded as a T-cell-driven disease with presumed (auto)immune mechanisms as its primary cause. This view was supported by clinical data and genetic studies that identified risk factors functioning in adaptive and innate immunity, such as HLA-C*06, ERAP1, the IL-23 pathway, and NF-κB signaling. Candidate gene approaches and genome-wide association studies, however, have identified copy number polymorphisms of the β-defensin cluster and deletion of late cornified envelope (LCE) 3B and 3C genes (LCE3C_LCE3B-del) as psoriasis risk factors. As these genes are expressed in epithelial cells and not by the immune system, these findings may cause a change of paradigm for psoriasis, not unlike the reported filaggrin association that has profoundly changed the views on atopic dermatitis. In addition to genetic polymorphisms of the immune system, genetic variations affecting the skin barrier are likely to contribute to psoriasis. Recent studies have shown epistatic interactions involving HLA-C*06, ERAP1, and LCE3C_LCE3B-del, which makes psoriasis a unique model to investigate genetic and biological interactions of associated genes in a complex disease. We present a model for disease initiation and perpetuation, which integrates the available genetic, immunobiological, and clinical data. [ABSTRACT FROM AUTHOR]

Epistasis-nonlinear genetic interactions between polymorphic loci-is the genetic basis of canalization and speciation, and epistatic interactions can be used to infer genetic networks affecting quantitative traits. However, the role that epistasis plays in the genetic architecture of quantitative traits is controversial. Here, we compared the genetic architecture of three Drosophila life history traits in the sequenced inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and a large outbred, advanced intercross population derived from 40 DGRP lines (Flyland). We assessed allele frequency changes between pools of individuals at the extremes of the distribution for each trait in the Flyland population by deep DNA sequencing. The genetic architecture of all traits was highly polygenic in both analyses. Surprisingly, none of the SNPs associated with the traits in Flyland replicated in the DGRP and vice versa. However, the majority of these SNPs participated in at least one epistatic interaction in the DGRP. Despite apparent additive effects at largely distinct loci in the two populations, the epistatic interactions perturbed common, biologically plausible, and highly connected genetic networks. Our analysis underscores the importance of epistasis as a principal factor that determines variation for quantitative traits and provides a means to uncover genetic networks affecting these traits. Knowledge of epistatic networks will contribute to our understanding of the genetic basis of evolutionarily and clinically important traits and enhance predictive ability at an individualized level in medicine and agriculture. [ABSTRACT FROM AUTHOR]

We study the trajectory of an allele that affects a polygenic trait selected toward a phenotypic optimum. Furthermore, conditioning on this trajectory we analyze the effect of the selected mutation on linked neutral variation. We examine the well- characterized two-locus two-allele model but we also provide results for diallelic models with up to eight loci. First, when the optimum phenotype is that of the double heterozygote in a two-locus model, and there is no dominance or epistasis of effects on the trait, the trajectories of selected mutations rarely reach fixation; instead, a polymorphic equilibrium at both loci is approached. Whether a polymorphic equilibrium is reached (rather than fixation at both loci) depends on the intensity of selection and the relative distances to the optimum of the homozygotes at each locus. Furthermore, if both loci have similar effects on the trait, fixation of an allele at a given locus is less likely when it starts at low frequency and the other locus is polymorphic (with alleles at intermediate frequencies). Weaker selection increases the probability of fixation of the studied allele, as the polymorphic equilibrium is less stable in this case. When we do not require the double heterozygote to be at the optimum we find that the polymorphic equilibrium is more difficult to reach, and fixation becomes more likely. Second, increasing the number of loci decreases the probability of fixation, because adaptation to the optimum is possible by various combinations of alleles. Summaries of the genealogy (height, total length, and imbalance) and of sequence polymorphism (number of polymorphisms, frequency spectrum, and haplotype structure) next to a selected locus depend on the frequency that the selected mutation approaches at equilibrium. We conclude that multilocus response to selection may in some cases prevent selective sweeps from being completed, as described in previous studies, but that conditions causing this to happen strongly depend on the genetic architecture of the trait, and that fixation of selected mutations is likely in many instances. [ABSTRACT FROM AUTHOR]

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and α2B-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p<0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment. [ABSTRACT FROM AUTHOR]

Abstract: Background: Complex behaviors such as suicidal behavior likely exhibit gene–gene interactions. The main aim of this study is to explore potential single nucleotide polymorphisms combinations with epistatic effect in suicidal behavior using a data mining tool (Multifactor Dimensionality Reduction). Methods: Genomic DNA from peripheral blood samples was analyzed using SNPlex Technology. Multifactor Dimensionality Reduction was used to detect epistatic interactions between single nucleotide polymorphisms from the main central nervous system (CNS) neurotransmitters (dopamine: 9; noradrenaline: 19; serotonin: 23; inhibitory neurotransmitters: 60) in 889 individuals (417 men and 472 women) aged 18years or older (585 psychiatric controls without a history of suicide attempts, and 304 patients with a history of suicide attempts). Individual analysis of association between single nucleotide polymorphisms and suicide attempts was estimated using logistic regression models. Results: Multifactor Dimensionality Reduction showed significant epistatic interactions involving four single nucleotide polymorphisms in female suicide attempters with a classification test accuracy of 60.7% (59.1%–62.4%, 95% CI): rs1522296, phenylalanine hydroxylase gene (PAH); rs7655090, dopamine receptor D5 gene (DRD5); rs11888528, chromosome 2 open reading frame 76, close to diazepam binding inhibitor gene (DBI); and rs2376481, GABA-A receptor subunit γ3 gene (GABRG3). The multivariate logistic regression model confirmed the relevance of the epistatic interaction [OR(95% CI)=7.74(4.60–13.37)] in females. Conclusions: Our results suggest an epistatic interaction between genes of all monoamines and GABA in female suicide attempters. [Copyright &y& Elsevier]

Objective: To identify whether epistasis between TG and HSD17B4 and whether polymorphisms in HSD17B4 are associated with premature ovarian failure (POF). Design: Case-control genetic association study. Setting: Research laboratory of a university. Patient(s): Female patients with POF (98) and controls (218) of Korean ethnicity participated in this study. Intervention(s): None. Main Outcome Measure(s): Genotype distribution, haplotype (HT) inference, and gene–gene interaction. Result(s): Distribution of one haplotype (A-G-A-A-G-G) on the HSD17B4 gene was significantly different between the POF group and the control group in a dominant model. In addition, the combined effect of the single nucleotide polymorphisms (SNPs) HSD17B4 rs28943592 and TG rs2076740 was significantly associated with POF (odds ratio = 7.74, 95% confidence interval = 1.67–35.94), although a significant association was not observed in the single SNP model. Conclusion(s): A haplotype in the HSD17B4 gene was identified that was significantly associated with resistance to POF. In addition, epistasis between two missense SNPs (rs28943592, rs2076740) located in HSD17B4 and TG was significantly associated with susceptibility to POF. [Copyright &y& Elsevier]

Abstract: Background: Based on biological interactions between the serotonergic system and the brain-derived neurotrophic factor (BDNF), BDNF is a plausible candidate for a gene–gene–environment interaction moderating the interaction between the s/l- promoter polymorphism of the serotonin transporter (5-HTTLPR) and childhood abuse. We tested the hypothesis of a three-way interaction with respect to depressive symptoms. Methods: 2035 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and the Childhood Trauma Questionnaire. All subjects were genotyped for the BDNF Val66Met (rs6265) and the s/l 5-HTTLPR polymorphisms. Results: Tobit regression analyses revealed a three-way-interaction between the three genotypes of 5-HTTLPR and the BDNF genotypes and overall childhood abuse for the BDI-II score (p =0.02). Emotional abuse carried the main effect of the interaction (p =0.008). The s/s genotype of the 5-HTTLPR exerted its negative impact on mental health after childhood abuse only in the presence of the BDNF Val/Val genotype but not in the presence of the BDNF Met allele. In contrast, the l allele of the 5-HTTLPR also emerged as a genetic risk factor for depression in carriers of one or two Met alleles. Conclusions: Our results point to a gene–gene–environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms. [Copyright &y& Elsevier]

Abstract: Objective: The epistasis influence of vascular homeostasis genes is vital to multigenetic diseases. This study was designed to perceive the possible role of epistasis in the etiology of essential hypertension. Methods: We investigated seven polymorphisms of ACE, CYP11B2 and NOS3 epistatically, and SBP, DBP, MAP, ACE activity, plasma aldosterone concentration (PAC) and NOx level in 860 age- and ethnicity-matched unrelated north-Indian subjects. Results: The hypertension risk in individuals with interacted-genotypes (IwIw+IwIc)+(4aa), (IcIc)+(4bb+4ba) and IcIc+4aa of the CYP11B2 and NOS3 was significantly higher with odds ratio 5.5 (95% CI=2.9–10.6, P <0.0001), 2.4 (95% CI=1.4–4.1, P <0.0008) and 7.5 (95% CI=1.6–34.8, P =0.010), respectively. The odds ratio for hypertension with interacted-haplotypes (−344T/Ic)+(−922A/−786T/4a/894G) and (−344T/Ic)+(−922G/−786C/4a/894G) of CYP11B2 and NOS3 was 5.3 (95% CI=2.0–14.2, P =0.005) and 3.9 (95% CI=1.4–10.4, P =0.04), respectively; whereas for the protective interacted-haplotypes (−344T/Iw)+(−922A/−786T/4b/894G), the odds ratio was 0.7 (95% CI=0.5–0.9, P =0.03). While the interacted-genotypes, IcIc+4aa correlated with higher SBP and MAP (P =0.006; P =0.04), the interacted-haplotypes, (−344T/Ic)+(−922A/−786T/4a/894G) and (−344T/Ic)+(−922G/−786C/4a/894G) correlated with higher MAP and lower NOx level (P =0.02 and P =0.03, respectively), and the protective interacted-haplotypes (−344T/Iw)+(−922A/−786T/4b/894G) correlated with lower PAC and MAP (P =0.024 and P =0.018, respectively). Conclusions: The epistasis between CYP11B2 and NOS3 and its correlation with varied clinical and biochemical parameters signify its possible contribution in the complex etiology of hypertension. [Copyright &y& Elsevier]

9012AB is a recessive epistatic genic male sterility (REGMS) two - type line of Brassica napus L. The sterility is controlled by two recessive duplicate genes ms3ms3ms4ms4 and one recessive epistatic inhibitor gene espesp. To effectively identify REGMS lines and their temporary maintainer lines, five AFLP (amplified fragment length polymorphism) markers (L1, L2, L3, L4, L5) in couple to esp and two AFLP markers (L6, L7) in repulsion to esp were identified through screening 1 024 primer combinations using 9012B and T45 segregation population. All the seven markers were located on one the same side of esp gene. Markers L6 and L7 co - segregated with Esp gene. Markers L1, L6 and L7 were successfully converted into SCAR (sequence characterized amplified region) markers as SCL1, SCL2 and WSCL3, respectively. The accuracy rates of SCL1, SCL2 and WSCL3 were 90% , 100% and 100% , respectively. Result showed their potential in marker assisted selection of 9012AB. [ABSTRACT FROM AUTHOR]

Abstract: Population subdivision and migration are generally considered to be important causes of linkage disequilibrium (LD). We explore the combined effects of recombination and gene flow on the amount of LD, the maintenance of polymorphism, and the degree of local adaptation in a subdivided population by analyzing a diploid, deterministic continent–island model with genic selection on two linked loci (i.e., no dominance or epistasis). For this simple model, we characterize explicitly all possible equilibrium configurations. Simple and intuitive approximations for many quantities of interest are obtained in limiting cases, such as weak migration, weak selection, weak or strong recombination. For instance, we derive explicit expressions for the measures and (the squared correlation in allelic state) of LD. They depend in qualitatively different ways on the migration rate. Remarkably high values of are maintained between weakly linked loci, especially if gene flow is low. We determine how the maximum amount of gene flow that admits preservation of the locally adapted haplotype, hence of polymorphism at both loci, depends on recombination rate and selection coefficients. We also investigate the evolution of differentiation by examining the invasion of beneficial mutants of small effect that are linked to an already present, locally adapted allele. Mutants of much smaller effect can invade successfully than predicted by naive single-locus theory provided they are at least weakly linked. Finally, the influence of linkage on the degree of local adaptation, the migration load, and the effective migration rate at a neutral locus is explored. We discuss possible consequences for the evolution of genetic architecture, in particular, for the emergence of clusters of tightly linked, slightly beneficial mutations and the evolution of recombination and chromosome inversions. [Copyright &y& Elsevier]

Poly (ADP-ribose) polymerase 1 (PARP1), which plays a critical role in the base excision DNA repair mechanism, and matrix metallopeptidase 2 (MMP2), a member of the matrix metalloprotease family, are involved in tumor formation and metastasis, respectively. In the present study, the possible association of single nucleotide polymorphisms (SNPs) and gene-gene interaction between PARP1 and MMP2 with the increased incidence of gastric cancer (GC) development and lymph node metastasis (LNM) was investigated in a Korean population. Samples were obtained from 326 patients with chronic gastritis and 153 patients with GC and genotyped using the GoldenGate® method. The PARP1 rs1136410 genotype showed a significant association with the frequency of LNM of GC (odds ratio [OR] = 2.19, p = 0.02), LNM stage ( p = 0.035), and tumor invasion ( p = 0.035). The allele frequency of MMP2 rs243865 was not associated with the development of GC or with the development of LNM of GC. Epistasis between the PARP1 SNP and the MMP2 SNP was associated with the development of LNM of GC. The combination of the MMP2 rs243865 CC genotype and the PARP1 rs1136410 CC or CC+CT genotypes showed a high risk of LNM of GC (OR = 2.47, p = 0.01; OR = 2.28, p = 0.01, respectively). In summary, PARP1 is associated with the risk of LNM of GC and the stage of LNM and tumor invasion. Epistasis between PARP1 rs1136410 and MMP2 rs243865 increased the risk of LNM of GC. [ABSTRACT FROM AUTHOR]

Abstract: Aging is a complex phenotype with multiple determinants but a strong genetic component significantly impacts on survival to extreme ages. The dysregulation of immune responses occurring with increasing age is believed to contribute to human morbidity and mortality. Conversely, some genetic determinants of successful aging might reside in those polymorphisms for the immune system genes regulating immune responses. Here we examined the main effects of single loci and multi-locus interactions to test the hypothesis that the adenosine deaminase (ADA) and tumor necrosis factor alpha (TNF-α) genes may influence human life-expectancy. ADA (22G>A, rs73598374) and TNF-α (−308G>A, rs1800629; −238G>A, rs361525) functional SNPs have been determined for 1071 unrelated healthy individuals from Central Italy (18–106years old) divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes: for men (women), the first class consists of individuals <66years old (<73years old), the second class of individuals 66–88years old (73–91years old), and the third class of individuals >88years old (>91years old). Single-locus analysis showed that only ADA 22G>A is significantly associated with human life-expectancy in males (comparison 1 (age class 2 vs. age class 1), O.R. 1.943, P =0.036; comparison 2 (age class 3 vs. age class 2), O.R. 0.320, P =0.0056). Age- and gender-specific patterns of epistasis between ADA and TNF-α were found using Generalized Multifactor Dimensionality Reduction (GMDR). In comparison 1, a significant two-loci interaction occurs in females between ADA 22G>A and TNF-α −238G>A (Sign Test P =0.011). In comparison 2, both two-loci and three-loci interaction are significant associated with increased life-expectancy over 88years in males. In conclusion, we report that a combination of functional SNPs within ADA and TNF-α genes can influence life-expectancy in a gender-specific manner and that males and females follow different pathways to attain longevity. [Copyright &y& Elsevier]

Epistasis and pleiotropy feature prominently in the genetic architecture of quantitative traits but are difficult to assess in outbred populations. We performed a diallel cross among coisogenic Drosophila P-element mutations associated with hyperaggressive behavior and showed extensive epistatic and pleiotropic effects on aggression, brain morphology, and genome-wide transcript abundance in head tissues. Epistatic interactions were often of greater magnitude than homozygous effects, and the topology of epistatic networks varied among these phenotypes. The transcriptional signatures of homozygous and double heterozygous genotypes derived from the six mutations imply a large mutational target for aggressive behavior and point to evolutionarily conserved genetic mechanisms and neural signaling pathways affecting this universal fitness trait. [ABSTRACT FROM AUTHOR]