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Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of the most consistent pathophysiological findings in depressive disorders. Cortisol signaling is affected by proteins that mediate its cellular responses or alters its availability to mineralocorticoid and glucocorticoid receptors. In our study, we evaluated candidate genes that may influence the risk for depression and suicide due to its involvement in cortisol signaling. The aim of the study was to assess whether the genotypes of these genes are associated with the risk for depression, severity of depressive symptoms, suicidal ideation, and suicide attempts. And whether there is interaction between genes and early-life stress. In this study, 100 healthy controls and 140 individuals with depression were included. The subjects were clinically assessed using the 21-item GRID-Hamilton questionnaires (GRID-HAMD-21), Beck Scale for Suicidal Ideation (BSI), and the Childhood Trauma Questionnaire (CTQ). A robust multifactorial dimensionality reduction analysis was used to characterize the interactions between the genes HSD11B1 , NR3C1, NR3C2 , and MDR1 and early-life stress. It was found a significant association of the heterozygous genotype of the MDR1 gene rs1128503 polymorphism with reduced risk of at least one suicide attempt (OR: 0.08, p = 0.003*) and a reduction in the number of suicide attempts (β = −0.79, p = 0.006*). Furthermore, it was found that the MDR1 rs1228503 and NR3C2 rs2070951 genes interact with early-life stress resulting in a strong association with depression (p = 0.001). Our findings suggest that polymorphisms in the MDR1 and NR3C2 genes and their interaction with childhood trauma may be important biomarkers for depression and suicidal behaviors. [ABSTRACT FROM AUTHOR]

Although genome-wide association studies have identified multiple Alzheimer's disease (AD)-associated loci by selecting the main effects of individual single-nucleotide polymorphisms (SNPs), the interpretation of genetic variance in AD is limited. Based on the linear regression method, we performed genome-wide SNP-SNP interaction on cerebrospinal fluid Aβ 42 to identify potential genetic epistasis implicated in AD, with age, gender, and diagnosis as covariates. A GPU-based method was used to address the computational challenges posed by the analysis of epistasis. We found 368 SNP pairs to be statistically significant, and highly significant SNP-SNP interactions were identified between the marginal main effects of SNP pairs, which explained a relatively high variance at the Aβ 42 level. Our results replicated 100 previously reported AD-related genes and 5 gene-gene interaction pairs of the protein-protein interaction network. Our bioinformatics analyses provided preliminary evidence that the 5-overlapping gene-gene interaction pairs play critical roles in inducing synaptic loss and dysfunction, thereby leading to memory decline and cognitive impairment in AD-affected brains. [ABSTRACT FROM AUTHOR]

The evolvability of proteins stems from their underlying biochemical, biophysical, and genetic properties. Initial states appear to drive the adaptability of proteins. There is mounting evidence, from evolutionary trajectories, that the availability of adaptive mutations is greatly influenced by epistasis. The underlying molecular mechanisms remain largely unexplored, however. Emerging techniques in single-molecule studies are revolutionizing the exploration of molecular heterogeneity in protein ensembles, a cryptic determinant of evolvability, providing a better understanding of this phenomenon. The plethora of biological functions that sustain life is rooted in the remarkable evolvability of proteins. An emerging view highlights the importance of a protein's initial state in dictating evolutionary success. A deeper comprehension of the mechanisms that govern the evolvability of these initial states can provide invaluable insights into protein evolution. In this review, we describe several molecular determinants of protein evolvability, unveiled by experimental evolution and ancestral sequence reconstruction studies. We further discuss how genetic variation and epistasis can promote or constrain functional innovation and suggest putative underlying mechanisms. By establishing a clear framework for these determinants, we provide potential indicators enabling the forecast of suitable evolutionary starting points and delineate molecular mechanisms in need of deeper exploration. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is a membrane-bound organelle responsible for protein folding, lipid synthesis, and calcium homeostasis. Maintenance of ER structural integrity is crucial for proper function, but much remains to be learned about the molecular players involved. To identify proteins that support the structure of the ER, we performed a proteomic screen and identified nodal modulator (NOMO), a widely conserved type I transmembrane protein of unknown function, with three nearly identical orthologs specified in the human genome. We found that overexpression of NOMO1 imposes a sheet morphology on the ER, whereas depletion of NOMO1 and its orthologs causes a collapse of ER morphology concomitant with the formation of membrane-delineated holes in the ER network positive for the lysosomal marker lysosomal-associated protein 1. In addition, the levels of key players of autophagy including microtubule-associated protein light chain 3 and autophagy cargo receptor p62/sequestosome 1 strongly increase upon NOMO depletion. In vitro reconstitution of NOMO1 revealed a "beads on a string" structure likely representing consecutive immunoglobulin-like domains. Extending NOMO1 by insertion of additional immunoglobulin folds results in a correlative increase in the ER intermembrane distance. Based on these observations and a genetic epistasis analysis including the known ER-shaping proteins Atlastin2 and Climp63, we propose a role for NOMO1 in the functional network of ER-shaping proteins. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified many loci associated with Alzheimer's dementia. However, these variants only explain part of the heritability of Alzheimer's disease (AD). As genetic epistasis can be a major contributor to the "missing heritability" of AD, we conducted genome-wide epistasis screening for AD pathologies in 2 independent cohorts. First, we performed a genome-wide epistasis study of AD-related brain pathologies (N max = 1318) in ROS/MAP. Candidate interactions were validated using cerebrospinal fluid biomarkers of AD in ADNI (N max = 1128). Further functional analysis tested the association of candidate interactions with neuroimaging phenotypes. For tau and amyloid-β pathology, we identified 2803 and 464 candidate SNP-SNP interactions, respectively. Associations of candidate SNP-SNP interactions with brain volume and white matter changes from neuroimages provides additional insights into their molecular functions. Transcriptional analysis supported possible gene-gene interactions identified by statistical screening through their co-expression in the brain. In summary, we outlined an exhaustive epistasis analysis to identify novel genetic interactions with potential roles in AD pathologies. We further delved into the functional relevance of candidate interactions by association with neuroimaging phenotypes and analysis of co-expression between corresponding gene pairs. • Genetic interactions help explain the "missing heritability" in Alzheimer's disease. • We conducted a genome-wide epistasis analysis for Alzheimer's disease pathologies. • The epistasis signals were replicated in independent data. • Transcriptome analysis supported the interactions (such as INPP4B / RBFOX1 interaction). • Association with neuroimages provides insights into molecular functions of interactions. [ABSTRACT FROM AUTHOR]

Abstract Background Accumulation of LDL cholesterol (LDL-c) within artery walls is strongly associated with the initiation and progression of atherosclerosis development. This complex trait is affected by multifactor involving polygenes, environments, and their interactions. Uncovering genetic architecture of LDL may help to increase the understanding of the genetic mechanism of cardiovascular diseases. Methods We used a genetic model to analyze genetic effects including additive, dominance, epistasis, and ethnic interactions for data from the Multi-Ethnic Study of Atherosclerosis (MESA). Three lifestyle behaviors (reading, intentional exercising, smoking) were used as cofactor in conditional models. Results We identified 156 genetic effects of 10 quantitative trait SNPs (QTSs) in base model and three conditional models. The total estimated heritability of these genetic effects was approximately 72.88% in the base model. Five genes (CELSR2, MARK2, ADAMTS12, PFDN4 , and MAGI2) have biological functions related to LDL. Conclusions Compared with the based model LDL, the results in three conditional models revealed that intentional exercising and smoking could have impacts for causing and suppressing some of genetic effects and influence the levels of LDL. Furthermore, these two lifestyles could have different genetic effects for each ethnic group on a specific QTS. As most of the heritability in based model LDL and conditional model LDL|Smk was contributed from epistasis effects, our result indicated that epistasis effects played important roles in determining LDL levels. Our study provided useful insight into the biological mechanisms underlying regulation of LDL and might help in the discovery of novel therapeutic targets for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Highlights • Methods used to identify genetic modifiers in polyglutamine diseases have progressed from candidate genes to unbiased genome-wide searches. • Unbiased genome-wide searches may disclose small cumulative effects of key genes and modifying pathways. • Variable results from candidate genes may be due to difference in population heterogeneity, population stratification and study design. • Incorporating network-based strategy may broaden exploration of disease pathophysiology, phenotype prediction and therapeutical target. Abstract Polyglutamine (polyQ) diseases are a group of clinically and genetically heterogeneous neurodegenerative diseases. Expansion size correlates with age-at-onset (AO) and severity, and shows a critical threshold for each polyQ disease. Although an expanded CAG tract is sufficient to trigger disease, not all variation in AO is explained by (CAG) n length, which suggests the contribution of other modifying factors. Methods used to identify genetic modifiers in polyQ diseases have progressed from candidate genes to unbiased genome-wide searches. Inconsistency of results from candidate-genes studies are partly explained by sample size, study design and variable population frequency of "polymorphisms"; a genome-wide search may help elucidating more precise disease mechanisms underlying specific interaction networks. We review known genetic modifiers for polyQ diseases, and discuss developing strategies to find modulation, from common variants to networks disclosing small cumulative effects of key genes and modifying pathways. This may lead to a better understanding of genotype-phenotype correlation and the proposal of new potential targets for therapeutical interventions. [ABSTRACT FROM AUTHOR]

The ability to detect and understand epistasis in natural populations is important for understanding how biological traits are influenced by genetic variation. However, identification and characterization of epistasis in natural populations remains difficult due to statistical issues that arise as a result of multiple comparisons, and the fact that most genetic variants segregate at low allele frequencies. In this review, we discuss how model organisms may be used to manipulate genotypic combinations to power the detection of epistasis as well as test interactions between specific genes. Findings from a number of species indicate that statistical epistasis is pervasive between natural genetic variants. However, the properties of experimental systems that enable analysis of epistasis also constrain extrapolation of these results back into natural populations. Highlights Identification of statistical epistasis in natural populations remains challenging due to the relationship between allele frequency and statistical power. Artificial populations have been constructed in model organisms to detect statistical epistasis between two regions of the genome; however, it is difficult to use these results to understand how epistasis operates in natural populations. Studies of focal perturbations in defined genetic backgrounds suggests that natural selection can influence the types of nonadditive relationships that exist. [ABSTRACT FROM AUTHOR]

Ankylosing spondylitis (AS) is a highly heritable kind of arthritis that affects the vertebral column. AS risk has been associated strongly with Human leukocyte antigen (HLA)-B*27 . In fact, some HLA-B*27 subtypes have been associated with the increased disease risk, although some specific subtypes have not shown such associations. It is supposed that HLA-B*27 plays a major role in the etiopathogenesis of the disease. However, the difference in pathogenic outcomes of HLA-B*27 certain subtypes needs to be clarified. The purpose of this review article is to overview on the detailed implications of the HLA-B*27 subtypes in the etiopathogenesis of AS. Moreover, the role of ERAP1 in AS and its epistasis with HLA-B*27 have been reviewed. [ABSTRACT FROM AUTHOR]

Evolutionary dynamics in laboratory microbial evolution experiments can be surprisingly complex. In the past two decades, observations of these dynamics have challenged simple models of adaptation and have shown that clonal interference, hitchhiking, ecological diversification, and contingency are widespread. In recent years, advances in high-throughput strain maintenance and phenotypic assays, the dramatically reduced cost of genome sequencing, and emerging methods for lineage barcoding have made it possible to observe evolutionary dynamics at unprecedented resolution. These new methods can now begin to provide detailed measurements of key aspects of fitness landscapes and of evolutionary outcomes across a range of systems. These measurements can highlight challenges to existing theoretical models and guide new theoretical work towards the complications that are most widely important. [ABSTRACT FROM AUTHOR]

Antibiotics target essential cellular functions but bacteria can become resistant by acquiring either exogenous resistance genes or chromosomal mutations. Resistance mutations typically occur in genes encoding essential functions; these mutations are therefore generally detrimental in the absence of drugs. However, bacteria can reduce this handicap by acquiring additional mutations, known as compensatory mutations. Genetic interactions (epistasis) either with the background or between resistances (in multiresistant bacteria) dramatically affect the fitness cost of antibiotic resistance and its compensation, therefore shaping dissemination of antibiotic resistance mutations. This Review summarizes current knowledge on the evolutionary mechanisms influencing maintenance of resistance mediated by chromosomal mutations, focusing on their fitness cost, compensatory evolution, epistasis, and the effect of the environment on these processes. [ABSTRACT FROM AUTHOR]

Introduction Obesity is a serious health problem that leads to low quality of life and early mortality. To the purpose of prevention and gene therapy for such a worldwide disease, genome wide association study is a powerful tool for finding SNPs associated with increased risk of obesity. To conduct an association analysis, kernel machine regression is a generalized regression method, has an advantage of considering the epistasis effects as well as the correlation between individuals due to unknown factors. Materials and methods In this study, information of the people who participated in Tehran cardio-metabolic genetic study was used. They were genotyped for the chromosomal region, evaluation 986 variations located at 16q12.2; build 38hg. Kernel machine regression and single SNP analysis were used to assess the association between obesity and SNPs genotyped data. Results We found that associated SNP sets with obesity, were almost in the FTO (P = 0.01), AIKTIP (P = 0.02) and MMP2 (P = 0.02) genes. Moreover, two SNPs, i.e., rs10521296 and rs11647470, showed significant association with obesity using kernel regression (P = 0.02). Conclusion In conclusion, significant sets were randomly distributed throughout the region with more density around the FTO, AIKTIP and MMP2 genes. Furthermore, two intergenic SNPs showed significant association after using kernel machine regression. Therefore, more studies have to be conducted to assess their functionality or precise mechanism. [ABSTRACT FROM AUTHOR]

Adaptive protein evolution may be facilitated by neutral amino acid mutations that confer no benefit when they first arise but which potentiate subsequent function-altering mutations via direct or indirect structural mechanisms. Theoretical and empirical results indicate that such compensatory interactions (intramolecular epistasis) can exert a strong influence on trajectories of protein evolution. For this reason, assessing the form and prevalence of intramolecular epistasis and characterizing biophysical mechanisms of compensatory interaction are important research goals at the nexus of structural biology and molecular evolution. Here I review recent insights derived from protein-engineering studies, and I describe an approach for identifying and characterizing mechanisms of epistasis that integrates experimental data on structure-function relationships with analyses of comparative sequence data. [ABSTRACT FROM AUTHOR]

Where convenient phenotypic readouts are available, saturation mutagenesis coupled to deep sequencing provides a rapid and facile method to infer sequence determinants of protein structure, stability and function. We provide brief descriptions and currently available options for the various steps involved, and mention limitations of current implementations. We also highlight recent applications such as estimating relative stabilities and affinities of protein variants, mapping epitopes, protein model discrimination and prediction of mutant phenotypes. Most mutational scans have so far been applied to single genes and proteins. Additional methodological improvements are required to expand the scope to study intergenic epistasis and intermolecular interactions in macromolecular complexes. [ABSTRACT FROM AUTHOR]

Biology has, and continues to be, shaped by evolutionary mechanisms. Within the past decade, local fitness landscapes have become experimentally tractable and are providing new perspectives on evolutionary mechanisms. Powered by next-generation sequencing, the impacts of all individual amino acid substitutions on function have been quantified for dozens of proteins. These fitness maps have been utilized to investigate the biophysical underpinnings of existing protein function as well as the appearance and enhancement of new protein functions. This review highlights emerging trends from this rapidly growing area of research, including an expanded understanding of the biophysical mechanisms underlying existing and new protein function, the roles epistasis and adaptation play in shaping evolution, and the prediction of disease-causing alleles in humans. [ABSTRACT FROM AUTHOR]

Plant architecture is important for crape myrtle ( Lagerstroemia indica ) cultivation and breeding. To investigate the genetic inheritance of plant architecture traits in Lagerstroemia , a mixed major gene plus polygene inheritance model was employed to analyze three traits in six generations (P 1 , P 2 , F 1 , B 1 , B 2 and F 2 ), including plant height (PH), internode length (IL) and primary lateral branch height (PLBH). The three traits showed extensive coefficient of variation and high broad sense heritability (0.60–0.84). Though transgressive segregations were present, transgressive heterosis was not observed in all the generations. The results showed that the IL fitted the D-0 model, which was followed by a one additive-dominance major gene plus additive-dominance-epistasis polygene genetic model. In addition, the PH and PLBH were quantitative traits fitting the E-0 model, namely two additive-dominance-epistasis major genes plus additive-dominance-epistasis polygene genetic model. The highest heritability of the major gene (83.62%) for the IL was observed in F 2 population, indicating that the IL trait was mainly controlled by genetic factors with a low effect of environmental factors and should be selected in early generations. However, the highest heritabilities of the major genes for the PH and PLBH were 43.23% and 70.29% in B 1 population, indicating that the PH and PLBH should be selected in late generations due to the large effect of environmental factors. Therefore, these findings will provide a theoretical instruction for the QTL mapping and breeding of desirable plant architecture in crape myrtle. [ABSTRACT FROM AUTHOR]

Interferon-γ-induced aminopeptidase ERAP1 trims peptides within the endoplasmic reticulum so that they can be loaded onto MHC class I and presented to the CD8 + T-cells. ERAP1 association and its interaction with HLA-C∗06 is controversial across different populations. We have investigated the association and possible functional role of non-synonymous SNPs at different exons of ERAP1 (rs26653: Arg127Pro, rs30187: Lys528Arg and rs27044: Gln730Glu) and their interactions with HLA-C∗06 in psoriasis. Significant associations of HLA-C∗06 (OR = 5.47, P < 2.2 × 10 −16 ), rs30187 (OR 1.35, P = 7.4 × 10 −4 ) and rs27044 (OR = 1.24, P = 5.8 × 10 −3 ) were observed. All three ERAP1 SNPs showed significant association only for HLA-C∗06 positive patients, while rs30187 and rs27044 showed significant association only for early onset patients (rs30187: OR = 1.47, P = 9.6 × 10 −5 ; rs27044: OR = 1.36, P = 3.3 × 10 −4 ). No differential expression of ERAP1 was observed either between paired uninvolved and involved skin tissues of psoriasis patients or between non-risk and risk variants in the involved skin. Significant epistatic interaction was observed between HLA-C∗06 and the SNP (rs27044) located at the peptide-binding cavity of ERAP1. Evolutionary conservation analysis among mammals showed confinement of Lys528 and Gln730 within highly conserved regions of ERAP1 and suggested the possible detrimental effect of this allele in ERAP1 regulation. [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]

Mycobacterium tuberculosis Beijing genotype strains increasingly circulate in different world regions, either as historical endemic, e.g. in East Asia, or recently imported, e.g. in South America, and this family is regarded as the most successful lineage of the global tuberculosis (TB) epidemic. Here we analysed the transmission capacity of these strains in the context of their phylogenetic background and drug resistance mutations. The study collection included all multidrug resistant (MDR) strains of Beijing genotype isolated in Beijing Chest Hospital, the largest tertiary TB facility in North China, in 2011–2013 ( n  = 278). Strains were subjected to NTF/IS 6110 and 24-loci MIRU-VNTR analysis. Drug resistance mutations were detected in rpoB , katG , inhA and oxyR–ahpC . A total of 58 and 220 strains were assigned to the ancient and modern Beijing sublineages, respectively. 24-MIRU-VNTR clustering was higher in modern versus ancient Beijing strains (35.9% vs. 12.1%; P  <   0.001). After taking into consideration the presence of rpoB and katG mutations, clustering decreased to 15.9% in modern and 0% in ancient strains. The most frequent combination of mutations ( rpoB 531-TTG and katG 315-ACC) was more prevalent in clustered versus non-clustered isolates in the modern sublineage (23/35 vs. 47/185; P  <   0.0001). To conclude, a combination of the known low-fitness-cost rpoB 531-TTG and katG 315-ACC mutations likely facilitates the increased transmission ability of MDR strains of the modern but not ancient Beijing sublineage. Accordingly, positive epistasis of major low-cost drug resistance-conferring mutations is influenced by the phylogenetic background of M. tuberculosis strains. [ABSTRACT FROM AUTHOR]

Potts Hamiltonian models of protein sequence co-variation are statistical models constructed from the pair correlations observed in a multiple sequence alignment (MSA) of a protein family. These models are powerful because they capture higher order correlations induced by mutations evolving under constraints and help quantify the connections between protein sequence, structure, and function maintained through evolution. We review recent work with Potts models to predict protein structure and sequence-dependent conformational free energy landscapes, to survey protein fitness landscapes and to explore the effects of epistasis on fitness. We also comment on the numerical methods used to infer these models for each application. [ABSTRACT FROM AUTHOR]

The contribution of epistasis to human disease remains unclear. However, several studies have now identified epistatic interactions between common variants that increase the risk of a neuropsychiatric disorder, while there is growing evidence that genetic interactions contribute to the pathogenicity of rare, multigenic copy-number variants (CNVs) that have been observed in patients. This review discusses the current evidence for epistatic events and genetic interactions in neuropsychiatric disorders, how paradigm shifts in the phenotypic classification of patients would empower the search for epistatic effects, and how network and cellular models might be employed to further elucidate relevant epistatic interactions. [ABSTRACT FROM AUTHOR]

The present work is the development of a simple and specific kinetic method based on RT-PCR technique coupled with direct sequencing for quantification of various amyloid precursor protein-mRNA isoforms (APP-mRNA isoforms) in biological samples, especially for identifying the most abundant one that may decisive for the normal status or disease risk. Application of this kinetic method to the Lesch-Nyhan disease (LND) was performed and results indicated an epistasis between mutated hypoxanthine phosphoribosyltransferase1 (HPRT1) and APP genes. APP-mRNA isoform of 624 bp, with a deletion starting after 49 bp of the 5′ end of exon 3 followed by a complete deletion of exons 4–15, mutations in exon 1: c.22C > T, p.L18F, and exon 3: c.269A > G, p.Q90R encoding APP 207 isoform, was the most abundant one in most of the LND patients and would be responsible for the neurobehavioral syndrome in these patients. The method is useful for identifying the defective APP-mRNA isoform in LND patients, and in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome, amyotrophic lateral sclerosis, and Alzheimer’s disease, and may pave the way for new strategies applicable to rational antisense drugs design. [ABSTRACT FROM AUTHOR]

Epistasis, the interaction between mutations and the genetic background, is a pervasive force in evolution that is difficult to predict yet derives from a simple principle − biological systems are interconnected. Therefore, one effect may be intimately linked to another, hence interdependent. Untangling epistatic interactions between and within genes is a vibrant area of research. Deriving a mechanistic understanding of epistasis is a major challenge. Particularly, elucidating how epistasis can attenuate the effects of otherwise dominant mutations that control phenotypes. Using the emergence of terpene cyclization in specialized metabolism as an excellent example, this review describes the process of discovery and interpretation of dominance and epistasis in relation to current efforts. Specifically, we outline experimental approaches to isolating epistatic networks of mutations in protein structure, formally quantifying epistatic interactions, then building biochemical models with chemical mechanisms in efforts to achieve an understanding of the physical basis for epistasis. From these models we describe informed conjectures about past evolutionary events that underlie the emergence, divergence and specialization of terpene synthases to illustrate key principles of the constraining forces of epistasis in enzyme function. [ABSTRACT FROM AUTHOR]

The genes interact according to classical mechanisms, namely, complementation, modification, polymery, and epistasis, in the cells and organisms carrying these genes. Here we describe a novel type of gene interaction when the interacting genes reside in parents, whereas the interaction event takes place in their progenies lacking these genes. The conditional mutations in the D. melanogaster male X chromosome caused the “prohibition on producing daughters” in its offspring. The chromosomal rearrangements in chromosomes 2 and 3 of its female partner removed the prohibition. The phenomena of “prohibition” and “removal of prohibition” appeared as a parental effect in both the male and female. Both phenomena ensued from the presence of the studied mutations in parents rather than their unviable or survived progenies. Thus, the gene interaction when the genes themselves are absent at the site of interaction and during the interaction event takes place in drosophila. [ABSTRACT FROM AUTHOR]

All plants must optimize their growth with finite resources. Water use efficiency (WUE) measures the relationship between biomass acquisition and transpired water. In the present study, we performed two experiments to understand the genetic basis of WUE and other parameters of plant-water interaction under control and water-limited conditions. Our study used two inbred natural accessions of Brachypodium distachyon , a model grass species with close phylogenetic affinity to temperate forage and cereal crops. First, we identify the soil water content which causes a reduction in leaf relative water content and an increase in WUE. Second, we present results from a large phenotyping experiment utilizing a recombinant inbred line mapping population derived from these same two natural accessions. We identify QTLs associated with environmentally-insensitive genetic variation in WUE, including a pair of epistatically interacting loci. We also identify QTLs associated with constitutive differences in biomass and a QTL describing an environmentally-sensitive difference in leaf carbon content. Finally, we present a new linkage map for this mapping population based on new SNP markers as well as updated genomic positions for previously described markers. Our studies provide an initial characterization of plant-water relations in B. distachyon and identify candidate genomic regions involved in WUE. [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]

The Lenski experiment investigates the long-term evolution of bacterial populations. In this paper we present an individual-based probabilistic model that captures essential features of the experimental design, and whose mechanism does not include epistasis in the continuous-time (intraday) part of the model, but leads to an epistatic effect in the discrete-time (interday) part. We prove that under some assumptions excluding clonal interference, the rescaled relative fitness process converges in the large population limit to a power law function, similar to the one obtained by Wiser et al. (2013), there attributed to effects of clonal interference and epistasis. [ABSTRACT FROM AUTHOR]

Epistasis in genetics denotes an impact of one gene on the expression of the another genes. This means that so called epistatic gene influences the characteristics of the so called hypostatic genes. As a matter of fact, there is no one-to-one correspondence between genes and traits in nature. On the other hand, values of offspring genes are inherited from the parents genes. In this paper, the impact of epistatic genes in evolutionary computation is studied, where each epistatic gene in offspring depends on the corresponding hypostatic genes of its parents by an epistatic arithmetic crossover used in differential evolution. Thus, epistatic genes are determined by the Cartesian graph product of both parents presented as linear graphs. The epistatic arithmetic crossover is applied as a mutation strategy to the ensemble differential evolution. The results of extensive experiments conducted on CEC-14 function benchmark suite showed a great potential of the proposed algorithm and encouraged us to start to experiment with other graph products as well. [ABSTRACT FROM AUTHOR]

Non-heading Chinese cabbage is one of the most popular leafy vegetables. Three cultivars, ‘Maertou’, ‘Rugaomaocai’ and ‘Suzhouqing’, were crossed to study gene effects and heritability involved in tiller and leaf development. The joint segregation analysis in six generation populations, P 1 , P 2 , F 1 , F 2 , B 1 and B 2 , indicating the influence of major genes mixed with polygenes. The results revealed the traits of tiller number and leaf number in non-heading Chinese cabbage were controlled by two major genes and polygenes with dominant, additive and epistasis effects, respectively. The heritability of the two major genes in F 2 was over 60%, indicating that the genetic factor was the main influence to the leaf number and tiller number traits. Data from the present study revealed that it had a significant positive correlation between tiller number and leaf number in non-heading Chinese cabbage. [ABSTRACT FROM AUTHOR]

Thermostable variants of the Cellulomonas sp. NT3060 glycerol kinase have been constructed by through the introduction of ancestral-consensus mutations. We produced seven mutants, each having an ancestral-consensus amino acid residue that might be present in the common ancestors of both bacteria and of archaea, and that appeared most frequently at the position of 17 glycerol kinase sequences in the multiple sequence alignment. The thermal stabilities of the resulting mutants were assessed by determining their melting temperatures ( T m ), which was defined as the temperature at which 50% of the initial catalytic activity is lost after 15 min of incubation, as well as when the half-life of the catalytic activity occurs at a temperature of 60°C ( t 1/2 ). Three mutants showed increased stabilities compared to the wild-type protein. We then produced five more mutants with multiple amino acid substitutions. Some of the resulting mutants showed thermal stabilities much greater than those expected given the stabilities of the respective mutants with single mutations. Therefore, the effects of mutations are not always simply additive and some amino acid substitutions, which do not affect or only slightly improve stability when individually introduced into the protein, show substantial stabilizing effects in combination with other mutations. [ABSTRACT FROM AUTHOR]

High total homocysteine (tHcy) is associated with cognitive impairment in the elderly. The impact of high tHcy on different cognitive domains deserves further investigation, as does the role of the C677T polymorphism of the 5,10 methylenetetrahydrofolate reductase ( MTHFR ) gene. A cross-sectional analysis of 903 subjects from the population-based “InveCe.Ab” study was performed. The participants had no psychosis or active neurological disorders. They underwent a neuropsychological assessment. Principal component analysis allowed cognitive performance to be condensed into two components: executive functions and memory. Novel components were evaluated for association with tHcy, controlling for potential confounders. Regression models showed that high serum tHcy was associated with lower executive functions, but not with memory. MTHFR C677T TT was associated with higher tHcy but did not affect cognitive performance per se. However, when combined with the apolipoprotein E ( APOE )-ε4 allele, it was a risk factor for lower executive performance, independently of tHcy levels. In summary, high tHcy per se, or MTHFR C677T TT in combination with the APOE -ε4 allele, might be associated primarily with executive dysfunctions rather than memory loss. [ABSTRACT FROM AUTHOR]

Ultrastructural studies on the female gametophyte are restricted to species at relatively derived positions in the angiosperm phylogenetic tree. Therefore, this topic remains mostly unknown for the early-divergent lineages, in which a four-celled megagametophyte is common. Here, ultrastructure of the megagametophyte and micropylar nucellar epidermis was investigated in Cabomba caroliniana A. Gray (Cabombaceae), Nymphaea gardneriana Planch. and Victoria cruziana Orb. (Nymphaeaceae). The micropylar nucellar epidermis of the studied species differentiates into an epistase. These cells have metabolically active cytoplasm and thickened inner tangential walls. Epistase ultrastructure is compatible with a transfer cell specialization. This tissue may play an adaptive role in the secretion of chemotropic substances to direct the pollen tube growth toward the female gametophyte. The cytological characteristics of the female germ unit in members of Cabombaceae and Nymphaeaceae are generally similar to other angiosperms that develop a typical seven-celled, eight-nucleate female gametophyte; however, they differ in some specific points. In V . cruziana and N . gardneriana , the micropylar end of the synergids develops a rudimentary filiform apparatus with slight inward projections. By contrast, the synergids lack a filiform apparatus in C. caroliniana. Unlike most studied angiosperms, the filiform apparatus in the clade Cabombaceae-Nymphaeaceae is underdeveloped or absent, therefore character state transformations have occurred within basal angiosperms. The potential evolutionary shifts of this reproductive feature are highlighted. [ABSTRACT FROM AUTHOR]

Late-onset Alzheimer disease (AD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance, and gene-gene interactions; however, the investigation of interactions in recent genome-wide association studies has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across 13 data sets from the Alzheimer Disease Genetics Consortium. Fifteen single nucleotide polymorphism (SNP)-SNP pairs within 3 gene-gene combinations were identified: SIRT1 × ABCB1 , PSAP × PEBP4 , and GRIN2B × ADRA1A. In addition, we extend a previously identified interaction from an endophenotype analysis between RYR3 × CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1 , and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this article highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis. [ABSTRACT FROM AUTHOR]

Psychiatric disease is believed to result from a combination of genetic vulnerability and environmental influence. At the crux are epigenetic modifications, which mediate the influence of environment on the genome. Twin and genome-wide association studies demonstrate a wide range of heritabilities across psychiatric disorders, while epidemiological and animal models implicate distinct developmental windows where environmental factors may interact with genetic vulnerability to confer risk. Certain developmental periods appear to be more prone to these influences including during gestation, in the early postnatal period, and during periods of major hormonal rearrangement. Here we review the role of environmental factors capable of epigenetic reprogramming during these periods and present evidence for the link between these modifications and disease. The cross tissue relevance of environmentally induced epigenetic change and its utility for identifying peripheral biomarkers is discussed. [ABSTRACT FROM AUTHOR]

Microbial evolution experiments enable us to watch adaptation in real time, and to quantify the repeatability and predictability of evolution by comparing identical replicate populations. Further, we can resurrect ancestral types to examine changes over evolutionary time. Until recently, experimental evolution has been limited to measuring phenotypic changes, or to tracking a few genetic markers over time. However, recent advances in sequencing technology now make it possible to extensively sequence clones or whole-population samples from microbial evolution experiments. Here, we review recent work exploiting these techniques to understand the genomic basis of evolutionary change in experimental systems. We first focus on studies that analyze the dynamics of genome evolution in microbial systems. We then survey work that uses observations of sequence evolution to infer aspects of the underlying fitness landscape, concentrating on the epistatic interactions between mutations and the constraints these interactions impose on adaptation. [ABSTRACT FROM AUTHOR]

Objective The COL4A1 / COL4A2 region on chromosome 13q34 is a highly replicated locus for coronary artery disease (CAD). In the normal arterial wall, type IV collagen acts to inhibit smooth muscle cell proliferation. Its production is in part a function of TGFβ signaling, but the specific regulatory mechanisms, especially in humans, have not been defined. Our aim was to decipher TGFβ signaling components important in the regulation of COL4A1 and COL4A2 and determine whether these components showed genetic interaction with the COL4A1 / COL4A2 locus for CAD association. Methods and results Experiments were performed in primary human aortic smooth muscle cells and HT1080 fibroblasts. Pharmacological inhibition of the TGFβ1 receptor and subsequent SMAD protein phosphorylation by treatment with an ALK5 inhibitor prevented the increase in COL4A1 / COL4A2 mRNA (p < 0.001) and protein expression in response to TGFβ1 stimulation. In contrast, inhibition of the non-canonical TGFβ signaling pathways was without effect. siRNA mediated knockdown of SMAD3 and SMAD4 abolished the stimulatory effects of TGFβ1 on COL4A1/COL4A2 (p < 0.001) whereas SMAD2 knockdown had no effect. In luciferase reporter assays, neither SMAD3 overexpression nor TGFβ1 treatment altered COL4A1 or COL4A2 promoter activity, supportive of more complex regulation of type IV collagen gene expression by the TGFβ/SMAD3 signaling pathway. Epistasis analysis in 5 CAD case/control cohorts revealed that SMAD3 and COL4A1 / COL4A2 display statistical interaction for CAD association. Conclusions These findings demonstrate that SMAD3 is a necessary factor for TGFβ-mediated stimulation of mRNA and protein expression of type IV collagen genes in human vascular smooth muscle cells. Epistasis analyses further supports the hypothesis that the SMAD3-dependent regulation of COL4A1/COL4A2 may be of functional significance for CAD pathogenesis. [ABSTRACT FROM AUTHOR]

Genetic prediction of different hair phenotypes can help reconstruct the physical appearance of an individual whose biological sample is analyzed in criminal and identification cases. Up to date, forensic prediction models for hair colour, hair shape, hair loss and hair greying have been developed, but studies investigating predictability of hair thickness and density traits are missing. First data suggesting overlapping associations in various hair features have emerged in recent years, suggesting partially common genetic basis and molecular mechanisms, and this knowledge can be used for predictive purposes. Here we aim to broaden our understanding of the genetics underlying head, facial and body hair thickness and density traits and examine the association for a set of literature SNPs. We characterize the overlap in SNP association for various hair phenotypes, the extent of genetic interactions and the potential for genetic prediction. The study involved 999 samples from Poland, genotyped for 240 SNPs with targeted next-generation sequencing. Logistic regression methods were applied for association and prediction analyses while entropy-based approach was used for interaction testing. As a result, we refined known associations for monobrow and hairiness (PAX3 , 5q13.2, TBX) and identified two novel association signals in IGFBP5 and VDR. Both genes were among top significant loci, showed broad association with different hair-related traits and were implicated in multiple interaction effects. Overall, for 14.7% of SNPs previously associated with head hair loss and/or hair shape, a positive signal of association was revealed with at least one hair feature studied in the current research. Overlap in association with at least two hair-related traits was demonstrated for 24 distinct loci. We showed that the associated SNPs explain ∼5–30% of the variation observed in particular hair traits and allow moderate accuracy of prediction. The highest accuracy was achieved for hairiness level prediction in females (AUC = 0.69 for the "none", 0.69 for the "low" and 0.76 for the "excessive" hairiness category) and monobrow (AUC = 0.69 for the "none", 0.62 for the "slight" and 0.70 for the "significant" monobrow category) with 33% of the variation in hairiness level in females explained by 7 SNPs and age, and 20% of the variation in monobrow captured by 7 SNPs and sex. Our study presents clear evidence of pleiotropy and epistasis in the genetics of hair traits. The acquired knowledge may have practical application in forensics, as well as in the cosmetic industry and anthropological research. • Pleiotropy and epistasis increase the complexity of human traits determination. • Overlapping associations for hair-related traits demonstrated for 24 literature loci. • Novel associations of the IGFBP5 and VDR genes with hair traits were discovered. • Analysed SNPs explain ∼5–30% of the variation observed in particular hair traits. • Hairiness in females and monobrow predicted with AUC= 0.69 and 0.68, respectively. [ABSTRACT FROM AUTHOR]

Inheritance of sex forms in watermelon ( Citrullus lanatus ) is not well described. In this study, we made five pairs of crosses of watermelon plants with different sex forms and grew progeny in two different seasons to investigate the inheritance of sex forms and the seasonal effect on sex expression. We showed that environmental factors have no effect on sex forms, but they affect sex expression on individual flowers as more pistillate flowers were observed in spring than in autumn. This suggests that short photoperiod and low temperatures promote formation of pistillate flowers in watermelon. In the F 2 population of the cross of andromonoecious (SL3H or AKKZW) × monoecious (XHB), the segregation ratio is 9 monoecious: 3 trimonoecious: 4 andromonoecious, and the segregation ratio in BC 1 P 1 (F 1 × andromonoecious parent) is 1 monoecious: 1 trimonoecious: 2 andromonoecious. The segregation ratio in the F 2 population of the gynoecious (XHBGM) × monoecious (XHB) is 3 monoecious: 1 gynoecious whereas the segregation ratio in the BC 1 P 1 (F 1 × gynoecious parent) is 1 monoecious: 1 gynoecious. The segregation ratio in the F 2 population of gynoecious × andromonecious cross is 27 monoecious: 12 andromonoecious: 9 gynoecious: 9 trimonoecious: 4 hermaphroditic: 3 gynomonoecious. The segregation ratio in the BC 1 P 1 population (F 1 × gynoecious) is 1 monoecious: 1 gynoecious whereas the segregation ratio in the BC 1 P 2 (F 1 × andromonoecious) is 1 monoecious: 1 trimonoecious: 2 andromonoecious. Taken together, the results suggested that three recessive alleles, andromonoecious ( a ), gynoecious ( gy ) and trimonoecious ( tm ) control the sex forms in watermelon, and a allele is epistatic to the tm allele. The following phenotype-genotype relationships are proposed for each of the sex forms in watermelon: monoecious, A_Gy_Tm_ ; trimonoecious , A_Gy_tmtm ; andromonoecious, aaGy_Tm_ or aaGy_tmtm; gynoecious, A_gygyTm_ ; gynomonoecious, A_gygytmtm ; and hermaphroditic, aagygyTm_ or aagygytmtm . [ABSTRACT FROM AUTHOR]

Accumulating evidences suggested that epistasis, interactions between genes, is an important component of the genetic determination of quantitative traits. In present study, four F 2 populations derived from pair wise crosses between 5 single segment substitution lines in the HJX74 background, harboring single QTL for heading date including Hd3a , RFT1 , OsFTL13 , OsMADS50 IR64 and OsMADS50 Lemont were used to characterize the epistasis between QTLs and QTL-by-environment interaction (QEI). Epistasis was found to be present between Hd3a and OsMADS50 IR64 , Hd3a and OsMADS50 Lemont , and RFT1 and OsMADS50 IR64 . The interaction between Hd3a and OsFTL13 was not detected by single environment analysis but detected by across-environment combined analysis. Genetic analysis using a bigenic model showed that the additive and dominant effects were more important than the overall epistatic effects for all pairs of QTLs. The additive-by-additive and additive-by-dominant effects were more important than the dominant-by-dominant effect. QEIs were significant for Hd3a , RFT1 , OsMADS50 IR64 and OsMADS50 Lemont but not for OsFTL13 . The additive-by-environment and dominant-by-environment interaction effects were significant while the epistasis-by-environment interaction was not. Utilization of the known major QTLs for heading date in breeding through gene pyramiding needs take epistasis into consideration. [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]

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]

Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene–gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC , VDR , CYP24A1 , CYP2R1 , and DHCR7 in two independent JIA case-control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene–gene combinations ( e.g. , GC rs1155563 and PTPN2 rs2542151, OR int = 0.45, p = 0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2 , CYP2R1 and VDR , and VDR and PTPN2 , similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case-control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene–gene combinations identified in the discovery sample ( p -values ranging from 5.6 × 10 −9 to 7.5 × 10 −7 ). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated. [ABSTRACT FROM AUTHOR]

The factors that determine the tempo and mode of protein evolution continue to be a central question in molecular evolution. Traditionally, studies of protein evolution focused on the rates of amino acid substitutions. More recently, with the availability of sequence data and advanced experimental techniques, the focus of attention has shifted toward the study of evolutionary trajectories and the overall layout of protein fitness landscapes. In this review we describe the effect of epistasis on the topology of evolutionary pathways that are likely to be found in fitness landscapes and develop a simple theory to connect the number of maladapted genotypes to the topology of fitness landscapes with epistatic interactions. Finally, we review recent studies that have probed the extent of epistatic interactions and have begun to chart the fitness landscapes in protein sequence space. [ABSTRACT FROM AUTHOR]

MLL1, located on human chromosome 11, is disrupted in distinct recurrent chromosomal translocations in several leukemia subsets. Studying the MLL1 gene and its oncogenic variants has provided a paradigm for understanding cancer initiation and maintenance through aberrant epigenetic gene regulation. Here we review the historical development of model systems to recapitulate oncogenic MLL1-rearrangement (MLL-r) alleles encoding mixed-lineage leukemia fusion proteins (MLL-FPs) or internal gene rearrangement products. These largely mouse and human cell/xenograft systems have been generated and used to understand how MLL-r alleles affect diverse pathways to result in a highly penetrant, drug-resistant leukemia. The particular features of the animal models influenced the conclusions of mechanisms of transformation. We discuss significant downstream enablers, inhibitors, effectors, and collaborators of MLL-r leukemia, including molecules that directly interact with MLL-FPs and endogenous mixed-lineage leukemia protein, direct target genes of MLL-FPs, and other pathways that have proven to be influential in supporting or suppressing the leukemogenic activity of MLL-FPs. The use of animal models has been complemented with patient sample, genome-wide analyses to delineate the important genomic and epigenomic changes that occur in distinct subsets of MLL-r leukemia. Collectively, these studies have resulted in rapid progress toward developing new strategies for targeting MLL-r leukemia and general cell-biological principles that may broadly inform targeting aberrant epigenetic regulators in other cancers. [ABSTRACT FROM AUTHOR]

Background Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia. Methods A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions. Results In the exploratory study, ten markers were in significant association with schizophrenia ( P < 0.01). One maker rs14251 ( HDAC3 ) was replicated ( P = 0.04) and remained significant in the whole sample ( P = 0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 ( HDAC9 ), rs7290710 ( HDAC10 ) and rs7634112 ( HDAC11 ) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia. Conclusion This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9 , HDAC10 , and HDAC11 was detected and seems biologically plausible. [ABSTRACT FROM AUTHOR]

The development of advanced medical imaging technologies and high-throughput genomic measurements has enhanced our ability to understand their interplay as well as their relationship with human behavior by integrating these two types of datasets. However, the high dimensionality and heterogeneity of these datasets presents a challenge to conventional statistical methods; there is a high demand for the development of both correlative and integrative analysis approaches. Here, we review our recent work on developing sparse representation based approaches to address this challenge. We show how sparse models are applied to the correlation and integration of imaging and genetic data for biomarker identification. We present examples on how these approaches are used for the detection of risk genes and classification of complex diseases such as schizophrenia. Finally, we discuss future directions on the integration of multiple imaging and genomic datasets including their interactions such as epistasis. [ABSTRACT FROM AUTHOR]

We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) ( p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal ( p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = −0.19, p = 0.0006) and cerebellum (β = −0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach. [ABSTRACT FROM AUTHOR]

A combinatorially complete data set consists of studies of all possible combinations of a set of mutant sites in a gene or mutant alleles in a genome. Among the most robust conclusions from these studies is that epistasis between beneficial mutations often shows a pattern of diminishing returns, in which favorable mutations are less fit when combined than would be expected. Another robust inference is that the number of adaptive evolutionary paths is often limited to a relatively small fraction of the theoretical possibilities, owing largely to sign epistasis requiring evolutionary steps that would entail a decrease in fitness. Here we summarize these and other results while also examining issues that remain unresolved and future directions that seem promising. [ABSTRACT FROM AUTHOR]