Gene Variance Research Articles

Revealing the characteristics of SETD2-mutated clear cell renal cell carcinoma through tumor heterogeneity analysis.

Renal cell carcinoma (RCC) is the most prevalent type of malignant kidney tumor in adults, with clear cell renal cell carcinoma (ccRCC) comprising about 75% of all cases. The SETD2 gene, which is involved in the modification of histone proteins, is often found to have alterations in ccRCC. Yet, our understanding of how these SETD2 mutations affect ccRCC characteristics and behavior within the tumor microenvironment is still not fully understood. We conducted a detailed analysis of single-cell RNA sequencing (scRNA-seq) data from ccRCC. First, the data was preprocessed using the Python package, "scanpy." High variability genes were pinpointed through Pearson's correlation coefficient. Dimensionality reduction and clustering identification were performed using Principal Component Analysis (PCA) and the Leiden algorithm. Malignant cell identification was conducted with the "InferCNV" R package, while cell trajectories and intercellular communication were depicted using the Python packages "VIA" and "cellphoneDB." We then employed the R package "Deseq2" to determine differentially expressed genes (DEGs) between groups. Using high-dimensional weighted gene correlation network analysis (hdWGCNA), co-expression modules were identified. We intersected these modules with DEGs to establish prognostic models through univariate Cox and the least absolute shrinkage and selection operator (LASSO) method. We identified 69 and 53 distinctive cell clusters, respectively. These were classified further into 12 unique cell types. This analysis highlighted the presence of an abnormal tumor sub-cluster (MT + group), identified by high mitochondrial-encoded protein gene expression and an indication of unfavorable prognosis. Investigation of cellular interactions spotlighted significant interactions between the MT + group and endothelial cells, macrophaes. In addition, we developed a prognostic model based on six characteristic genes. Notably, risk scores derived from these genes correlated significantly with various clinical features. Finally, a nomogram model was established to facilitate more accurate outcome prediction, incorporating four independent risk factors. Our findings provide insight into the crucial transcriptomic characteristics of ccRCC associated with SETD2 mutation. We discovered that this mutation-induced subcluster could stimulate M2 polarization in macrophages, suggesting a heightened propensity for metastasis. Moreover, our prognostic model demonstrated effectiveness in forecasting overall survival for ccRCC patients, thus presenting a valuable clinical tool.

Exploring Wild Hordeum spontaneum and Hordeum marinum Accessions as Genetic Resources for Fungal Resistance.

Crop Wild Relatives (CWRs), as potential sources of new genetic variants, are being extensively studied to identify genotypes that will be able to confer resistance to biotic stresses. In this study, a collection of barley wild relatives was assessed in the field, and their phenotypic variability was evaluated using a Barley Description List, reflecting the identified ecosites. Overall, the CWRs showed significant field resistance to various fungal diseases. To further investigate their resistance, greenhouse tests were performed, revealing that several CWRs exhibited resistance against Fusarium culmorum, Pyrenophora teres, and Puccinia hordei G.H. Otth. Additionally, to characterize the genetic diversity within the collection, DNA polymorphisms at 21 loci were examined. We successfully employed barley-specific SSR markers, confirming their suitability for identifying H. spontaneum and even H. marinum, i.e., perennial species. The SSR markers efficiently clustered the investigated collection according to species and ecotypes, similarly to the phenotypic assessment. Moreover, SSR markers associated with disease resistance revealed different alleles in comparison to those found in resistant barley cultivars. Overall, our findings highlight that this evaluated collection of CWRs represents a valuable reservoir of genetic variability and resistance genes that can be effectively utilized in breeding programs.

Apoptosis and inflammatory genes variants in primary non-response to anti-TNF therapy in Crohn's disease patients.

Anti-TNF therapy has indeed revolutionized the treatment of Crohn's disease, leading to higher rates of response and remission in patients. However, a significant proportion of 20-40% of patients do not respond to the initial therapy, others experience a secondary loss of response with ongoing treatment. Adverse drug reactions also occur in some patients. The effectiveness of anti-TNF treatment may be influenced by genetic variability, including FCGR3A, ADAM17, TNFRSF1A, TNFRSF1B, FAS, FASL, IL1B, CASP9 , and MIF genes. In this article, we provide an overview of the current knowledge and findings in the pharmacogenetics of anti-TNF drugs in CD focusing on the aspect of apoptosis and inflammatory genes variants in primary non-response. Pharmacogenetic investigations have been conducted to identify genetic markers that can predict response to anti-TNF therapy. However, large multi-center validation studies and multi-loci algorithms development are required to effectively prognose the treatment effect. The identification of predictive markers of response to anti-TNF therapy can help clinicians make informed decisions about treatment options and minimize adverse drug reactions in patients.

Distribution of drug-resistant genes in alveolar lavage fluid from patients with psittacosis and traceability analysis of causative organisms.

Chlamydia psittaci is a small bacterium often found in birds, including poultry, and domesticated mammals, which causes psittacosis (or parrot fever) in humans. Different strains of C. psittaci respond variably to antibiotics, suggesting a possible risk of antibiotic resistance. In general, different genotypes of C. psittaci have relatively stable hosts and different pathogenicity. Macrogenomic sequencing was performed using nucleic acids extracted from psittacosis patients' alveolar lavage fluid samples and analyzed for genetic variability and antibiotic resistance genes. Nucleic acid amplification sequences specific to the core coding region of the C. psittaci ompA gene were used, and a phylogenetic tree was constructed with C. psittaci genotypic sequences from other sources, including Chinese published sources. The C. psittaci found in each patient were genotyped by comparing ompA gene sequences. In addition, to better illustrate the relationship between genotype and host of C. psittaci, 60 bird fecal samples were collected from bird-selling stores for screening and C. psittaci typing. Macrogenomic sequence alignment revealed the presence of resistance genes in varying abundance in samples from all three patients, including C. psittaci resistance gene sequences from two patients that matched those previously published on NCBI. Based on ompA genotyping, two patients were infected with C. psittaci genotype A and one patient was infected with genotype B. All five C. psittaci-positive samples obtained from bird-selling stores were genotype A. Both genotypes are reported to be infectious to humans. The host origin of the samples and the previously reported main sources of each genotype suggested that all but one of the C. psittaci genotype A in this study were derived from parrots, while genotype B was probably derived from chickens. The presence of bacterial resistance genes in psittacosis patients may affect the efficacy of clinical antibiotic therapy. Focusing on the developmental progression of bacterial resistance genes and differences in the therapeutic efficacy may facilitate effective treatment of clinical bacterial infections. Pathogenicity genotypes (e.g., genotype A and genotype B) are not limited to one animal host, suggesting that monitoring the development and changes of C. psittaci may help prevent transmission to humans.

Assessing the population structure of trematode Metagonimus suifunensis using three mitochondrial markers.

In this work, for the first time, the genetic variability of the Metagonimus suifunensis population in the Russian southern Far East was estimated based on the full-length sequences of the nad1 gene of mitochondrial DNA. In addition, for a sample of the same size, the sequences of cox1 and cytb genes, previously used for population studies for M. suifunensis, were reanalysed. Three markers were combined to a common sequence, and the obtained data were studied. Despite the higher level of variability, nad1 and cox1 mtDNA genes did not reveal subdivisions within the population. The combined dataset made it possible to determine that the sample from the Odyr River was the centre of the species' range formation and clarified the continental migration route of the parasite from south to north. According to the data obtained, it was presumed that piscivorous birds participate in the life cycle of the parasite. The subdivision within population revealed that using all three mitochondrial markers is consistent with the features of differentiation within populations of related species, but the reasons for its formation remain unclear due to the insufficient amount of data and the use of different markers in studies of different species.

Tilletia indica: biology, variability, detection, genomics and future perspective

India’s wheat production has reached 107.19 million tonnes during 2019–2020. Now country is in a position to export wheat to other countries. However, Karnal bunt disease is a major constraint in wheat export and causes huge monetary loss to wheat trade. The disease is caused by a typical basidiomycetes fungus Tilletia indica. It is an important quarantined fungus which affects wheat trade and causes economic loss under changing climatic scenarios. The pathogen was first reported from India then intercepted in other countries. Currently, 77 countries have restricted the import of wheat from the areas where the disease occurs. Recently, the disease has become more severe in the north-western plains zone of India. The pathogen is seed, soil and air-borne in nature. The pathogen has complex genetics, its genetic recombination or mating behaviour between two compatible allantoid sporidia just before infection. We illustrated briefly the complex biology of the pathogen, high genetic variability, detection, genomics, and pathogenesis-related genes in T. indica.

Insights into microbial community variability and functional genes of various Candidatus Scalindua-based anammox processes treating nitrogen-rich saline wastewater

Marine anammox bacteria (MAB) has been enriched in four sequencing batch reactors to treat nitrogen-rich saline wastewater. The community variability and cell activity of MAB were studied under different operating conditions. Besides, a novel hydrazine oxidoreductase (Hzo) primer set was designed and used for fast detection of MAB. The results indicated that, independent of operating conditions, Candidatus Scalindua wagneri was the dominant species in nitrogen-rich saline wastewater treatment. Low inoculation pretreatment temperature was a useful operational method to enhance the MAB abundance. Both the enzyme synthesis and cell penetrativity were promoted by Fe(III) addition, which benefited to improve the nitrogen removal performance. High influent NH4+-N and NO2−-N could decrease the synthesis of enzyme and protein which related with nitrogen removal from saline wastewater through MAB. The Hzo gene was an effective functional gene for specific and fast detection of MAB in engineered systems.

Single‐cell profiling screen identifies microtubule‐dependent reduction of variability in signaling

Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell‐to‐cell variability in signal strength and cellular response. Here, we screened 1,141 non‐essential genes to identify 50 “variability genes”. Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct “axes” of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2, and GIM4. We used genetic and chemical perturbations to show that, without microtubules, PRS output is reduced but variability is unaffected, while, when microtubules are present but their function is perturbed, output is sometimes lowered, but its variability is always high. The increased variability caused by microtubule perturbations required the PRS MAP kinase Fus3 and a process at or upstream of Ste5, the membrane‐localized scaffold to which Fus3 must bind to be activated. Visualization of Ste5 localization dynamics demonstrated that perturbing microtubules destabilized Ste5 at the membrane signaling site. The fact that such microtubule perturbations cause aberrant fate and polarity decisions in mammals suggests that microtubule‐dependent signal stabilization might also operate throughout metazoans.

Platelet WDR1 suppresses platelet activity and is associated with cardiovascular disease

AbstractPlatelet activity plays a major role in hemostasis with increased platelet activity likely contributing to the pathogenesis of atherothrombosis. We sought to identify associations between platelet activity variability and platelet-related genes in healthy controls. Transcriptional profiling of platelets revealed that WD-40 repeat domain 1 (WDR1), an enhancer of actin-depolymerizing factor activity, is downregulated in platelet messenger RNA (mRNA) from subjects with a hyperreactive platelet phenotype. We used the human megakaryoblastic cell line MEG-01 as an in vitro model for human megakaryocytes and platelets. Stimulation of MEG-01 with thrombin reduced levels of WDR1 transcripts and protein. WDR1 knockdown (KD) in MEG-01 cells increased adhesion and spreading in both the basal and activated states, increased F-actin content, and increased the basal intracellular calcium concentration. Platelet-like particles (PLPs) produced by WDR1 KD cells were fewer in number but larger than PLPs produced from unmodified MEG-01 cells, and had significantly increased adhesion in the basal state and upon thrombin activation. In contrast, WDR1 overexpression reversed the WDR1 KD phenotype of megakaryocytes and PLPs. To translate the clinical significance of these findings, WDR1 expression was measured in platelet RNA from subjects with established cardiovascular disease (n = 27) and age- and sex-matched controls (n = 10). The WDR1 mRNA and protein level was significantly lower in subjects with cardiovascular disease. These data suggest that WDR1 plays an important role in suppressing platelet activity, where it alters the actin cytoskeleton dynamics, and downregulation of WDR1 may contribute to the platelet-mediated pathogenesis of cardiovascular disease.

Abstract P194: Gene-Environment Interactions and Blood Lipid levels: a Twin Study

Genetic variation may affect blood lipid levels by directly determining levels (‘level genes’) and/or by influencing the response to environmental factors (‘variability genes’), i.e. gene-environment interaction. Previous dietary studies assessing variability gene effects have produced inconsistent results, perhaps due to a lack of statistical power, different dietary protocols, and/or differences in the age, sex, habitual diet, baseline lipid values and other genes of the participants. Monozygotic (MZ) twins can enhance our ability to identify variability genes because they are genetically identical and also share the same age, sex and aspects of their early environment. Therefore, all intrapair differences in blood lipid levels are due to environmental factors such as diet and lifestyle, and variation between genotypes in intrapair differences will indicate the existence of variability genes. We investigated the hypothesis that polymorphisms within the genes for apoB, apoE and lipoprotein lipase influence the blood lipid response to environmental factors. The subjects studied were 64 MZ male and female twin pairs aged 18-75 years who had been recruited for a study of coronary heart disease risk factors in twins. Blood samples already taken for analysis of fasting lipid levels were used for DNA extraction. Genotypes were determined for the polymorphisms apoB signal peptide insertion/deletion (I/D), apoB Xba I, apoE, and lipoprotein lipase Pvu II, Hind III and S447X. Mean intrapair differences in lipid levels adjusted for mean twin pair lipid level were calculated for each genotype group. In MZ twins, carriers of the apoB signal peptide D allele had smaller intrapair differences in total cholesterol (p=0.044) but larger intrapair differences in apoAI (p=0.035) than I/I twins, and apoE ε4 carriers had smaller intrapair differences in HDL-cholesterol than E3/3 and E3/2 twins (p=0.024). MZ twins with the Pvu II P-P- genotype had significantly greater intrapair differences in apoB than P-P+ or P+P+ twins. The Xba I, Hind III and S447X polymorphisms did not influence intrapair differences in lipid levels. In conclusion, the apoB signal peptide I/D, apoE and lipoprotein lipase Pvu II polymorphisms may act as variability genes and influence the susceptibility of blood lipid levels to dietary and pharmacological interventions for dyslipidaemia. The approach of using MZ twins to identify variability genes can be applied to other phenotypes, prior to determining the environmental factors that interact with the genes to influence the phenotype.

High Throughput Isolation and Glycosylation Analysis of IgG–Variability and Heritability of the IgG Glycome in Three Isolated Human Populations

All immunoglobulin G molecules carry N-glycans, which modulate their biological activity. Changes in N-glycosylation of IgG associate with various diseases and affect the activity of therapeutic antibodies and intravenous immunoglobulins. We have developed a novel 96-well protein G monolithic plate and used it to rapidly isolate IgG from plasma of 2298 individuals from three isolated human populations. N-glycans were released by PNGase F, labeled with 2-aminobenzamide and analyzed by hydrophilic interaction chromatography with fluorescence detection. The majority of the structural features of the IgG glycome were consistent with previous studies, but sialylation was somewhat higher than reported previously. Sialylation was particularly prominent in core fucosylated glycans containing two galactose residues and bisecting GlcNAc where median sialylation level was nearly 80%. Very high variability between individuals was observed, approximately three times higher than in the total plasma glycome. For example, neutral IgG glycans without core fucose varied between 1.3 and 19%, a difference that significantly affects the effector functions of natural antibodies, predisposing or protecting individuals from particular diseases. Heritability of IgG glycans was generally between 30 and 50%. The individual's age was associated with a significant decrease in galactose and increase of bisecting GlcNAc, whereas other functional elements of IgG glycosylation did not change much with age. Gender was not an important predictor for any IgG glycan. An important observation is that competition between glycosyltransferases, which occurs in vitro, did not appear to be relevant in vivo, indicating that the final glycan structures are not a simple result of competing enzymatic activities, but a carefully regulated outcome designed to meet the prevailing physiological needs.

Gene Expression and Ex Vivo Drug Sensitivity Profiles in Children with Acute Leukemia: An Insight for High-Dose Therapy and Role of Etoposide and Fludarabine.

Abstract 2747Poster Board II-723 Background:A distinct phenotype of combined ex vivo drug resistance and gene expression associated with this phenotype discriminates treatment outcome and identifies a subset of patients with a markedly inferior outcome in childhood acute lymphoblastic leukemia (ALL). No similar relationship was found so far in acute myeloblastic leukemia (AML). We hypothesized that drug sensitivity profile combined with gene expression profile can provide a new insight into selection of drugs used in high-dose therapy before hematopoietic stem cell transplantation and determine the role of specific drugs. Objective:The aim of the study was to analyze the gene expression profile in correlation to the ex vivo obtained chemosensitivity profile of drugs used in high-dose therapy before hematopoietic stem cell transplantation in children with ALL and AML. Methods:We tested leukemic cells from 56 children (43 ALL de novo, 8 relapsed ALL, 5 AML de novo) for ex vivo sensitivity to etoposide, fludarabine, 4-HOO-cyclophosphamide, busulfan, treosulfan and melphalan. The cells were then subjected to an assessment of global profile of gene expression to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Cells were isolated from bone marrow at the initial diagnosis of leukemia or its relapse. In vitro cytotoxicity was analyzed by means of the MTT assay. The drug resistance was expressed as the IC50, the inhibitory concentration to 50% of the cells. RNA was extracted with the use of Trizol, purified and assessed for integrity. Samples were hybridized to the Human Genome U133A Chip oligonucleotide microarrays (Affymetrix) according to manufacturer's protocol. Dataset was pre-processed by RMA method and small variability genes were filtered out. The final analysis was carried out in 13 835 probe sets. Non-parametric Spearman's correlations of IC50 and gene expression values were analyzed. Results:From all analyzed drugs, the largest number of genes significantly associated with the chemosensitivity profile across samples was observed for etoposide. We found 386 probests significantly correlated with the IC50 values (Spearman's correlation coefficient ranging from R==0.7 to R=0.61, p<0.001). NUDT21 gene (Nudix, nucleoside diphosphate linked moiety X-type, motif 21) was found to be highly significantly (False Discovery Rate, FDR<0.0001%) associated with chemosensitivity (larger expression associated with decreased IC50). Global test of association confirmed (p<0.001) that overall gene expression profile is associated with etoposide resistance, among selected genes there was over-representation of transcripts from chromosomes 1, 16 and 19. Two other drugs were found to exhibit noticeable association: fludarabine chemosensitivity was correlated with the expression of 197 probesets, global test of significance p=0.002; for cyclophosphamide 111 probesets and p=0.006 in global test was obtained. Much less significant association was observed for melphalan (72 genes, global test p=0.02) and almost no association was found for treosulfan (28 probesets, global test p=0.12) and busulfan (22 probesets, global test p=0.18). Fludarabine resistance was associated with an increased expression of FRY gene (Drosophila Furry homolog), Spearman's correlation coefficient R=0.61 (FDR=0.27%). Melphalan sensitivity was associated with biologically interesting differences in gene expression of PIP4K2A (Phosphatidyloinositol-5-phosphate 4-kinase, type II, alpha; over-expressed in patients with high IC50 for this drug) and POLR2C (RNA Polymerase II, DNA directed, polypeptide C, 33 kDa; down-regulated in this subset of cases). Conclusions:Expression of a single genes is strongly associated with drug resistance in childhood acute leukemia, and it may aid to determine drug sensitivity to high-dose chemotherapy. Etoposide and fludarabine sensitivity seem to be related to the significant number of biologically important genes. Acknowledgments:This study was supported by grants MNiSW N407 078 32/2964 and UMK BW 10/09. JSz and MJ contributed equally to the study. Disclosures:No relevant conflicts of interest to declare.

The β 3 subunit of the Na +,K +-ATPase mediates variable nociceptive sensitivity in the formalin test

It is widely appreciated that there is significant inter-individual variability in pain sensitivity, yet only a handful of contributing genetic variants have been identified. Computational genetic mapping and quantitative trait locus analysis suggested that variation within the gene coding for the β 3 subunit of the Na +,K +-ATPase pump ( Atp1b3) contributes to inter-strain differences in the early phase formalin pain behavior. Significant strain differences in Atp1b3 gene expression, β 3 protein expression, and biophysical properties of the Na +,K + pump in dorsal root ganglia neurons from resistant (A/J) and sensitive (C57BL/6J) mouse strains supported the genetic prediction. Furthermore, in vivo siRNA knockdown of the β 3 subunit produced strain-specific changes in the early phase pain response, completely rescuing the strain difference. These findings indicate that the β 3 subunit of the Na +,K +-ATPase is a novel determinant of nociceptive sensitivity and further supports the notion that pain variability genes can have very selective effects on individual pain modalities.

The complete mitochondrial genome of the tobacco hornworm, Manduca sexta, (Insecta: Lepidoptera: Sphingidae), and an examination of mitochondrial gene variability within butterflies and moths

The entire mitochondrial genome of the tobacco hornworm, Manduca sexta (Lepidoptera: Spinghidae) was sequenced — a circular molecular 15516 bp in size. The arrangement of the protein coding genes (PCGs) was the same as that found in the ancestral insect, however Manduca possessed the derived tRNA arrangement of CR-M-I-Q which has been found in all Lepidoptera sequenced to date. Additionally, Manduca, like all lepidopteran mt genomes, has numerous large intergenic spacer regions and microsatellite-like repeat regions. Nucleotide composition is highly A+T biased, and the lepidopterans have the second most biased nucleotide composition of the insect orders after Hymenoptera. Secondary structural features of the PCGs identified in other Lepidoptera were present but highly modified by the presence of microsatellite-like repeat regions which may significantly alter their function in the post-transcriptional modification of pre-mRNAs. Secondary structure models of the ribosomal RNA genes of Manduca are presented and are similar to those proposed for other insect orders. Conserved regions were identified within non-translated spacer regions which correspond to sites for the origin and termination of replication and transcription. Comparisons of gene variability across the order suggest that the mitochondrial genes most frequently used in phylogenetic analysis of the Lepidoptera, cox1 and cox2, are amongst the least variable genes in the genome and phylogenetic resolution could be improved by using alternative, higher variability genes such as nad2, nad3, nad4 and nad5.

Genetics of coronary heart disease and its risk factors.

Lipoprotein parameters related to coronary heart disease (CHD) exhibit impressive heritability, and several traditional genetic marker systems are associated with lipid levels or CHD. Recent studies indicate a population-attributable risk of 28% for myocardial infarction for men below age 60 in the top quartile of Lp(a) lipoprotein levels. Thus, a high level of Lp(a) lipoprotein emerges as a major genetic risk factor for premature CHD. Studies of DNA polymorphisms at apolipoprotein loci have uncovered associations with lipid levels and genetic linkage between DNA polymorphisms at the apolipoprotein B (apoB) locus and the Ag(x) antigenic polymorphism of low density lipoprotein. This finding proves that the Ag(x) antigenic variation resides in apoB and co-assigns its locus to chromosome 2. Lipid associations of the Ag(x) polymorphism and of DNA polymorphisms at the apoB locus are internally consistent and consistent with association between Ag(x) and DNA variants. A new approach to the study of gene-environment interactions, using monozygotic twin pairs makes it possible to uncover genes that contribute to the frame within which lifestyle factors can cause changes in a clinically relevant quantitative parameter such as serum cholesterol concentration. A new concept of interaction between 'level genes' and 'variability genes' in the aetiology of atherosclerosis emerges from these studies.

Détection des gènes ica et de la production de slime parmi des souches de Staphylococcus epidermidis isolées d'infections liées aux cathéters chez des patients neutropéniques

Slime production, principal virulence factor of Staphylococcus epidermidis associated with catheter-related infections is mediated by icaADBC operon wich expression is subject to phase variation. Reversible transposition of IS256 element into this operon is one of the most important mechanisms of biofilm phenotypic variation. Our study compared 28 S. epidermidis strains from catheter-related infection to 28 strains from nasal carriage concerning slime production on Congo red agar plate and ica genes and IS256 presence by PCR. ica operon was present among all slime-producing strains, and was absent among slime-negative strains. Only 79% of ica-positive strains were slime producers and no insertion of IS256 element was detected inside ica genes. A significative difference was found between catheter-related infections strains and commensal ones in terms of oxacillin (67,8 versus 35,7%) and ofloxacin resistance (75 versus 35,7%), slime production (64,2 versus 28,5%), phase variability (46,4 versus 7,1%) and ica genes presence (82,1 versus 35,7%). Our study demonstrates the role of ica genes, of phenotypic variability of slime production and antibiotic multiresistance as virulence factors of S. epidermidis associated with catheter-related infections; it confirms also the complexity and the diversity of regulation mechanisms implicated in biofilm formation.

Genotype–Environment Interactions: Cognitive Aging and Social Factors

The possibility of genotype-environment interaction for memory performance and change was examined in 150 monozygotic (MZ) twin pairs from the Swedish Adoption Twin Study of Aging (SATSA). We used an MZ twin pair difference approach to examine the possibility that genotype was associated with intrapair variability and thus suggestive of genotype-nonshared environment interactions. Multiple 'variability genes' were found for longitudinal change in a semantic memory task including candidates coding for apolipoprotein E (APOE) and estrogen receptor alpha (ESR1) as well as serotonin candidates (HTR2A and 5HTT). One candidate also related to variability in change in episodic memory (5HTT). Of the significant associations observed, generally results indicated that MZ pairs who carry putative risk alleles were less variable than noncarriers, suggesting that noncarriers may be more sensitive to environmental contexts. We sought to 'contextualize' the possible nonshared environmental influences for found gene-environment (G x E) effects by considering intrapair differences in measured social and stress factors, including social support, life events and depressive symptoms. Results suggested that nonshared environmental influences associated with depressive symptoms may moderate the G x E relationship observed for ESR1 and APOE and longitudinal semantic memory change whereby noncarriers of putative risk alleles may be relatively more sensitive to depressionevoking environmental contexts than carriers of the risk allele. Thus, the contexts that facilitate or reduce depressive symptoms may affect semantic memory resiliency dependent on genotype. Further work ought to consider larger sample sizes as well as consider additional social and contextual factors.

Comparative sequence analysis of Solanum and Arabidopsis in a hot spot for pathogen resistance on potato chromosome V reveals a patchwork of conserved and rapidly evolving genome segments

BackgroundQuantitative phenotypic variation of agronomic characters in crop plants is controlled by environmental and genetic factors (quantitative trait loci = QTL). To understand the molecular basis of such QTL, the identification of the underlying genes is of primary interest and DNA sequence analysis of the genomic regions harboring QTL is a prerequisite for that. QTL mapping in potato (Solanum tuberosum) has identified a region on chromosome V tagged by DNA markers GP21 and GP179, which contains a number of important QTL, among others QTL for resistance to late blight caused by the oomycete Phytophthora infestans and to root cyst nematodes.ResultsTo obtain genomic sequence for the targeted region on chromosome V, two local BAC (bacterial artificial chromosome) contigs were constructed and sequenced, which corresponded to parts of the homologous chromosomes of the diploid, heterozygous genotype P6/210. Two contiguous sequences of 417,445 and 202,781 base pairs were assembled and annotated. Gene-by-gene co-linearity was disrupted by non-allelic insertions of retrotransposon elements, stretches of diverged intergenic sequences, differences in gene content and gene order. The latter was caused by inversion of a 70 kbp genomic fragment. These features were also found in comparison to orthologous sequence contigs from three homeologous chromosomes of Solanum demissum, a wild tuber bearing species. Functional annotation of the sequence identified 48 putative open reading frames (ORF) in one contig and 22 in the other, with an average of one ORF every 9 kbp. Ten ORFs were classified as resistance-gene-like, 11 as F-box-containing genes, 13 as transposable elements and three as transcription factors. Comparing potato to Arabidopsis thaliana annotated proteins revealed five micro-syntenic blocks of three to seven ORFs with A. thaliana chromosomes 1, 3 and 5.ConclusionComparative sequence analysis revealed highly conserved collinear regions that flank regions showing high variability and tandem duplicated genes. Sequence annotation revealed that the majority of the ORFs were members of multiple gene families. Comparing potato to Arabidopsis thaliana annotated proteins suggested fragmented structural conservation between these distantly related plant species.

AnovArray: a set of SAS macros for the analysis of variance of gene expression data

BackgroundAnalysis of variance is a powerful approach to identify differentially expressed genes in a complex experimental design for microarray and macroarray data. The advantage of the anova model is the possibility to evaluate multiple sources of variation in an experiment.ResultsAnovArray is a package implementing ANOVA for gene expression data using SAS® statistical software. The originality of the package is 1) to quantify the different sources of variation on all genes together, 2) to provide a quality control of the model, 3) to propose two models for a gene's variance estimation and to perform a correction for multiple comparisons.ConclusionAnovArray is freely available at and requires only SAS® statistical software.

Heritability of Longitudinal Changes in Coronary-Heart-Disease Risk Factors in Women Twins

Numerous studies have demonstrated genetic influences on levels of coronary heart disease (CHD) risk factors, but there also may be genetic effects on the intraindividual variation in these risk factors over time. Changes in risk factors are likely to reflect genetic-environmental interactions and may have important implications for understanding CHD risk. The present study examines the heritability of changes in CHD risk factors, using data from the two examinations by the Kaiser Permanente Women Twins Study, performed a decade apart. The sample consisted of 348 pairs of women twins who participated in both examinations, including 203 MZ pairs and 145 DZ pairs. Average ages at the two examinations were 41 and 51 years, respectively. By means of three different statistical analytic approaches, moderate heritability estimates were demonstrated for changes in LDL cholesterol (h2 = .25-.36) and in HDL cholesterol (h2 = .23-.58), some of which were statistically significant. Although small to moderate heritability estimates were found for systolic blood pressure (.18-.37; P < .05 for some estimates), no genetic influence on changes in diastolic blood pressure was detected. Based on longitudinal twin data in women, this study demonstrates a genetic influence on changes in both lipoprotein risk factors and systolic blood pressure over a decade. In addition to environmental factors, which clearly are operating, the effect of various "variability genes" may be acting independently of the genetic influences on the absolute levels of these risk factors. Both mapping the gene(s) underlying intraindividual variations in these CHD risk factors and understanding their function(s) could lead to targeted intervention strategies to reduce CHD risk among genetically susceptible individuals.