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The expression of Neuritin-1 (NRN1), a neurotrophic factor crucial for neurodevelopment and synaptic plasticity, is enhanced by the Brain Derived Neurotrophic Factor (BDNF). Although the receptor of NRN1 remains unclear, it is suggested that NRN1's activation of the insulin receptor (IR) pathway promotes the transcription of the calcium voltage-gated channel subunit alpha1 C (CACNA1C). These three genes have been independently associated with schizophrenia (SZ) risk, symptomatology, and brain differences. However, research on how they synergistically modulate these phenotypes is scarce. We aimed to study whether the genetic epistasis between these genes affects the risk and clinical presentation of the disorder via its effect on brain structure. First, we tested the epistatic effect of NRN1 and BDNF or CACNA1C on (i) the risk for SZ, (ii) clinical symptoms severity and functionality (onset, PANSS, CGI and GAF), and (iii) brain cortical structure (thickness, surface area and volume measures estimated using FreeSurfer) in a sample of 86 SZ patients and 89 healthy subjects. Second, we explored whether those brain clusters influenced by epistatic effects mediate the clinical profiles. Although we did not find a direct epistatic impact on the risk, our data unveiled significant effects on the disorder's clinical presentation. Specifically, the NRN1-rs10484320 x BDNF-rs6265 interplay influenced PANSS general psychopathology, and the NRN1-rs4960155 x CACNA1C-rs1006737 interaction affected GAF scores. Moreover, several interactions between NRN1 SNPs and BDNF-rs6265 significantly influenced the surface area and cortical volume of the frontal, parietal, and temporal brain regions within patients. The NRN1-rs10484320 x BDNF-rs6265 epistasis in the left lateral orbitofrontal cortex fully mediated the effect on PANSS general psychopathology. Our study not only adds clinical significance to the well-described molecular relationship between NRN1 and BDNF but also underscores the utility of deconstructing SZ into biologically validated brain-imaging markers to explore their mediation role in the path from genetics to complex clinical manifestation. [ABSTRACT FROM AUTHOR]

Heterotrimeric (αβγ) G protein signaling pathways are critical environmental sensing systems found in eukaryotic cells. Exchange of GDP for GTP on the Gα subunit leads to its activation. In contrast, GTP hydrolysis on the Gα is accelerated by Regulator of G protein Signaling (RGS) proteins, resulting in a return to the GDP-bound, inactive state. Here, we analyzed growth, development and extracellular cellulase production in strains with knockout mutations in the seven identified RGS genes (rgs-1 to rgs-7) in the filamentous fungus, Neurospora crassa. We compared phenotypes to those of strains with either knockout mutations or expressing predicted constitutively activated, GTPase-deficient alleles for each of the three Gα subunit genes (gna-1Q204L, gna-2Q205L or gna-3Q208L). Our data revealed that six RGS mutants have taller aerial hyphae than wild type and all seven mutants exhibit reduced asexual sporulation, phenotypes shared with strains expressing the gna-1Q204L or gna-3Q208L allele. In contrast, Δrgs-1 and Δrgs-3 were the only RGS mutants with a slower growth rate phenotype, a defect in common with gna-1Q204L strains. With respect to female sexual development, Δrgs-1 possessed defects most similar to gna-3Q208L strains, while those of Δrgs-2 mutants resembled strains expressing the gna-1Q204L allele. Finally, we observed that four of the seven RGS mutants had significantly different extracellular cellulase levels relative to wild type. Of interest, the Δrgs-2 mutant had no detectable activity, similar to the gna-3Q208L strain. In contrast, the Δrgs-1 and Δrgs-4 mutants and gna-1Q204L and gna-2Q205L strains exhibited significantly higher cellulase activity than wild type. With the exception of sexual development, our results demonstrate the greatest number of genetic interactions between rgs-1 and gna-1 and rgs-2 and gna-3 in N. crassa.

Associations of CRISPLD2 (cysteine-rich secretory protein LCCL domain containing 2) and genes belonging to its activation pathway, including FOS (Fos proto-oncogene), CASP8 (caspase 8) and MMP2 (matrix metalloproteinase 2), with nonsyndromic orofacial cleft risk, have been reported, but the results are yet unclear. The aim of this study was to evaluate single nucleotide polymorphisms (SNPs) in FOS, CASP8 and MMP2 and to determine their SNP-SNP interactions with CRISPLD2 variants in the risk of nonsyndromic cleft lip with or without cleft palate (NSCL±P) in the Brazilian population. The SNPs rs1046117 (FOS), rs3769825 (CASP8) and rs243836 (MMP2) were genotyped using TaqMan allelic discrimination assays in a case-control sample containing 801 NSCL±P patients (233 nonsyndromic cleft lip only (NSCLO) and 568 nonsyndromic cleft lip and palate (NSCLP)) and 881 healthy controls via logistic regression analysis adjusted for the effects of sex and genomic ancestry proportions with a multiple comparison p value set at ≤0.01. SNP-SNP interactions with rs1546124, rs8061351, rs2326398 and rs4783099 in CRISPLD2 were performed with the model-based multifactor dimensionality reduction test complemented with a 1000 permutation-based strategy. Although the association between FOS rs1046117 and risk of NSCL±P reached only nominal p values, NSCLO risk was significantly higher in carriers of the FOS rs1046117 C allele (OR: 1.28, 95% CI: 1.10–1.64, p = 0.004), TC heterozygous genotype (OR: 1.59, 95% CI: 1.16–2.18, p = 0.003), and in the dominant model (OR: 1.50, 95% CI: 1.10–2.02, p = 0.007). Individually, no significant associations between cleft risk and the SNPs in CASP8 and MMP2 were observed. SNP-SNP interactions involving CRISPLD2 variants and rs1046117 (FOS), rs3769825 (CASP8) and rs243836 (MMP2) yielded several significant p values, mostly driven by FOS rs1046117 and CASP8 rs3769825 in NSCL±P, FOS rs1046117 in NSCLO and CRISPLD2 rs8061351 in NSCLP. Our study is the first in the Brazilian population to reveal the association of FOS rs1046117 with NSCLO risk, and to support that CRISPLD2, CASP8, FOS and MMP2 interactions may be related to the pathogenesis of this common craniofacial malformation. [ABSTRACT FROM AUTHOR]

Melanoma is a heterogenous malignancy with an unpredictable clinical course. Most patients who present in the clinic are diagnosed with primary melanoma, yet large‐scale sequencing efforts have focused primarily on metastatic disease. In this study we sequence‐profiled 524 American Joint Committee on Cancer Stage I–III primary tumours. Our analysis of these data reveals recurrent driver mutations, mutually exclusive genetic interactions, where two genes were never or rarely co‐mutated, and an absence of co‐occurring genetic events. Further, we intersected copy number calls from our primary melanoma data with whole‐genome CRISPR screening data to identify the transcription factor interferon regulatory factor 4 (IRF4) as a melanoma‐associated dependency. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Associations of CRISPLD2 (cysteine-rich secretory protein LCCL domain containing 2) and genes belonging to its activation pathway, including FOS (Fos proto-oncogene), CASP8 (caspase 8) and MMP2 (matrix metalloproteinase 2), with nonsyndromic orofacial cleft risk, have been reported, but the results are yet unclear. The aim of this study was to evaluate single nucleotide polymorphisms (SNPs) in FOS, CASP8 and MMP2 and to determine their SNP-SNP interactions with CRISPLD2 variants in the risk of nonsyndromic cleft lip with or without cleft palate (NSCL±P) in the Brazilian population. The SNPs rs1046117 (FOS), rs3769825 (CASP8) and rs243836 (MMP2) were genotyped using TaqMan allelic discrimination assays in a case-control sample containing 801 NSCL±P patients (233 nonsyndromic cleft lip only (NSCLO) and 568 nonsyndromic cleft lip and palate (NSCLP)) and 881 healthy controls via logistic regression analysis adjusted for the effects of sex and genomic ancestry proportions with a multiple comparison p value set at ≤0.01. SNP-SNP interactions with rs1546124, rs8061351, rs2326398 and rs4783099 in CRISPLD2 were performed with the model-based multifactor dimensionality reduction test complemented with a 1000 permutation-based strategy. Although the association between FOS rs1046117 and risk of NSCL±P reached only nominal p values, NSCLO risk was significantly higher in carriers of the FOS rs1046117 C allele (OR: 1.28, 95% CI: 1.10–1.64, p = 0.004), TC heterozygous genotype (OR: 1.59, 95% CI: 1.16–2.18, p = 0.003), and in the dominant model (OR: 1.50, 95% CI: 1.10–2.02, p = 0.007). Individually, no significant associations between cleft risk and the SNPs in CASP8 and MMP2 were observed. SNP-SNP interactions involving CRISPLD2 variants and rs1046117 (FOS), rs3769825 (CASP8) and rs243836 (MMP2) yielded several significant p values, mostly driven by FOS rs1046117 and CASP8 rs3769825 in NSCL±P, FOS rs1046117 in NSCLO and CRISPLD2 rs8061351 in NSCLP. Our study is the first in the Brazilian population to reveal the association of FOS rs1046117 with NSCLO risk, and to support that CRISPLD2, CASP8, FOS and MMP2 interactions may be related to the pathogenesis of this common craniofacial malformation.

Heterotrimeric (αβγ) G protein signaling pathways are critical environmental sensing systems found in eukaryotic cells. Exchange of GDP for GTP on the Gα subunit leads to its activation. In contrast, GTP hydrolysis on the Gα is accelerated by Regulator of G protein Signaling (RGS) proteins, resulting in a return to the GDP-bound, inactive state. Here, we analyzed growth, development and extracellular cellulase production in strains with knockout mutations in the seven identified RGS genes (rgs-1 to rgs-7) in the filamentous fungus, Neurospora crassa. We compared phenotypes to those of strains with either knockout mutations or expressing predicted constitutively activated, GTPase-deficient alleles for each of the three Gα subunit genes (gna-1Q204L, gna-2Q205L or gna-3Q208L). Our data revealed that six RGS mutants have taller aerial hyphae than wild type and all seven mutants exhibit reduced asexual sporulation, phenotypes shared with strains expressing the gna-1Q204L or gna-3Q208L allele. In contrast, Δrgs-1 and Δrgs-3 were the only RGS mutants with a slower growth rate phenotype, a defect in common with gna-1Q204L strains. With respect to female sexual development, Δrgs-1 possessed defects most similar to gna-3Q208L strains, while those of Δrgs-2 mutants resembled strains expressing the gna-1Q204L allele. Finally, we observed that four of the seven RGS mutants had significantly different extracellular cellulase levels relative to wild type. Of interest, the Δrgs-2 mutant had no detectable activity, similar to the gna-3Q208L strain. In contrast, the Δrgs-1 and Δrgs-4 mutants and gna-1Q204L and gna-2Q205L strains exhibited significantly higher cellulase activity than wild type. With the exception of sexual development, our results demonstrate the greatest number of genetic interactions between rgs-1 and gna-1 and rgs-2 and gna-3 in N. crassa.

The breadth and scope of new information makes difficult a selection of topics to be included in a limited review of highlights of the year. Admittedly, the choices are idiosyncratic. The eight topics presented here are (1) structural and copy number variants in the human genome; (2) progress in defining genetic factors in the etiology of schizophrenia; (3) microRNAs in central nervous system development and function; (4) progress in elucidation of risk factors for complex common disorders through large scale association studies; (5) epigenetics and the epigenomic era; (6) reprogramming of somatic cell nuclei to generate pluripotent stem cells; (7) new concepts regarding factors involved in sexual differentiation; and (8) Duffy blood group antigens: new concepts, and new discoveries on the role of these antigens in malaria and HIV-AIDS.

Invariant floral forms are important for reproductive success and robust to natural perturbations. Petal number, for example, is invariant in Arabidopsis thaliana flowers. However, petal number varies in the closely related species Cardamine hirsuta, and the genetic basis for this difference between species is unknown. Here we show that divergence in the pleiotropic floral regulator APETALA1 (AP1) can account for the species-specific difference in petal number robustness. This large effect of AP1 is explained by epistatic interactions: A. thaliana AP1 confers robustness by masking the phenotypic expression of quantitative trait loci controlling petal number in C. hirsuta. We show that C. hirsuta AP1 fails to complement this function of A. thaliana AP1, conferring variable petal number, and that upstream regulatory regions of AP1 contribute to this divergence. Moreover, variable petal number is maintained in C. hirsuta despite sufficient standing genetic variation in natural accessions to produce plants with four-petalled flowers.

Cellular and organismal phenotypes are controlled by complex gene regulatory networks. However, reference maps of gene function are still scarce across different organisms. Here, we generated synthetic genetic interaction and cell morphology profiles of more than 6,800 genes in cultured Drosophila cells. The resulting map of genetic interactions was used for machine learning-based gene function discovery, assigning functions to genes in 47 modules. Furthermore, we devised Cytoclass as a method to dissect genetic interactions for discrete cell states at the single-cell resolution. This approach identified an interaction of Cdk2 and the Cop9 signalosome complex, triggering senescence-associated secretory phenotypes and immunogenic conversion in hemocytic cells. Together, our data constitute a genome-scale resource of functional gene profiles to uncover the mechanisms underlying genetic interactions and their plasticity at the single-cell level., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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]

Associations of CRISPLD2 (cysteine-rich secretory protein LCCL domain containing 2) and genes belonging to its activation pathway, including FOS (Fos proto-oncogene), CASP8 (caspase 8) and MMP2 (matrix metalloproteinase 2), with nonsyndromic orofacial cleft risk, have been reported, but the results are yet unclear. The aim of this study was to evaluate single nucleotide polymorphisms (SNPs) in FOS , CASP8 and MMP2 and to determine their SNP-SNP interactions with CRISPLD2 variants in the risk of nonsyndromic cleft lip with or without cleft palate (NSCL±P) in the Brazilian population. The SNPs rs1046117 ( FOS ), rs3769825 ( CASP8 ) and rs243836 ( MMP2 ) were genotyped using TaqMan allelic discrimination assays in a case-control sample containing 801 NSCL±P patients (233 nonsyndromic cleft lip only (NSCLO) and 568 nonsyndromic cleft lip and palate (NSCLP)) and 881 healthy controls via logistic regression analysis adjusted for the effects of sex and genomic ancestry proportions with a multiple comparison p value set at ≤0.01. SNP-SNP interactions with rs1546124, rs8061351, rs2326398 and rs4783099 in CRISPLD2 were performed with the model-based multifactor dimensionality reduction test complemented with a 1000 permutation-based strategy. Although the association between FOS rs1046117 and risk of NSCL±P reached only nominal p values, NSCLO risk was significantly higher in carriers of the FOS rs1046117 C allele (OR: 1.28, 95% CI: 1.10-1.64, p = 0.004), TC heterozygous genotype (OR: 1.59, 95% CI: 1.16-2.18, p = 0.003), and in the dominant model (OR: 1.50, 95% CI: 1.10-2.02, p = 0.007). Individually, no significant associations between cleft risk and the SNPs in CASP8 and MMP2 were observed. SNP-SNP interactions involving CRISPLD2 variants and rs1046117 ( FOS ), rs3769825 ( CASP8 ) and rs243836 ( MMP2 ) yielded several significant p values, mostly driven by FOS rs1046117 and CASP8 rs3769825 in NSCL±P, FOS rs1046117 in NSCLO and CRISPLD2 rs8061351 in NSCLP. Our study is the first in the Brazilian population to reveal the association of FOS rs1046117 with NSCLO risk, and to support that CRISPLD2 , CASP8 , FOS and MMP2 interactions may be related to the pathogenesis of this common craniofacial malformation.

We have explored the patterns of fitness recovery in the vesicular stomatitis RNA virus. We show that, in our experimental setting, reversions to the wild-type genotype were rare and fitness recovery was at least partially driven by compensatory mutations. We compared compensatory adaptation for genotypes carrying (1) mutations with varying deleterious fitness effects, (2) one or two deleterious mutations, and (3) pairs of mutations showing differences in the strength and sign of epistasis. In all cases, we found that the rate of fitness recovery and the proportion of reversions were positively affected by population size. Additionally, we observed that mutations with large fitness effect were always compensated faster than mutations with small fitness effect. Similarly, compensatory evolution was faster for genotypes carrying a single deleterious mutation than for those carrying pairs of mutations. Finally, for genotypes carrying two deleterious mutations, we found evidence of a negative correlation between the epistastic effect and the rate of compensatory evolution.

Little is known about the inheritance of agronomic traits in cassava (Manihot esculenta Crantz). The vegetative multiplication of cassava allows cloning of individual genotypes, and separates environmental from genetic variation in the within-family variation. Knowing the magnitude of between- and within-family variation is important for defining breeding strategies and for measuring different components of genetic variances, particularly the seldom-estimated epistasis. A group of nine genotypes, adapted to midaltitude environments, was used for a diallel study. Thirty clones were obtained from every [F.sub.1] cross (each clone was represented by six plants), and planted in three replications at two locations. Statistical differences among crosses were found for fresh-root yield, harvest index, root dry-matter content, and reaction to mites (Mononychellus tanajoa Bondar) and to whiteflies (Aleurotrachelus socialis Bondar). General combining ability (GCA) was significant for all traits except fresh-root yield and dry-matter content, and specific combining ability (SCA) was significant for all traits except whitefly damage score. Fresh-root yield was the only trait with significant epistatic effects, which, combined with a large dominance variance, suggested a prevalence of nonadditive effects. The introduction of inbreeding would be one approach for the efficient exploitation of these nonadditive effects found for fresh-root yield. For the remaining traits, epistasis was negligible and current schemes exploiting additive effects may suffice. Abbreviations: GCA, general combining ability; SCA, specific combining ability., CASSAVA, ALONG WITH MAIZE (Zea mays L.), sugarcane (Saccharum spp.), and rice (Oryza sativa L.), constitutes the most important source of energy in the diet of most tropical countries of [...]

Abstract: Genetic interaction (GI) detection impacts the understanding of human disease and the ability to design personalized treatment. The mapping of every GI in most organisms is far from complete due to the combinatorial amount of gene deletions and knockdowns required. Computational techniques to predict new interactions based only on network topology have been developed in network science but never applied to GI networks. We show that topological prediction of GIs is possible with high precision and propose a graph dissimilarity index that is able to provide robust prediction in both dense and sparse networks. Computational prediction of GIs is a strong tool to aid high-throughput GI determination. The dissimilarity index we propose in this article is able to attain precise predictions that reduce the universe of candidate GIs to test in the lab. [Copyright &y& Elsevier]

Abstract: Bacterial transcription activators regulate transcription by making essential protein–protein interactions with RNA polymerase, for example, with region 4 of the σ70 subunit (σ70 R4). Rob, SoxS, and MarA comprise a closely related subset of members of the AraC/XylS family of transcription factors that activate transcription of both class I and class II promoters. Recently, we showed that interactions between SoxS and σ70 R4 occlude the binding of σ70 R4 to the −35 promoter element of class II promoters. Although Rob shares many similarities with SoxS, it contains a C-terminal domain (CTD) that the other paralogs do not. Thus, a goal of this study was to determine whether Rob makes protein–protein interactions with σ70 R4 at class II promoters and, if so, whether the interactions occlude the binding of σ70 R4 to the −35 hexamer despite the presence of the CTD. We found that although Rob makes fewer interactions with σ70 R4 than SoxS, the two proteins make the same, unusual, position-dependent interactions. Importantly, we found that Rob occludes σ70 R4 from binding the −35 hexamer, just as does SoxS. Thus, the CTD does not substantially alter the way Rob interacts with σ70 R4 at class II promoters. Moreover, in contrast to inferences drawn from the co-crystal structure of Rob bound to robbox DNA, which showed that only one of Rob''s dual helix–turn–helix (HTH) DNA binding motifs binds a recognition element of the promoter''s robbox, we determined that the two HTH motifs each bind a recognition element in vivo. [Copyright &y& Elsevier]

Abstract: Escherichia coli SoxS activates transcription of the genes of the soxRS regulon, which provide the cell''s defense against oxidative stress. In response to this stress, SoxS is synthesized de novo. Because the DNA binding site of SoxS is highly degenerate, SoxS efficiently activates transcription by the mechanism of prerecruitment. In prerecruitment, newly synthesized SoxS first forms binary complexes with RNA polymerase. These complexes then scan the chromosome for class I and II SoxS-dependent promoters, using the specific DNA-recognition properties of SoxS and σ70 to distinguish SoxS-dependent promoters from the vast excess of sequence-equivalent soxboxes that do not reside in promoters. Previously, we determined that SoxS interacts with RNA polymerase in two ways: by making protein–protein interactions with the DNA-binding determinant of the α subunit and by interacting with σ70 region 4 (σ70 R4) both “on-DNA” and “off-DNA.” Here, we address the question of how SoxS and σ70 R4 coexist at class II promoters, where the binding site for SoxS either partially or completely overlaps the −35 region of the promoter, which is usually bound by σ70 R4. To do so, we created a tri-alanine scanning library that covers all of σ70 R4. We determined that interactions between σ70 R4 and the DNA in the promoter''s −35 region are required for activation of class I promoters, where the binding site lies upstream of the −35 hexamer, but they are not required at class II promoters. In contrast, specific three-amino-acid stretches are required for activation of class I (lac) and class II (galP1) cyclic AMP receptor protein-dependent promoters. We conclude from these data that SoxS and σ70 R4 interact with each other in a novel way at class II SoxS-dependent promoters such that the two proteins do not accommodate one another in the −35 region but instead SoxS binding there occludes the binding of σ70 R4. [Copyright &y& Elsevier]

While advances in network and pathway analysis have flourished in the era of genome-wide association analysis, understanding the genetic mechanism of individual loci on phenotypes is still readily accomplished using genetic modeling approaches. Here, we demonstrate two novel genotype-phenotype models implemented in a flexible genetic modeling platform. The examples come from analysis of families with specific language impairment (SLI), a failure to develop normal language without explanatory factors such as low IQ or inadequate environment. In previous genome-wide studies, we observed strong evidence for linkage to 13q21 with a reading phenotype in language-impaired families. First, we elucidate the genetic architecture of reading impairment and quantitative language variation in our samples using a bivariate analysis of reading impairment in affected individuals jointly with language quantitative phenotypes in unaffected individuals. This analysis largely recapitulates the baseline analysis using the categorical trait data (posterior probability of linkage (PPL) = 80%), indicating that our reading impairment phenotype captured poor readers who also have low language ability. Second, we performed epistasis analysis using a functional coding variant in the brain-derived neurotrophic factor (BDNF) gene previously associated with reduced performance on working memory tasks. Modeling epistasis doubled the evidence on 13q21 and raised the PPL to 99.9%, indicating that BDNF and 13q21 susceptibility alleles are jointly part of the genetic architecture of SLI. These analyses provide possible mechanistic insights for further cognitive neuroscience studies based on the models developed herein. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: According to the prerecruitment hypothesis, Escherichia coli SoxS activates the transcription of the genes of the SoxRS regulon by forming binary complexes with RNA polymerase (RNAP) that scan the chromosome for class I and class II SoxS-dependent promoters. We showed previously that the α subunit''s C-terminal domain plays a role in activating both classes of promoter by making protein–protein contacts with SoxS; some of these contacts are made in solution in the absence of promoter DNA, a critical prediction of the prerecruitment hypothesis. Here, we identified seven single-alanine substitutions of the region 4 of σ70 (σ70 R4) of RNAP that reduce SoxS activation of class II promoters. With genetic epistasis tests between these σ70 R4 mutants and positive control mutants of SoxS, we identified 10 pairs of amino acids that interact with each other in E. coli. Using the yeast two-hybrid system and affinity immobilization assays, we showed that SoxS and σ70 R4 can interact in solution (i.e., “off-DNA”). The interaction requires amino acids of the class I/II (but not the class II) positive control surface of SoxS, and five amino acids of σ70 R4 that reduce activation in E. coli also reduce the SoxS–σ70 R4 interaction in yeast. One of the epistatic interactions that occur in E. coli also occurs in the yeast two-hybrid system (i.e., off-DNA). Importantly, we infer that the five epistatic interactions occurring in E. coli that require an amino acid of the class II surface occur “on-DNA” at class II promoters. Finding that SoxS contacts σ70 R4 both off-DNA and on-DNA is consistent with the prerecruitment hypothesis. Moreover, SoxS is now the first example of an E. coli transcriptional activator that uses a single positive control surface to make specific protein–protein contacts with two different subunits of RNAP. [Copyright &y& Elsevier]

BACKGROUND: Asthma is one of the most common chronic diseases of childhood and results from the interaction of several genes and environmental influences. Interleukin 4 (IL4) and its receptor IL4R have a central role in the regulation of immunoglobulin E (IgE) production and thereby in the induction and maintenance of allergy and asthma. The single nucleotide polymorphisms (SNPs) Q551R in the IL4RA gene and C-33T in the IL4 gene probably influence IL4/IL4R pathway signaling; however, findings in association studies exploring the role of these two genes in asthma pathogenesis are contradictory. We have studied the association of IL4RA Q551R and IL4 C-33T SNPs with asthma, asthma phenotypes, and clinical and laboratory parameters. METHODS: The study group comprised 106 children aged between 5 and 18 years with mild or moderate persistent asthma: 78 children were atopic and 28 had nonatopic asthma. The children underwent allergy and spirometry tests, a bronchoprovocation test with methacholine, measurement of exhaled nitric oxide in expired air and genotyping for IL4RA Q551R and IL4 C-33T SNPs. Genotype data from 89 nonatopic nonasthmatics served as a control group. RESULTS: The frequency of the IL4RA Arg551 allele in the children with nonatopic asthma was 7.1%, significantly lower than 21.9% in the control group ( P = 0.01, OR: 0.33, 95% CI: 0.12-0.87). Allelic and genotype frequencies in IL4 C-33T polymorphism in the asthma group and the control group were not significantly different. The mean value of total IgE in asthmatics with the IL4-33C allele was 556.0 IU/l, significantly higher than 371.6 IU/l in those with the T allele ( P = 0.02). In an interaction study we did not find significant differences in the frequencies of any combinations of IL4RA Q551R and IL4 C-33T alleles between asthmatics and controls. CONCLUSIONS: The IL4RA Q551R SNP is associated with nonatopic asthma in Slovenian children. This finding contributes to knowledge about an important asthma phenotype pathogenesis and could serve in future research into new strategies for asthma management. [ABSTRACT FROM AUTHOR]

Whole-genome epistasis analysis may add a new layer of knowledge to whole-genome association studies, permitting the identification of new candidate genes which are completely transparent during conventional single-locus analysis. We present the first whole-genome conditional two-locus analysis in Parkinson’s disease (PD). We scanned the entire genome and selected markers that interacted with a set of well-known loci previously associated to PD (SNCA, Parkin, LRRK2, UCHL1, DJ-1, PINK and MAPT). Our work describes several loci potentially related to PD risk which interact with SNCA, PARK1 and LRRK2 markers. We propose conditional whole-genome two-locus association analysis as a valuable method that might be helpful in re-analysing and re-interpreting data from whole-genome association studies. [ABSTRACT FROM AUTHOR]

Abstract: The genetic basis of complex diseases is expected to be highly heterogeneous, with complex interactions among multiple disease loci and environment factors. Due to the multi-dimensional property of interactions among large number of genetic loci, efficient statistical approach has not been well developed to handle the high-order epistatic complexity. In this article, we introduce a new approach for testing genetic epistasis in multiple loci using an entropy-based statistic for a case-only design. The entropy-based statistic asymptotically follows a distribution. Computer simulations show that the entropy-based approach has better control of type I error and higher power compared to the standard test. Motivated by a schizophrenia data set, we propose a method for measuring and testing the relative entropy of a clinical phenotype, through which one can test the contribution or interaction of multiple disease loci to a clinical phenotype. A sequential forward selection procedure is proposed to construct a genetic interaction network which is illustrated through a tree-based diagram. The network information clearly shows the relative importance of a set of genetic loci on a clinical phenotype. To show the utility of the new entropy-based approach, it is applied to analyze two real data sets, a schizophrenia data set and a published malaria data set. Our approach provides a fast and testable framework for genetic epistasis study in a case-only design. [Copyright &y& Elsevier]

Abstract: Altered synovial fibroblast (SF) transcriptional activity is a key factor in the disease progression of rheumatoid arthritis (RA). To determine the transcriptional regulatory network associated with SF response to an RA proinflammatory stimulus we applied a CARRIE reverse engineering approach to microarray gene expression data from SFs treated with RA synovial fluid. The association of the inferred gene network with RA susceptibility was further analyzed by a case–control study of promoter single-nucleotide polymorphisms, and the presence of epistatic interactions was determined using the multifactor dimensionality reduction methodology. Our findings suggest that a specific NF-κB transcriptional regulatory network of 13 genes is associated with SF response to RA proinflammatory stimulus and identify a significant epistatic association of two of its genes, IL6 and IL4I1, with RA susceptibility. [Copyright &y& Elsevier]

The serotonin (5-HT) and norepinephrine (NE) systems are likely involved in the aetiology of anorexia nervosa (AN) as sufferers are premorbidly anxious. Specifically, we hypothesize that genes encoding proteins, which clear 5-HT and NE from the synapse, are prime candidates for affecting susceptibility to AN. Supporting our hypothesis, we earlier showed that the NE transporter (NET) and monoamine oxidase A (MAOA) genes appear to contribute additively to increased risk of developing restricting AN (AN-R). With regard to the MAOA gene, a sequence variant that increases MAOA activity and has suggested association with the anxiety condition, panic disorder was preferentially transmitted from parents to affected children. Here we provide evidence in support of interaction between the MAOA and serotonin transporter (SERT) genes in 114 AN nuclear families (patient with AN plus biological parents). A SERT gene genotype with no apparent individual effect on risk and known to be associated with anxiety is preferentially transmitted to children with AN (?2 trend=9.457, 1 df, P=0.0021) and AN-R alone (?2 trend=7.477, 1 df, P=0.0063) when the‘more active’MAOA gene variant is also transmitted. The increased risk of developing the disorder is up to eight times greater than the risk imposed by the MAOA gene variant alone-an example of synergistic epistatic interaction. If independently replicated, our findings to date suggest that we may have identified three genes affecting susceptibility to AN, particularly AN-R: the MAOA, SERT, and NET genes.European Journal of Human Genetics (2005) 13, 370-375. doi:10.1038/sj.ejhg.5201328 Published online 3 November 2004 [ABSTRACT FROM AUTHOR]

Insulin resistance is believed to be under the control of several genes often interacting each other. However, whether genetic epistasis does in fact modulate human insulin sensitivity is unknown. In 338 healthy unrelated subjects from Sicily, all nondiabetic and not morbidly obese, we investigated whether two gene polymorphisms previously associated with insulin resistance (namely PC-1 K121Q and PPARγ2 P12A) affect insulin sensitivity by interacting. PC-1 X121Q subjects showed higher level of fasting glucose, lower insulin sensitivity (by both the Matsuda insulin sensitivity index and M values at clamp, the latter performed in a subgroup of 113 subjects representative of the overall cohort) and higher insulin levels during the oral glucose tolerance test (OGTT) than PC-1 K121K subjects. In contrast, no difference in any of the measured variables was observed between PPARγ2 P12P and X12A individuals. The deleterious effect of the PC-1 X121Q genotype on each of these three variables was significant and entirely dependent upon the coexistence of the PPARγ2 P12P genotype. Among PPARγ2 P12P carriers also fasting insulin and glucose levels during OGTT were higher in PC-1 X121Q than in K121K individuals. In contrast, no deleterious effect of the PC-1 X121Q genotype was observed among PPARγ2 X12A carriers; rather, in these subjects a lower body mass index and consequently lower fasting insulin level was observed in PC-1 X121Q than in K121K carriers. Overall, a significant interaction between the two genes was observed on body mass index, insulin levels (both fasting and after OGTT) and both insulin sensitivity (i.e., insulin sensitivity index and M value) and insulin secretion (i.e., HOMA-B%) indexes. [ABSTRACT FROM AUTHOR]

Weight-restored patients with anorexia nervosa (AN) respond favorably to the selective serotonin reuptake inhibitor fluoxetine, which justifies association studies of the serotonin transporter gene (SLC6A4, alias SERT) and AN. Case-control studies suggest that the least transcriptionally active allele of the SERT gene promoter polymorphism (5-HTTLPR) has an increased frequency in AN patients. However, this finding was not replicated with 55 trios (AN child+parents) and the transmission disequilibrium test (TDT). To clarify the role of the 5-HTTLPR in susceptibility to AN, we used the TDT and 106 Australian trios to provide 93% power to detect a genotypic relative risk (GRR) of 2.0. Our results were negative for this GRR (McNemar's χ²=0.01, df=1, p=0.921, odds ratio 1.0, 95% CI 0.7-1.5). Additionally, we found no association with AN females, AN subtype, age at onset, or minimum BMI. We then performed the first reported investigation of epistasis between the SERT gene and norepinephrine transporter gene (SLC6A2, alias NET) in AN, as an earlier study suggested that atypical AN responds to the dual serotonin-norepinephrine reuptake inhibitor venlafaxine. We observed no epistasis between the 5-HTTLPR and a polymorphism within the NET gene promoter polymorphic region (NETpPR) (χ²=0.48, df=1, p=0.490). Although 5-HTTLPR modulates serotonin reuptake by the serotonin transporter, our analyses provide no evidence that susceptibility to AN is modified by 5-HTTLPR alone, nor in concert with as yet undetermined functional effects of the NETpPR polymorphism. [ABSTRACT FROM AUTHOR]

Barley awns are highly active in photosynthesis and account for 30–50% of grain weight in barley. They are diverse in length, ranging from long to awnless, and in shape from straight to hooded or crooked. Their diversity and importance have intrigued geneticists for several decades. A large collection of awnness mutants are available—over a dozen of them have been mapped on chromosomes and a few recently cloned. Different awnness genes interact with each other to produce diverse awn phenotypes. With the availability of the sequenced barley genome and application of new mapping and gene cloning strategies, it will now be possible to identify and clone more awnness genes. A better understanding of the genetic basis of awn diversity will greatly facilitate development of new barley cultivars with improved yield, adaptability and sustainability. [ABSTRACT FROM AUTHOR]

In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 Nkx2-5+/− mice from two inbred strain crosses illustrates the fundamental role of epistasis. Modifier genes raise or lower the risk of specific defects via pairwise (G×GNkx) and higher-order (G×G×GNkx) interactions with Nkx2-5. Their effect sizes correlate with the severity of a defect. The risk loci for mild, atrial septal defects exert predominantly small G×GNkx effects, while the loci for severe, atrioventricular septal defects exert large G×GNkx and G×G×GNkx effects. The loci for moderately severe ventricular septal defects have intermediate effects. Interestingly, G×G×GNkx effects are three times more likely to suppress risk when the genotypes at the first two loci are from the same rather than different parental inbred strains. This suggests the genetic coadaptation of interacting G×G×GNkx loci, a phenomenon that Dobzhansky first described in Drosophila. Thus, epistasis plays dual roles in the pathogenesis of congenital heart disease and the robustness of cardiac development. The empirical results suggest a relationship between the fitness cost and genetic architecture of a disease phenotype and a means for phenotypic robustness to have evolved. [ABSTRACT FROM AUTHOR]

Background: Neuropeptide S Receptor 1 ( NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes., Methods: Interaction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies. The results were validated and extended in children from the Manchester Asthma and Allergy Study (N = 723) and the Children Allergy Milieu Stockholm and Epidemiological cohort (N = 1646)., Results: RORA* NPSR1 interactions seemed to affect both asthma and nocturnal asthma. In stratified analyses, however, interactions mainly affected nocturnal asthma and less so asthma without nocturnal symptoms or asthma severity. Results were replicated in two independent cohorts and seemed to remain constant over time throughout youth., Conclusion: RORA* NPSR1 interactions appear to be involved in mechanisms specific for nocturnal asthma. In contrast to previous studies focusing on the role of beta 2 receptor polymorphisms in nocturnal asthma as a feature of asthma control or severity in general, our data suggest that changes in circadian rhythm control are associated with nighttime asthma symptoms., (© 2019 Wiley Periodicals, Inc.)