An evaluation of potential candidate genes involved in salinity tolerance in striped catfish (Pangasianodon hypopthalmus) using an RNA-SEQ approach

The project investigated the molecular response of Tra catfish (Pangasianodon hypophthalmus) to elevated salinity conditions. We employed Next generation sequencing platform to evaluate differential gene expression profiles of key genes under two salinity conditions. Results of the current project can form the basis for further studies to confirm the functional roles of specific genes that influence salinity tolerance in the target species and more broadly in other freshwater teleost fishes. Ultimately, the approach can contribute to developing superior culture stocks of the target species.

Identifying candidate gene effects by restricting search space in a multivariate genetic analysis of white matter microstructure

Several genetic variants are thought to influence white matter (WM) integrity, measured with diffusion tensor imaging (DTI). Voxel based methods can test genetic associations, but heavy multiple comparisons corrections are required to adjust for searching the whole brain and for all genetic variants analyzed. Thus, genetic associations are hard to detect even in large studies. Using a recently developed multi-SNP analysis, we examined the joint predictive power of a group of 18 cholesterol-related single nucleotide polymorphisms (SNPs) on WM integrity, measured by fractional anisotropy. To boost power, we limited the analysis to brain voxels that showed significant associations with total serum cholesterol levels. From this space, we identified two genes with effects that replicated in individual voxel-wise analyses of the whole brain. Multivariate analyses of genetic variants on a reduced anatomical search space may help to identify SNPs with strongest effects on the brain from a broad panel of genes.

A candidate gene association study for growth performance in an improved Giant Freshwater Prawn (Macrobrachium rosenbergii) culture line

A candidate gene approach using type I single nucleotide polymorphism (SNP) markers can provide an effective method for detecting genes and gene regions that underlie phenotypic variation in adaptively significant traits. In the absence of available genomic data resources, transcriptomes were recently generated in Macrobrachium rosenbergii to identify candidate genes and markers potentially associated with growth. The characterisation of 47 candidate loci by ABI re-sequencing of four cultured and eight wild samples revealed 342 putative SNPs. Among these, 28 SNPs were selected in 23 growth-related candidate genes to genotype in 200 animals selected for improved growth performance in an experimental GFP culture line in Vietnam. The associations between SNP markers and individual growth performance were then examined. For additive and dominant effects, a total of three exonic SNPs in glycogen phosphorylase (additive), heat shock protein 90 (additive and dominant) and peroxidasin (additive), and a total of six intronic SNPs in ankyrin repeats-like protein (additive and dominant), rolling pebbles (dominant), transforming growth factor-β induced precursor (dominant), and UTP-glucose-1-phosphate uridylyltransferase 2 (dominant) genes showed significant associations with the estimated breeding values in the experimental animals (P =0.001−0.031). Individually, they explained 2.6−4.8 % of the genetic variance (R2=0.026−0.048). This is the first large set of SNP markers reported for M. rosenbergii and will be useful for confirmation of associations in other samples or culture lines as well as having applications in marker-assisted selection in future breeding programs.

A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. © 2013 Mechelli et al.

The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (TRADD)

Objective: To replicate and refine the reported association of ankylosing spondylitis (AS) with two nonsynonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1. Methods: Firstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls. Results: The association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified. Conclusions: The region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain (TRADD), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.

Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspects

Introduction: A number of genetic-association studies have identified genes contributing to ankylosing spondylitis (AS) susceptibility but such approaches provide little information as to the gene activity changes occurring during the disease process. Transcriptional profiling generates a 'snapshot' of the sampled cells' activity and thus can provide insights into the molecular processes driving the disease process. We undertook a whole-genome microarray approach to identify candidate genes associated with AS and validated these gene-expression changes in a larger sample cohort. Methods: A total of 18 active AS patients, classified according to the New York criteria, and 18 gender- and age-matched controls were profiled using Illumina HT-12 whole-genome expression BeadChips which carry cDNAs for 48,000 genes and transcripts. Class comparison analysis identified a number of differentially expressed candidate genes. These candidate genes were then validated in a larger cohort using qPCR-based TaqMan low density arrays (TLDAs). Results: A total of 239 probes corresponding to 221 genes were identified as being significantly different between patients and controls with a P-value <0.0005 (80% confidence level of false discovery rate). Forty-seven genes were then selected for validation studies, using the TLDAs. Thirteen of these genes were validated in the second patient cohort with 12 downregulated 1.3- to 2-fold and only 1 upregulated (1.6-fold). Among a number of identified genes with well-documented inflammatory roles we also validated genes that might be of great interest to the understanding of AS progression such as SPOCK2 (osteonectin) and EP300, which modulate cartilage and bone metabolism. Conclusions: We have validated a gene expression signature for AS from whole blood and identified strong candidate genes that may play roles in both the inflammatory and joint destruction aspects of the disease.

Discovery of candidate serum proteomic and metabolomic biomarkers in ankylosing spondylitis

Ankylosing Spondylitis (AS) is a common inflammatory rheumatic disease with a predilection for the axial skeleton, affecting 0.2% of the population. Current diagnostic criteria rely on a composite of clinical and radiological changes, with a mean time to diagnosis of 5 to 10 years. In this study we employed nano liquid-chromatography mass spectrometry analysis to detect and quantify proteins and small compounds including endogenous peptides and metabolites in serum from 18 AS patients and nine healthy individuals. We identified a total of 316 proteins in serum, of which 22 showed significant up- or down-regulation (p < 0.05) in AS patients. Receiver operating characteristic analysis of combined levels of serum amyloid P component and inter-α-trypsin inhibitor heavy chain 1 revealed high diagnostic value for Ankylosing Spondylitis (area under the curve = 0.98). We also depleted individual sera of proteins to analyze endogenous peptides and metabolic compounds. We detected more than 7000 molecular features in patients and healthy individuals. Quantitative MS analysis revealed compound profiles that correlate with the clinical assessment of disease activity. One molecular feature identified as a Vitamin D3 metabolite-(23S,25R)-25-hydroxyvitamin D3 26,23-peroxylactone-was down-regulated in AS. The ratio of this vitamin D metabolite versus vitamin D binding protein serum levels was also altered in AS as compared with controls. These changes may contribute to pathological skeletal changes in AS. Our study is the first example of an integration of proteomic and metabolomic techniques to find new biomarker candidates for the diagnosis of Ankylosing Spondylitis

Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene

Ankylosing spondylitis (AS) is polygenic with contributions from the immunologically relevant genes HLA-B27, ERAP1 and IL23R. A recent genome-wide association screen (GWAS) identified associations (P0.005) with the non-synonymous single-nucleotide polymorphisms (nsSNPs), rs4077515 and rs3812571, in caspase recruitment domain-containing protein 9 (CARD9) and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) on chromosome 9q that had previously been linked to AS. We replicated these associations in a study of 730 AS patients compared with 2879 historic disease controls (rs4077515 P0.0004, odds ratio (OR)1.2, 95% confidence interval (CI)1.1-1.4; rs3812571 P0.0003, OR1.2, 95% CI1.1-1.4). Meta-analysis revealed strong associations of both SNPs with AS, rs4077515 P0.000005, OR1.2, 95% CI1.1-1.3 and rs3812571 P0.000006, OR1.2, 95% CI1.1-1.3. We then typed 1604 AS cases and 1020 controls for 13 tagging SNPs; 6 showed at least nominal association, 5 of which were in CARD9. We imputed genotypes for 13 additional SNPs but none was more strongly associated with AS than the tagging SNPs. Finally, interrogation of an mRNA expression database revealed that the SNPs most strongly associated with AS (or in strong linkage disequilibrium) were those most associated with CARD9 expression. CARD9 is a plausible candidate for AS given its central role in the innate immune response.

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of approximately 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25,000 single-nucleotide polymorphisms (SNPs) located within approximately 14,000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case-control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

Evaluation of potential candidate genes involved in salinity tolerance in striped catfish (Pangasianodon hypophthalmus) using an RNA-Seq approach

Increasing salinity levels in freshwater and coastal environments caused by sea level rise linked to climate change is now recognized to be a major factor that can impact fish growth negatively, especially for freshwater teleost species. Striped catfish (Pangasianodon hypophthalmus) is an important freshwater teleost that is now widely farmed across the Mekong River Delta in Vietnam. Understanding the basis for tolerance and adaptation to raised environmental salinity conditions can assist the regional culture industry to mitigate predicted impacts of climate change across this region. Attempt of next generation sequencing using the ion proton platform results in more than 174 million raw reads from three tissue libraries (gill, kidney and intestine). Reads were filtered and de novo assembled using a variety of assemblers and then clustered together to generate a combined reference transcriptome. Downstream analysis resulted in a final reference transcriptome that contained 60,585 transcripts with an N50 of 683 bp. This resource was further annotated using a variety of bioinformatics databases, followed by differential gene expression analysis that resulted in 3062 transcripts that were differentially expressed in catfish samples raised under two experimental conditions (0 and 15 ppt). A number of transcripts with a potential role in salinity tolerance were then classified into six different functional gene categories based on their gene ontology assignments. These included; energy metabolism, ion transportation, detoxification, signal transduction, structural organization and detoxification. Finally, we combined the data on functional salinity tolerance genes into a hypothetical schematic model that attempted to describe potential relationships and interactions among target genes to explain the molecular pathways that control adaptive salinity responses in P. hypophthalmus. Our results indicate that P. hypophthalmus exhibit predictable plastic regulatory responses to elevated salinity by means of characteristic gene expression patterns, providing numerous candidate genes for future investigations.

Critical success factors of process modeling for enterprise systems

The integrated and process oriented nature of Enterprise Systems (ES) has led organizations to use process modeling as an aid in managing these systems. Enterprise Systems success factor studies explicitly and implicitly state the importance of process modeling and its contribution to overall Enterprise System success. However, no empirical evidence exists on how to conduct process modeling successfully and possibly differentially in the main phases of the ES life-cycle. This paper reports on an empirical investigation of the factors that influence process modeling success. An a-priori model with 8 candidate success factors has been developed to this stage. This paper introduces the research context and objectives, describes the research design and the derived model, and concludes by looking ahead to the next phases of the research design.

Two main challenges in service description : Web service tunnel vision and semantic myopia

Through media such as newspapers, letterbox flyers, corporate brochures and television we are regularly confronted with descriptions for conventional (bricks 'n' mortar style) services. These representations vary in the terminology utilised, the depth of the description, the aspects of the service that are characterised and their applicability to candidate service requestors. Existing service catalogues (such as the Yellow Pages) provide little relief for service requestors from the burdensome task of discovering, comparing and substituting services. Add to this environment the rapidly evolving area of web services with its associated surfeit of standards, and the result is a considerably fragmented approach to the description of services. It leaves the reality of the Semantic Web somewhat clouded. --------- Let's consider service description briefly, before discussing our concerns with existing approaches to description. The act of describing is performed prior to advertising. This simple fact provides an interesting paradox as services cannot be described exactly before advertisement. This doesn't mean they can't be described comprehensively. By "exactly", we are referring to the fact that context provided by a service requestor (and their service needs) will alter the description of the service that is presented to the discoverer. For example, a service provider who operates a cinema wants to describe the price of their service. Let's say the advertised price is $15. They also want to state that a pensioner discount and a student discount is available which provides a 50% discount. A customer (i.e. service requestor) uses the cinema web site to purchase tickets online. They find the movie of their choice at a time that suits. However, its not until some context is provided by the requestor that the exact price is determined. The requestor might state that they are a pensioner. The same is applicable for a service requestor who purchases multiple tickets perhaps on behalf of other people. The disconnect between when the service is described and when a requestor provides context introduces challenges to the description process. A service provider would be ill-advised to offer independent descriptions that represent all the permutations possible for a single service. The descriptive effort would be prohibitive.

The guide to the project management body of knowledge (PMBOK Guide) : applicability and contribution to project success in Australia

The PMBOK Guide is one of the most influential publications concerning the knowledge of the project manangement. Moreover, the pervasion of this guide seems to be set to increase as the basis of accreditation - in conjunction with the increasing global trend toward obtaining project management professional status. However, despite the influence and strengthening profile of this guide, reports continue to be published that detail numerous project failures in a wide range of different industries. The PMBOK Guide comprises mainly declarative (know-what) and procedural (know-how) information. In this sense, the guide is largely normative and provides a very good example of the limitations of this approach as highlighted by proponents of a move to the genuine application of positibe theory in project management.----- The aim of this paper is to determine the applicability of the guide in Australia and to determine the extent to which project success can be attributed to the guide. Project Managers from a variety of organisations were surveyed. This postal survey yielded 48 replies. Descriptive statistics was used to assess the incidence and effectivieness of all the processes in the guide. The results indicate that there were no processes that could be considered as peripheral or as a candidate for elimination from the guide. More specifically, all the processes were identified as either a key routine process or a key selective process and positively related to the level of project success. However, the results also indicated that other major factors pertaining to causal knowledge (know-why) are, at least, equally important determinants of project success. It is concluded that declarative, procedural and causal knowledge are all valuable, and given the preponderance of the first two types of knowledge, there seems to be an urgent need to now ensure an equal quest for causal knowledge. In terms of developing causal knowledge, a good starting point would appear to be both positive theory from production and economics.