Role of a Signalling System in Gene Interaction in Inheritance of Root System Characteristics of Arabidopsis thaliana (L.) Heynh.

The central problem of genetics is gene interaction since genes in the course of individual organism development interact with other genes, that’s why their effects may change. Studies for the last 100 years managed to discover that the entire diversity of inter-gene interactions is presented in four major forms: complementarity, epistasis, polymery, and modifying effect of genes. However, gene interaction mechanism which is reflected on the segregation nature of variously crossed hybrids has not been sufficiently studied. Exclusive of molecular genetics, biochemistry and physiology, a genetic analysis of inheritance of characteristics in gene interaction taken by itself cannot reveal nature of this interaction. Lately, molecular-genetic and physiological studies on A. thaliana mutants have enabled to isolate and sequence a wide range of genes controlling certain links of the signalling chain. At the same time, effect of the plant development regulation signalling system on interaction of these genes in inheritance of characteristics of Arabidopsis root system haven’t been studied so far which was a cause for our studies. Gene interaction problem is closely related to the plant development regulation signalling system. Mechanism involved in gene interaction may be explained based on current idea of molecular principles of biological response. Affected by mutations occurring in various genes that control certain links of the signalling chain, signalling path to the cell nucleus and response are blocked partially or in full which leads to distortion in expression of the characteristic on the plant level in general or its organ level. Such phenomenon is observed in realization of many characteristics in animals and plants, including in A. thaliana. In inheritance of such characteristics, as a rule, both allelic, and non-allelic gene interactions are observed. Results of a study of the plant signalling system interconnection and gene interaction in inheritance of characteristics of Arabidopsis root system are presented. It is established that complementary interaction of genes RHD3 and SAR1 is observed in the second crossing generation for plants of rhd3-1 × sar-1 mutant lines. When gpa1-3 × slr-1 mutant-line plants are crossed, recessive epistasis (slr-1 slr-1 > GPA1_) occurs in F2 generation. Polymeric interaction of genes SHY2 and MSG1 is observed in F2 in crossing of shy2-2 × msg1-2 mutant-line plants.

Exploring Mechanisms of Panax notoginseng Saponins in Treating Coronary Heart Disease by Integrating Gene Interaction Network and Functional Enrichment Analysis

Objective： To investigate the mechanisms of Panax notoginseng saponins（PNS） in treating coronary heart disease（CHD） by integrating gene interaction network and functional enrichment analysis. Methods： Text mining was used to get CHD and PNS associated genes. Gene–gene interaction networks of CHD and PNS were built by the Gene MANIA Cytoscape plugin. Advanced Network Merge Cytoscape plugin was used to analyze the two networks. Their functions were analyzed by gene functional enrichment analysis via DAVID Bioinformatics. Joint subnetwork of CHD network and PNS network was identified by network analysis. Results： The 11 genes of the joint subnetwork were the direct targets of PNS in CHD network and enriched in cytokine-cytokine receptor interaction pathway. PNS could affect other 85 genes by the gene–gene interaction of joint subnetwork and these genes were enriched in other 7 pathways. The direct mechanisms of PNS in treating CHD by targeting cytokines to relieve the inflammation and the indirect mechanisms of PNS in treating CHD by affecting other 7 pathways through the interaction of joint subnetwork of PNS and CHD network. The genes in the 7 pathways could be potential targets for the immunologic adjuvant, anticoagulant, hypolipidemic, anti-platelet and anti-hypertrophic activities of PNS. Conclusion： The key mechanisms of PNS in treating CHD could be anticoagulant and hypolipidemic which are indicated by analyzing biological functions of hubs in the merged network.

Association of TSHR gene intron 1 and 4p14 single-nucleotide polymorphisms and gene-gene interactions with Graves' disease

Objective To identify the association of thyroid stimulating hormone receptor(TSHR)gene intron 1 susceptible loci and 4p14 susceptible locus rs6832151 polymorphisms with Graves’disease(GD)in Han Chinese population in Bengbu,Anhui,China.The gene-gene interaction among TSHR intron 1 susceptible loci and 4p14susceptible locus rs6832151 was also investigated.Methods The genotypes of the single-nucleotide polymor-

Interactions of the apolipoprotein A5 gene polymorphisms and alcohol consumption on serum lipid levels

Objectives Apolipoprotein(Apo) A5 gene poly-morphisms and alcohol consumption have been associated with increased serum triglyceride(TG) levels,but little is known about their interactions on serum lipid levels.The present study was undertaken polymorphismsand alcohol consumption on serum lipid levels.Methods A total of 516 unrelated nondrinkers and 514 drinkers aged 15 -89 were randomly selected from our previous stratified randomized cluster samples.Genotyping of the ApoA5was performed by polymerase chain reaction and restriction fragment length polymorphism,and then confirmed by direct sequencing.Interactions of the ApoA5alcohol consumption were assessed by using a cross-product term between genotypes and the aforementioned factor.Results The levels of total cholesterol (TC),TG,high-density lipoprotein cholesterol(HDL-C), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P【0.05-0.001).The genotypic and allelic frequencies of the three single nucleotide polymorphisms(SNPs) were not different between the two groups.The levels of TG in non-drinkers, and TC,TG,low-density lipoprotein cholesterol (LDL-C)and ApoB in drinkers were different among the three -1131T】C genotypes(P【0.05-0.001).The -1131C allele carriers had higher serum TC,TG,LDL-C and ApoB levels than the allele noncarriers.The levels of TG,HDL-C and ApoB in nondrinkers,and TG and HDL-C in drinkers were different between the two c.553G】T genotypes(P【0.05-0.01).The C.553T allele carriers had higher serum TG and ApoB levels,and lower HDL-C levels than the allele noncarriers.Serum lipid levels in nondrinkers were not different among the three c.457G】A genotypes(P【0.05 for all), but the levels of HDL-C,LDL-C,ApoA1 and ApoB in drinkers were different between the GG and GA/AA geno-types (P【0.05-0.001).The C.457A allele carriers had lower serum HDL-C,LDL-C,ApoAl and ApoB levels than the allele noncarriers.We also observed four haplotypes:G-G-T, G-G-C,G-A-T,and T-G-C with frequencies ranging from 0.06 to 0.87,representing 100%of all haplotypes in the both populations.The ApoA5 haplotypes were significantly(P【0.05) associated at the global level with TC,TG,HDL-C, LDL-C,Apo1,and ApoB,even after correction for multiple testing with permutation test.In particular,carriers of haplo-type G-G-C had significantly higher TC,TG,LDL-C,ApoB than noncarriers,whereas carriers of haplotype C-A-T had significantly lower TC,LDL-C,ApoAl and ApoB,and higher HDL-C than noncarriers.Serum TC levels in nondrinkers were correlated with -1131T】C genotype and allele(P【0.05 for each),whereas serum TC,TG and LDL-C levels in drinkers were associated with -1131 T】C and C.553G】T genotypes,or c.457G】A alleles(P【0.05-0.001).Serum lipid parameters were also correlated with several environmental factors in the both groups.Conclusions The differences in serum lipid profiles between the drinkers and nondrinkers might partly result from different interactions of ApoA5 gene polymor phisms and alcohol consumption.genotypes and -1131T】C, c.553G】T and c.457G】A to detect the interactions of the ApoA5

Gene×environment interaction in major depressive disorder

Major depressive disorder(MDD)is a multifactorial disorder,where multiple susceptibility genes interact with environmental factors,predisposing individuals to the development of the illness.In this article,we reviewed different gene×environment interaction(G×E)studies shifting from a candidate gene to a genome-wide approach.Among environmental factors,childhood adversities and stressful life events have been suggested to exert crucial impacts on MDD.Importantly,the diathesis-stress conceptualization of G×E has been challenged by the differential susceptibility theory.Finally,we summarized several limitations of G×E studies and suggested how future G×E studies might reveal complex interactions between genes and environments in MDD.

The NAC transcription factor LuNAC61 negatively regulates fiber development in flax (Linum usitatissimum L.)

Flax is a crucial fiber crop that exhibits excellent textile properties and serves as a model plant for investigating phloem fiber development. The regulation of multiple genes significantly influences fiber development, notably involving NAC(NAM, ATAF1/2, CUC2) transcription factors in forming the fiber secondary cell wall(SCW).Overexpression of LuNAC61 in flax resulted in sparse top meristematic zone leaves and significantly reduced stem cellulose content. Scanning electron microscopy and staining observations revealed a significant reduction in fiber bundles. β-Glucuronidase(GUS) staining analysis demonstrated high activity of the LuNAC61 promoter in the bast fibers of the flax stem. Additionally, several members of the LuPLATZ and LuCesA families exhibited significant coexpression with LuNAC61. Subcellular localization indicated the presence of LuPLATZ24 protein in the nucleus and cytoplasm, LuNAC61 protein exclusively in the nucleus, and LuCesA10 in the nucleus and endoplasmic reticulum. LuPLATZ24 positively regulates LuNAC61, whereas LuNAC61 negatively affects LuCesA10, suggesting the involvement of a metabolic network in regulating flax fiber development. In conclusion, this study provides a critical opportunity for a comprehensive and in-depth analysis of the mechanisms governing flax fiber development and the potential use of biotechnology to enhance flax fiber yield.

Three co-located resistance genes confer resistance to leaf rust and stripe rust in wheat variety Borlaug 100

Leaf rust(LR) and stripe rust(YR) are important diseases in wheat producing areas worldwide and cause severe yield losses under favorable environmental conditions when susceptible varieties are grown. We determined the genetic basis of resistance to LR and YR in variety Borlaug 100 by developing and phenotyping a population of 198 F6 recombinant inbred lines derived from a cross with the susceptible parent Apav#1. LR and YR phenotyping were conducted for 4 and 3 seasons, respectively, at CIMMYT research stations in Mexico under artificial epidemics. Mendelian segregation analyses indicated that 3–5 LR and 2 YR genes conferred resistance in Borlaug 100. Lr46/Yr29(1 BL), Yr17(2 AS) and Yr30(3 BS) were present in the resistant parent and segregated in the RIL population based on characterization by molecular markers linked to these genes. When present alone, Lr46/Yr29 caused average 13% and 16% reductions in LR and YR severities, respectively, in RILs. Similarly, Yr17 and Yr30 reduced YR severities by 57% and 11%, respectively. The Yr30 and the Yr17 translocation were also associated with 27% and 14% reductions, respectively, in LR severity, indicating that the 3 BS and 2 AS chromosomal regions likely carry new slow rusting LR resistance genes, temporarily designated as Lr B1 and Lr B2, respectively. Additive effects of Yr30*Yr17, Yr29*Yr17 and Yr29*Yr30 on YR and LR were significant and reduced YR severities by 56%,55%, and 45%, respectively, and LR severities by 34%, 40%, and 45%, respectively. Furthermore, interaction between the three genes was also significant, with mean reductions of 70% for YR and 54% for LR severities. Borlaug 100, or any one of the 21 lines with variable agronomic traits but carrying all three colocated resistance loci, can be used as resistance sources in wheat breeding programs.

Interaction of the major inflammatory bowel disease susceptibility alleles in Crohn’s disease patients

AIM:To investigate the interaction of interleukin-23 receptor(IL23R)(rs1004819 and rs2201841),autophagy-related 16-like 1(ATG16L1)(rs2241880), caspase recruitment domain-containing protein 15 (CARD15)genes,and IBD5 locus in Crohn's disease(CD) patients. METHODS:A total of 315 unrelated subjects with CD and 314 healthy controls were genotyped.Interactions and specific genotype combinations of a total of eight variants were tested.The variants of IBD5locus(IGR2198a_1 rs11739135 and IGR2096a_1 rs12521868),CARD15(R702W rs2066845 and L1007fs rs2066847),ATG16L1(rs2241880)and IL23R (rs1004819,rs2201841)genes were genotyped by PCR-RFLP,the G908R(rs2066844)in CARD15 was determined by direct sequencing. RESULTS:The association of ATG16L1 T300A with CD was confirmed[P=0.004,odds ratio(OR)=1.69, 95%CI:1.19-2.41],and both IL23R variants were found to represent significant risk for the disease(P= 0.008,OR=2.05,95%CI:1.20-3.50 for rs1004819 AA;P<0.001,OR=2.97,95%CI:1.65-5.33 for rs2201841 CC).Logistic regression analysis of pairwise interaction of the inflammatory bowel disease (IBD)loci indicated that IL23R,ATG16L1,CARD15 and IBD5(IGR2198a_1)contribute independently to disease risk.We also analysed the specific combina- tions by pair of individual ATG16L1,IL23R rs1004819, rs2201841,IGR2198a_1,IGR2096a_1 and CARD15 genotypes for disease risk influence.In almost all cases,the combined risk of susceptibility pairs was higher in patients carrying two different risk-associated gene variants together than individuals with just one polymorphism.The highest OR was found for IL23R rs2201841 homozygous genotype with combination of positive CARD15 status(P<0.001,OR=9.15,95% CI:2.05-40.74). CONCLUSION:The present study suggests a cumulative effect of individual IBD susceptibility loci.

Assessing effect of interaction between the FTO A/T polymorphism(rs9939609)and physical activity on obesity-related traits

Background： The first described obesity-susceptibility gene was the fat mass and obesity-associated （FTO） gene. However, knowledge about FTO＇s potential modifying effect on changes in body weight achieved through a training program is still limited. We decided to study the association between the FTO A/T polymorphism （rs9939609） and obesity-related traits. Additionally, we investigated whether body mass and body composition, as well as metabolic variables observed in physically active participants, are modulated by the FTO polymorphism. Methods： A group of 201 young Polish women were recruited for the study. The genotype distribution was examined in participants measured for selected changes before and after the completion of a 12-week training program. Results： Our results confirm the association between the common FTO A/T polymorphism and increased body mass index （BMI）. Subjects with AA and AT genotypes had higher BMI during the entire study period compared with the TT genotype. Although parameters such as BMI, basal metabolism rate, tissue independence, fat mass percentage, fat mass, fat-free mass, total body water, high-density lipoprotein, and glucose changed significantly during the training program, none of the examined parameters changed significantly across the FTO genotypes （genotype × training interaction）. Conclusion： We confirm an association between the FTO A/T polymorphism and increased BMI; this polymorphism is therefore a candidate for influencing obesity and other disease-related phenotypes. Although the gene x physical activity interaction was not shown, we want to point out that promoting physical activity is an important approach to controlling the increasing obesity epidemic.2018 Published by Elsevier B.V. on behalf of Shanghai University of Sport. This is an open access article under the CC BY-NC-ND license. （http：//creativecommons.org/licenses/by-nc-nd/4.0/）.

Identification of potential immune-related prognostic biomarkers of lung cancer using gene co-expression network analysis

Objective The objective of this study was to identify new carcinogenetic hub genes and develop the integration of differentially expressed genes to predict the prognosis of lung cancer.Methods GSE139032 microarray data packages were downloaded from the Gene Expression Omnibus for planning,testing,and review of data.We identified KRT6C,LAMC2,LAMB3,KRT6A,and MYEOV from a key module for validation.Results We found that the five genes were related to a poor prognosis,and the expression levels of these genes were associated with tumor stage.Furthermore,Kaplan-Meier plotter showed that the five hub genes had better prognostic values.The mean levels of methylation in lung adenocarcinoma(LUAD)were significantly lower than those in healthy lung tissues for the hub genes.However,gene set enrichment analysis(GSEA)for single hub genes showed that all of them were immune-related.Conclusion Our findings demonstrated that KRT6C,LAMC2,LAMB3,KRT6A,and MYEOV are all candidate diagnostic and prognostic biomarkers for LUAD.They may have clinical implications in LUAD patients not only for the improvement of risk stratification but also for therapeutic decisions and prognosis prediction.

Clinical utilities and end-user experience of pharmacogenomics:39 mo of clinical implementation experience in an Australian hospital setting

BACKGROUND Pharmacogenomics(PG)testing is under-utilised in Australia.Our research provides Australia-specific data on the perspectives of patients who have had PG testing and those of the clinicians involved in their care,with the aim to inform wider adoption of PG into routine clinical practice.AIM To investigate the frequency of actionable drug gene interactions and assess the perceived utility of PG among patients and clinicians.METHODS We conducted a retrospective audit of PG undertaken by 100 patients at an Australian public hospital genetics service from 2018 to 2021.Via electronic surveys we compared and contrasted the experience,understanding and usage of results between these patients and their clinicians.RESULTS Of 100 patients who had PG,84% were taking prescription medications,of which 67% were taking medications with actionable drug-gene interactions.Twenty-five out of 81 invited patients and 17 out of 89 invited clinicians completed the surveys.Sixty-eight percent of patients understood their PG results and 48% had medications changed following testing.Paired patient-clinician surveys showed patient-perceived utility and experience was positive,contrasting their clinicians’hesitancy on PG adoption who identified insufficient education/training,lack of clinical support,test turnaround time and cost as barriers to adoption.CONCLUSION Our dichotomous findings between the perspectives of our patient and clinician cohorts suggest the uptake of PG is likely to be driven by patients and clinicians need to be prepared to provide information and guidance to their patients.

Comprehensive multi-omics analysis identified core molecular processes in esophageal cancer and revealed GNGT2 as a potential prognostic marker

BACKGROUND Esophageal cancer is one of the most poorly diagnosed and fatal cancers in the world.Although a series of studies on esophageal cancer have been reported,the molecular pathogenesis of the disease remains elusive.AIM To investigate comprehensively the molecular process of esophageal cancer.METHODS Differential expression analysis was performed to identify differentially expressed genes(DEGs)in different stages of esophageal cancer from The Cancer Genome Atlas data.Exacting gene interaction modules were generated,and hub genes in the module interaction network were found.Further,through survival analysis,methylation analysis,pivot analysis,and enrichment analysis,some important molecules and related functions/pathways were identified to elucidate potential mechanisms in esophageal cancer.RESULTS A total of 7457 DEGs and 14 gene interaction modules were identified.These module genes were significantly involved in the positive regulation of protein transport,gastric acid secretion,insulin-like growth factor receptor binding,and other biological processes as well as p53 signaling pathway,epidermal growth factor signaling pathway,and epidermal growth factor receptor signaling pathway.Transcription factors(including hypoxia inducible factor 1A)and noncoding RNAs(including colorectal differentially expressed and hsa-miR-330-3p)that significantly regulate dysfunction modules were identified.Survival analysis showed that G protein subunit gamma transducin 2(GNGT2)was closely related to survival of esophageal cancer.DEGs with strong methylation regulation ability were identified,including SST and SH3GL2.Furthermore,the expression of GNGT2 was evaluated by quantitative real time polymerase chain reaction,and the results showed that GNGT2 expression was significantly upregulated in esophageal cancer patient samples and cell lines.Moreover,cell counting kit-8 assay revealed that GNGT2 could promote the proliferation of esophageal cancer cell lines.CONCLUSION This study not only revealed the potential regulatory factors involved in the development of esophageal cancer but also deepens our understanding of its underlying mechanism.

Identification and Cloning of Differentially Expressed Genes Involved in the Interaction Between Potato and Phytophthora infestans using a Subtractive Hybridization and cDNA-AFLP Combinational Approach

Using a subtractive hybridization （SH）/cDNA-AFLP combinational approach, differentially expressed genes involved in the potato-Phytophthora infestans interaction were identified. These included genes potentially controlling pathogenesis or avr genes in P. infestans as well as those potentially involved in potato resistance or susceptibility to this pathogen. Forty-one differentially expressed transcript, derived fragments （TDFs）, resulting from the interaction, were cloned and sequenced. Two TDFs, suggested as potential pathogenicity factors, have sequence similarity to N-succinyl diaminopimelate aminotransferase and a transcriptional regulator, TetR family gene, respectively. Two other TDFs, suggested as potential avr genes, have sequence similarity to an EST sequence from Avr41Cf.41Avr91Cf- 9 and a P. infestans avirulence-associated gene, respectively. Genes＇ expression and origin were confirmed using Southern blots, Northern blots and qRT-PCR, he., potential resistance gene DL81 was induced at 12 hpi in the moderately resistant cultivar, whereas it was down-regulated as early as 6 hpi in the susceptible cultivar. On the other hand, DL21 was induced at 6 hpi （3.38-fold） in response to the highly aggressive isolate （US8） and strongly up-regulated thereafter （25.13-fold at 120 hpi.）, whereas it was only slightly up-regulated in response to the weakly aggressive isolate US11 （3.82-fold at 96 hpi）, suggesting its potential involvement as a susceptibility gene.

Constructing protein-protein interaction network of hypertension with blood stasis syndrome via digital gene expression sequencing and database mining

OBJECTIVE： To construct a protein-protein interaction（PPI） network in hypertension patients with blood-stasis syndrome（BSS） by using digital gene expression（DGE） sequencing and database mining techniques.METHODS： DGE analysis based on the Solexa Genome Analyzer platform was performed on vascular endothelial cells incubated with serum of hypertension patients with BSS. The differentially expressed genes were f iltered by comparing the expression levels between the different experimental groups. Then functional categories and e nriched pathways of the unique genes for BSS were analyzed using Database for Annotation, Visualization and Integrated Discovery（DAVID） to select those in the enrichment pathways. I nterologous Interaction Database（I2D） was used to construct PPI networks with the selected genes for hypertension patients with BSS. The potential candidate genes related to BSS were identif ied by comparing the number of relationships among genes. Confi rmed by quantitative reverse transcription-polymerase chain reaction（q RTPCR）, gene ontology（GO） analysis was used to infer the functional annotations of the potential candidate genes for BSS.RESULTS： With gene enrichment analysis using DAVID, a list of 58 genes was chosen from the unique genes. The selected 58 genes were analyzed using I2 D, and a PPI network was constructed. Based on the network analysis results, candidate genes for BSS were identifi ed：DDIT3, JUN, HSPA8, NFIL3, HSPA5, HIST2H2 BE, H3F3 B, CEBPB, SAT1 and GADD45 A. Verif ied through qRT-PCR and analyzed by GO, the functional annotations of the potential candidate genes were explored.CONCLUSION： Compared with previous methodologies reported in the literature, the present DGE analysis and data mining method have shown a great improvement in analyzing BSS.

Comparative Analysis of Protein-Protein Interactions in Cancer-Associated Genes

Protein-protein interactions （PPIs） have been widely studied to understand the biological processes or molecular functions associated with different disease systems like cancer. While focused studies on individual cancers have generated valuable information, global and comparative analysis of datasets from different cancer types has not been done. In this work, we carried out bioinformatic analysis of PPIs corresponding to differentially expressed genes from microarrays of various tumor tissues （belonging to bladder, colon, kidney and thyroid cancers） and compared their associated biological processes and molecular functions （based on Gene Ontology terms）. We identified a set of processes or functions that are common to all these cancers, as well as those that are specific to only one or partial cancer types. Similarly, protein interaction networks in nucleic acid metabolism were compared to identify the common/specific clusters of proteins across different cancer types. Our results provide a basis for further experimental investigations to study protein interaction networks associated with cancer. The methodology developed in this work can also be applied to study similar disease systems.

Strengthening the functional research on the interaction between host genes and microbiota

In recent years,many studies have focused on the interaction between host genes and microbiota and their mutual influence(Bonder et al.,2016;Goodrich et al.,2014;Rothschild et al.,2018;Wang et al.,2016;Zhang et al.,2019).Host genetic variation influences the composition of the microbial community,for instance in inflammatory bowel disease,host genetic susceptibilities induce pathological shifts in microbiome composition.

Toxicogenomic investigation of Tetrahymena thermophila exposed to dichlorodiphenyltrichloroethane (DDT),tributyltin (TBT),and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Dichlorodiphenyltrichloroethane (DDT),tributyltin (TBT),and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are persistent in the environment and cause continuous toxic effects in humans and aquatic life.Tetrahymena thermophila has the potential for use as a model for research regarding toxicants.In this study,this organism was used to analyze a genome-wide microarray generated from cells exposed to DDT,TBT and TCDD.To accomplish this,genes differentially expressed when treated with each toxicant were identified,after which their functions were categorized using GO enrichment analysis.The results suggested that the responses of T.thermophila were similar to those of multicellular organisms.Additionally,the context likelihood of relatedness method (CLR) was applied to construct a TCDD-relevant network.The T-shaped network obtained could be functionally divided into two subnetworks.The general functions of both subnetworks were related to the epigenetic mechanism of TCDD.Based on analysis of the networks,a model of the TCDD effect on T.thermophila was inferred.Thus,Tetrahymena has the potential to be a good unicellular eukaryotic model for toxic mechanism research at the genome level.