Genes Overlapped Research Articles

Revisiting Connectivity Map from a gene co‑expression network analysis

The Connectivity Map (CMap) is a tool that has been extensively utilized to study drug repositioning and side-effect prediction. However, most of these analyses rely on signature genes, ignoring the pathways by which those genes are regulated, as well as the functional overlap of redundant genes. The present study utilized a systems biology approach referred to as Weighted Gene Co-expression Network Analysis (WGCNA) to dissect the transcriptional profiles of CMap and reveal these hidden factors. Seven common modules associated with protein binding, extracellular matrix organization and translation were identified. Furthermore, drugs were clustered based on module expression to infer their mechanism of action (MoA) based on common activity profiles. As an extension of this, an example of disease-based module projection to identify novel drugs was provided. The analysis developed in the present study may provide a novel framework for drug repositioning or discovering MoAs.

Cross talk of chromosome instability, CpG island methylator phenotype and mismatch repair in colorectal cancer.

Colorectal cancer is a severe cancer associated with a high prevalence and fatality rate. There are three major mechanisms for colorectal cancer: (1) Chromosome instability (CIN), (2) CpG island methylator phenotype (CIMP) and (3) mismatch repair (MMR), of which CIN is the most common type. However, these subtypes are not exclusive and overlap. To investigate their biological mechanisms and cross talk, the gene expression profiles of 585 colorectal cancer patients with CIN, CIMP and MMR status records were collected. By comparing the CIN+ and CIN-samples, CIMP+ and CIMP-samples, MMR+ and MMR-samples with minimal redundancy maximal relevance (mRMR) and incremental feature selection (IFS) methods, the CIN, CIMP and MMR associated genes were selected. Unfortunately, there was little direct overlap among them. To investigate their indirect interactions, downstream genes of CIN, CIMP and MMR were identified using the random walk with restart (RWR) method and a greater overlap of downstream genes was indicated. The common downstream genes were involved in biosynthetic and metabolic pathways. These findings were consistent with the clinical observation of wide range metabolite aberrations in colorectal cancer. To conclude, the present study gave a gene level explanation of CIN, CIMP and MMR, but also showed the network level cross talk of CIN, CIMP and MMR. The common genes of CIN, CIMP and MMR may be useful for cross-subtype general colorectal cancer drug development.

Genes and functions from breast cancer signatures

BackgroundBreast cancer is a heterogeneous disease and personalized medicine is the hope for the improvement of the clinical outcome. Multi-gene signatures for breast cancer stratification have been extensively studied in the past decades and more than 30 different signatures have been reported. A major concern is the minimal overlap of genes among the reported signatures. We investigated the breast cancer signature genes to address our hypothesis that the genes of different signature may share common functions, as well as to use these previously reported signature genes to build better prognostic models.MethodsA total of 33 signatures and the corresponding gene lists were investigated. We first examined the gene frequency and the gene overlap in these signatures. Then the gene functions of each signature gene list were analysed and compared by the KEGG pathways and gene ontology (GO) terms. A classifier built using the common genes was tested using the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) data. The common genes were also tested for building the Yin Yang gene mean expression ratio (YMR) signature using public datasets (GSE1456 and GSE2034).ResultsAmong a total of 2239 genes collected from the 33 breast cancer signatures, only 238 genes overlapped in at least two signatures; while from a total of 1979 function terms enriched in the 33 signature gene lists, 429 terms were common in at least two signatures. Most of the common function terms were involved in cell cycle processes. While there is almost no common overlapping genes between signatures developed for ER-positive (e.g. 21-gene signature) and those developed for ER-negative (e.g. basal signatures) tumours, they have common function terms such as cell death, regulation of cell proliferation. We used the 62 genes that were common in at least three signatures as a classifier and subtyped 1141 METABRIC cases including 144 normal samples into nine subgroups. These subgroups showed different clinical outcome. Among the 238 common genes, we selected those genes that are more highly expressed in normal breast tissue than in tumours as Yang genes and those more highly expressed in tumours than in normal as Yin genes and built a YMR model signature. This YMR showed significance in risk stratification in two datasets (GSE1456 and GSE2034).ConclusionsThe lack of significant numbers of overlapping genes among most breast cancer signatures can be partially explained by our discovery that these signature genes represent groups with similar functions. The genes collected from these previously reported signatures are valuable resources for new model development. The subtype classifier and YMR signature built from the common genes showed promising results.

Deciphering the Origin and Evolution of Hepatitis B Viruses

Hepatitis B viruses constitute the family Hepadnaviridae, enveloped viruses with reverse‐transcribed DNA genomes. An outstanding feature is their streamlined genome organization with extensive gene overlap. Remarkably, the ~1,100 bp long open reading frame (ORF) coding for the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of hepatitis B viruses including genome replication via protein‐primed reverse‐transcription and utilization of structurally related capsids. Phylogenetic reconstruction revealed that both virus families separated more than 400 million years ago before the rise of tetrapods. We show that hepatitis B viruses are of ancient origin, descending from non‐enveloped progenitors in fishes. Their envelope protein gene emerged de novo leading to a major transition in viral life‐style, followed by co‐evolution with their hosts over geologic eras.

O4.2. HERITABILITY AND CORRELATION TO SCHIZOPHRENIA SPECTRUM DISORDER OF GLUTAMATE AND OTHER NEUROMETABOLITE LEVELS IN ANTERIOR CINGULATE AND LEFT THALAMUS: A REGISTER BASED MAGNETIC RESONANCE TWIN STUDY

BackgroundGlutamatergic changes in schizophrenia may precede dopaminergic alterations leading to psychopathology as part of a dopaminergic pathway, or they may represent a distinct pathophysiology. It is unknown if these glutamatergic alterations are due to genetic influences, although findings in gene studies implicate the NMDA receptor. Higher levels of glutamate and glutamine have been reported in the thalamus of patients with schizophrenia, while studies of the anterior cingulate cortex (ACC) have reported increased, decreased, and unaltered levels compared to healthy controls.By studying discordant mono- (MZ) and dizygotic (DZ) twins it is possible to estimate heritability and correlation to disease in the same population. This kind of study has only been done once on glutamate levels, but no heritability estimates were reported.1 A study of older healthy twins found N-acetyl aspartate (NAA), choline (Cho), creatinine (Cr), and myo-inositol (MI) levels to be heritable in posterior cingulate cortex.2 Of these metabolites, NAA has generally been found to correlate negatively with schizophrenia. Here we present our final results on heritability, and correlation to liability for schizophrenia spectrum disorder (ICD-10 F2x.x) of the neurometabolite levels in the ACC and the left thalamus.MethodsBy linking The Danish Twin Register and The Danish Psychiatric Central Research Register, 25 complete MZ and 21 complete DZ twin pairs con- or discordant for schizophrenia spectrum disorder (ICD 10 F2x.x) and 29 complete MZ and 20 complete DZ healthy control pairs were included. Thirteen additional twins were scanned without their siblings. Spectra of glutamate, Glx, NAA, Cho, Cr and MI were obtained by [1H]-MR spectroscopy at 3 tesla and analyzed by using LCModel. Additive genetic, common environmental and unique environmental effects on metabolite levels were calculated by structural equation modeling with openMX software. The best fitting model was determined by the Akaike Information Criterion.ResultsIn the ACC heritability estimates were significant for glutamate (29%), Glx (31%), NAA (39%), Cho (38%), Cr (37%) and MI (33%). In the left thalamus we found significant estimates of heritability for glutamate (16%), Glx (31%), Cho (60%), and of common environment for Cr (29%). A significant positive correlation to schizophrenia spectrum liability was found for glutamate in the left thalamus (r=0.16; p = 0.03), and negative correlations were found for NAA (r = -0.16; p = 0.02) and Cr (r = -0.25; p = 0.006) in the ACC. For glutamate in the thalamus and Cr in the ACC the significant correlation to disease was due to overlapping genetic effects influencing both metabolite and disease.DiscussionIn this the first study to estimate heritability of glutamate levels in the brain, the primary findings are that glutamate levels in both the ACC and the left thalamus are heritable, and in the left thalamus also correlated to disease with a significant genetic overlap. This emphasizes glutamate levels in the left thalamus as a potential endophenotypic marker for schizophrenia. NAA and Cr were negatively correlated to disease in the ACC, which could point to disturbances of neuronal health and metabolism. For Cr an overlap of genes influencing both metabolite levels and disease suggests Cr as a possible candidate endophenotype.

Trade-offs in aging lung diseases: a review on shared but opposite genetic risk variants in idiopathic pulmonary fibrosis, lung cancer and chronic obstructive pulmonary disease.

Purpose of reviewThe process of aging involves biological changes that increases susceptibility for disease. In the aging lung disease IPF, GWAS studies identified genes associated with risk for disease. Recently, several of these genes were also found to be involved in risk for COPD or lung cancer. This review describes GWAS-derived risk genes for IPF that overlap with risk genes for lung cancer or COPD.Recent findingsRisk genes that overlap between aging lung diseases, include FAM13A, DSP and TERT. Most interestingly, disease predisposing alleles for IPF are opposite to those for COPD or lung cancer. Studies show that the alleles are associated with differential gene expression and with physiological traits in the general population. The opposite allelic effect sizes suggest the presence of trade-offs in the aging lung. For TERT, the trade-off involves cellular senescence versus proliferation and repair. For FAM13A and DSP, trade-offs may involve protection from noxious gases or tissue integrity.SummaryThe overlap in risk genes in aging lung diseases provides evidence that processes associated with FAM13A, DSP and TERT are important for healthy aging. The opposite effect size of the disease risk alleles may represent trade-offs, for which a model involving an apicobasal gene expression gradient is presented.

A systematic approach for identifying shared mechanisms in epilepsy and its comorbidities.

Cross-sectional epidemiological studies have shown that the incidence of several nervous system diseases is more frequent in epilepsy patients than in the general population. Some comorbidities [e.g. Alzheimer’s disease (AD) and Parkinson’s disease] are also risk factors for the development of seizures; suggesting they may share pathophysiological mechanisms with epilepsy. A literature-based approach was used to identify gene overlap between epilepsy and its comorbidities as a proxy for a shared genetic basis for disease, or genetic pleiotropy, as a first effort to identify shared mechanisms. While the results identified neurological disorders as the group of diseases with the highest gene overlap, this analysis was insufficient for identifying putative common mechanisms shared across epilepsy and its comorbidities. This motivated the use of a dedicated literature mining and knowledge assembly approach in which a cause-and-effect model of epilepsy was captured with Biological Expression Language. After enriching the knowledge assembly with information surrounding epilepsy, its risk factors, its comorbidities, and anti-epileptic drugs, a novel comparative mechanism enrichment approach was used to propose several downstream effectors (including the GABA receptor, GABAergic pathways, etc.) that could explain the therapeutic effects carbamazepine in both the contexts of epilepsy and AD. We have made the Epilepsy Knowledge Assembly available at https://www.scai.fraunhofer.de/content/dam/scai/de/downloads/bioinformatik/epilepsy.bel and queryable through NeuroMMSig at http://neurommsig.scai.fraunhofer.de. The source code used for analysis and tutorials for reproduction are available on GitHub at https://github.com/cthoyt/epicom.

Oral cancer databases: A comprehensive review.

Cancer database is a systematic collection and analysis of information on various human cancers at genomic and molecular level that can be utilized to understand various steps in carcinogenesis and for therapeutic advancement in cancer field. Oral cancer is one of the leading causes of morbidity and mortality all over the world. The current research efforts in this field are aimed at cancer etiology and therapy. Advanced genomic technologies including microarrays, proteomics, transcrpitomics, and gene sequencing development have culminated in generation of extensive data and subjection of several genes and microRNAs that are distinctively expressed and this information is stored in the form of various databases. Extensive data from various resources have brought the need for collaboration and data sharing to make effective use of this new knowledge. The current review provides comprehensive information of various publicly accessible databases that contain information pertinent to oral squamous cell carcinoma (OSCC) and databases designed exclusively for OSCC. The databases discussed in this paper are Protein-Coding Gene Databases and microRNA Databases. This paper also describes gene overlap in various databases, which will help researchers to reduce redundancy and focus on only those genes, which are common to more than one databases. We hope such introduction will promote awareness and facilitate the usage of these resources in the cancer research community, and researchers can explore the molecular mechanisms involved in the development of cancer, which can help in subsequent crafting of therapeutic strategies.

Genetic contributions to precocity traits in racing Thoroughbreds.

Adaptation to early training and racing (i.e. precocity), which is highly variable in racing Thoroughbreds, has implications for the selection and training of horses. We hypothesised that precocity in Thoroughbred racehorses is heritable. Age at first sprint training session (work day), age at first race and age at best race were used as phenotypes to quantify precocity. Using high-density SNP array data, additive SNP heritability (hSNP2) was estimated to be 0.17, 0.14 and 0.17 for the three traits respectively. In genome-wide association studies (GWAS) for age at first race and age at best race, a 1.98-Mb region on equine chromosome 18 (ECA18) was identified. The most significant association was with the myostatin (MSTN) g.66493737C>T SNP (P=5.46×10-12 and P=1.89×10-14 respectively). In addition, two SNPs on ECA1 (g.37770220G>A and g.37770305T>C) within the first intron of the serotonin receptor gene HTR7 were significantly associated with age at first race and age at best race. Although no significant associations were identified for age at first work day, the MSTN:g.66493737C>T SNP was among the top 20 SNPs in the GWAS (P=3.98×10-5 ). Here we have identified variants with potential roles in early adaptation to training. Although there was an overlap in genes associated with precocity and distance aptitude (i.e. MSTN), the HTR7 variants were more strongly associated with precocity than with distance. Because HTR7 is closely related to the HTR1A gene, previously implicated in tractability in young Thoroughbreds, this suggests that behavioural traits may influence precocity.

Gene expression profiles of M1 and M2 microglia characterized by comparative analysis of public datasets

AbstractObjectiveMicroglia, immunocompetent cells in the central nervous system, adopt two distinct activation phenotypes, composed of a pro‐inflammatory and neurotoxic “classical” activation (M1) phenotype by exposure to lipopolysaccharide and interferon‐γ, and an anti‐inflammatory and neuroprotective “alternative” activation (M2) phenotype after treatment with interleukin‐4 and interleukin‐13. Recently, gene expression profiling using DNA microarray and high‐throughput sequencing technologies identified valid markers specific for microglia. However, we have fairly limited knowledge on comprehensive gene expression signatures of functionally polarized microglia. By comparative analysis of public datasets, we attempted to characterize the set of the genes specific for microglia polarized to M1, M2a and Mtgf, and the overlap of these marker genes in distinct activation phenotypes.MethodsWe retrieved five different microarray datasets of microglial gene expression from Gene Expression Omnibus, and analyzed them by GEO2R. We identified overlapping genes in various experimental conditions by Gene List Venn Diagram.ResultsWe found that the set of M1, M2a and Mtgf marker genes are highly variable among distinct datasets analyzed. Human microglia showed gene expression profiles quite different from those of mouse microglia. Rat amoeboid microglia in part showed the M1‐polarized phenotype. A substantial number of the genes upregulated under both M1‐polarizing and M2a‐polarizing conditions suggest common signaling pathways for M1 and M2 activation of microglia. Counteracting regulation was found between M1 and Mtgf gene expression.ConclusionsThe great variability of M1 and M2 microglial gene expression profiles is attributable to differences in the methods of preparation of microglia, culture conditions and platforms of microarray analyzed.

Species-specific genes under selection characterize the co-evolution of slavemaker and host lifestyles

BackgroundThe transition to a parasitic lifestyle entails comprehensive changes to the selective regime. In parasites, genes encoding for traits that facilitate host detection, exploitation and transmission should be under selection. Slavemaking ants are social parasites that exploit the altruistic behaviour of their hosts by stealing heterospecific host brood during raids, which afterwards serve as slaves in slavemaker nests. Here we search for evidence of selection in the transcriptomes of three slavemaker species and three closely related hosts. We expected selection on genes underlying recognition and raiding or defense behaviour. Analyses of selective forces in species with a slavemaker or host lifestyle allowed investigation into whether or not repeated instances of slavemaker evolution share the same genetic basis.To investigate the genetic basis of host-slavemaker co-evolution, we created orthologous clusters from transcriptome sequences of six Temnothorax ant species - three slavemakers and three hosts - to identify genes with signatures of selection. We further tested for functional enrichment in selected genes from slavemakers and hosts respectively and investigated which pathways the according genes belong to.ResultsOur phylogenetic analysis, based on more than 5000 ortholog sequences, revealed sister species status for two slavemakers as well as two hosts, contradicting a previous phylogeny based on mtDNA. We identified 309 genes with signs of positive selection on branches leading to slavemakers and 161 leading to hosts. Among these were genes potentially involved in cuticular hydrocarbon synthesis, thus species recognition, and circadian clock functionality possibly explaining the different activity patterns of slavemakers and hosts. There was little overlap of genes with signatures of positive selection among species, which are involved in numerous different functions and different pathways.ConclusionsWe identified different genes, functions and pathways under positive selection in each species. These results point to species-specific adaptations rather than convergent trajectories during the evolution of the slavemaker and host lifestyles suggesting that the evolution of parasitism, even in closely related species, may be achieved in diverse ways.

Environmental variation partitioned into separate heritable components.

Trait variation is normally separated into genetic and environmental components, yet genetic factors also control the expression of environmental variation, encompassing plasticity across environmental gradients and within-environment responses. We defined four components of environmental variation: plasticity across environments, variability in plasticity, variation within environments, and differences in within-environment variation across environments. We assessed these components for cold tolerance across five rearing temperatures using the Drosophila melanogaster Genetic Reference Panel (DGRP). The four components were found to be heritable, and genetically correlated to different extents. By whole genome single marker regression, we detected multiple candidate genes controlling the four components and showed limited overlap in genes affecting them. Using the binary UAS-GAL4 system, we functionally validated the effects of a subset of candidate genes affecting each of the four components of environmental variation and also confirmed the genetic and phenotypic correlations obtained from the DGRP in distinct genetic backgrounds. We delineate selection targets associated with environmental variation and the constraints acting upon them, providing a framework for evolutionary and applied studies on environmental sensitivity. Based on our results we suggest that the traditional quantitative genetic view of environmental variation and genotype-by-environment interactions needs revisiting.

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease.Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer-derived murine cell lines.Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy.Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. Clin Cancer Res; 23(22); 7072-83. ©2017 AACR.

OverGeneDB: a database of 5' end protein coding overlapping genes in human and mouse genomes.

Gene overlap plays various regulatory functions on transcriptional and post-transcriptional levels. Most current studies focus on protein-coding genes overlapping with non-protein-coding counterparts, the so called natural antisense transcripts. Considerably less is known about the role of gene overlap in the case of two protein-coding genes. Here, we provide OverGeneDB, a database of human and mouse 5′ end protein-coding overlapping genes. The database contains 582 human and 113 mouse gene pairs that are transcribed using overlapping promoters in at least one analyzed library. Gene pairs were identified based on the analysis of the transcription start site (TSS) coordinates in 73 human and 10 mouse organs, tissues and cell lines. Beside TSS data, resources for 26 human lung adenocarcinoma cell lines also contain RNA-Seq and ChIP-Seq data for seven histone modifications and RNA Polymerase II activity. The collected data revealed that the overlap region is rarely conserved between the studied species and tissues. In ∼50% of the overlapping genes, transcription started explicitly in the overlap regions. In the remaining half of overlapping genes, transcription was initiated both from overlapping and non-overlapping TSSs. OverGeneDB is accessible at http://overgenedb.amu.edu.pl.

Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model.

Background & AimsThe incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis.MethodsA time-course study in low-density lipoprotein–receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets.ResultsHigh-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis.ConclusionsAn early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames.

Hypoxia-inducible factor 2α (HIF-2α) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity

Colorectal cancer (CRC) is the third-leading cause of cancer mortality in the United States and other industrialized countries. A hypoxic microenvironment is a hallmark for solid tumors. The hypoxia-induced signal transduction is transcriptionally mediated by hypoxia-inducible factor (HIF). Three major HIF isoforms, HIF-1α, HIF-2α, and HIF-3α, are present in the intestine. Our previous work demonstrates that HIF-2α is essential for CRC growth and progression. However, the mechanisms mediating cell proliferation after hypoxia or HIF-2α activation in CRC are unclear. Data mining of RNA-Seq experiments with mouse models of intestinal HIF-2α or Yes-associated protein 1 (YAP1) overexpression indicates a significant overlap of genes in these conditions. YAP1 is a transcriptional co-activator in the Hippo signaling pathway, and YAP1-induced transcriptional responses are essential in cancer cell proliferation. Here, we report that HIF-2α robustly increases YAP1 expression and activity in CRC-derived cell lines and in mouse models. The potentiation of YAP1 activity by HIF-2α was not via canonical signaling mechanisms such as Src (non-receptor tyrosine kinase), PI3K, ERK, or MAPK pathways. Moreover, we detected no direct interaction of HIF-2α with YAP1. Of note, YAP1 activation was critical for cancer cell growth under hypoxia. Our findings indicate that HIF-2α increases cancer cell growth by up-regulating YAP1 activity, suggesting that this pathway might be targeted in potential anti-cancer approaches for treating CRC patients.

Genetic Architecture of Charcoal Rot (Macrophomina phaseolina) Resistance in Soybean Revealed Using a Diverse Panel.

Charcoal rot (CR) disease caused by Macrophomina phaseolina is responsible for significant yield losses in soybean production. Among the methods available for controlling this disease, breeding for resistance is the most promising. Progress in breeding efforts has been slow due to the insufficient information available on the genetic mechanisms related to resistance. Genome-wide association studies (GWAS) enable unraveling the genetic architecture of resistance and identification of causal genes. The aims of this study were to identify new sources of resistance to CR in a collection of 459 diverse plant introductions from the USDA Soybean Germplasm Core Collection using field and greenhouse screenings, and to conduct GWAS to identify candidate genes and associated molecular markers. New sources for CR resistance were identified from both field and greenhouse screening from maturity groups I, II, and III. Five significant single nucleotide polymorphism (SNP) and putative candidate genes related to abiotic and biotic stress responses are reported from the field screening; while greenhouse screening revealed eight loci associated with eight candidate gene families, all associated with functions controlling plant defense response. No overlap of markers or genes was observed between field and greenhouse screenings suggesting a complex molecular mechanism underlying resistance to CR in soybean with varied response to different environments; but our findings provide useful information for advancing breeding for CR resistance as well as the genetic mechanism of resistance.

Characterization of Truncated dsz Operon Responsible for Dibenzothiophene Biodesulfurization in Rhodococcus sp. FUM94.

Numerous desulfurizing bacteria from the Rhodococcus genus harbor conserved dsz genes responsible for the degradation of sulfur compounds through 4S pathway. This study describes a newly identified desulfurizing bacterium, Rhodococcus sp. FUM94, which unlike previously identified strains encodes a truncated dsz operon. DNA sequencing revealed a frameshift mutation in the dszA gene, which led to an alteration of 66 amino acids and deletion of other C-terminal 66 amino acids. The resulting DszA polypeptide was shorter than DszA in Rhodococcus sp. IGTS8 reference strain. Despite the truncation, desulfurizing activity of the operon was observed and attributed to the removal of an overlap of dszA and dszB genes, and lack of active site in the altered region. Desulfurization experiments resulted in specific production rate of 6.3mmol 2-hydroxy biphenyl (kgDCW)-1h-1 at 2gl-1 biocatalyst concentration and 68.8% biodesulfurization yield at 20gl-1 biocatalyst concentration, both at 271μM dibenzothiophene concentration which is comparable to similar wild-type biocatalysts.

A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors

Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 × 10−5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.

Deciphering the Origin and Evolution of Hepatitis B Viruses by Means of a Family of Non-enveloped Fish Viruses

SummaryHepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome organization with extensive gene overlap. Remarkably, the ∼1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via protein-primed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras.