CytoSolve: A Scalable Computational Method for Dynamic Integration of Multiple Molecular Pathway Models

A grand challenge of computational systems biology is to create a molecular pathway model of the whole cell. Current approaches involve merging smaller molecular pathway models’ source codes to create a large monolithic model (computer program) that runs on a single computer. Such a larger model is difficult, if not impossible, to maintain given ongoing updates to the source codes of the smaller models. This paper describes a new system called CytoSolve that dynamically integrates computations of smaller models that can run in parallel across different machines without the need to merge the source codes of the individual models. This approach is demonstrated on the classic Epidermal Growth Factor Receptor (EGFR) model of Kholodenko. The EGFR model is split into four smaller models and each smaller model is distributed on a different machine. Results from four smaller models are dynamically integrated to generate identical results to the monolithic EGFR model running on a single machine. The overhead for parallel and dynamic computation is approximately twice that of a monolithic model running on a single machine. The CytoSolve approach provides a scalable method since smaller models may reside on any computer worldwide, where the source code of each model can be independently maintained and updated

Right-Wing Politicians Prefer the Emotional Left

Physiological research suggests that social attitudes, such as political beliefs, may be partly hard-wired in the brain. Conservatives have heightened sensitivity for detecting emotional faces and use emotion more effectively when campaigning. As the left face displays emotion more prominently, we examined 1538 official photographs of conservative and liberal politicians from Australia, Canada, the United Kingdom and the United States for an asymmetry in posing. Across nations, conservatives were more likely than liberals to display the left cheek. In contrast, liberals were more likely to face forward than were conservatives. Emotion is important in political campaigning and as portraits influence voting decisions, conservative politicians may intuitively display the left face to convey emotion to voters

Sex Differences in Genetic Architecture of Complex Phenotypes?

We examined sex differences in familial resemblance for a broad range of behavioral, psychiatric and health related phenotypes (122 complex traits) in children and adults. There is a renewed interest in the importance of genotype by sex interaction in, for example, genome-wide association (GWA) studies of complex phenotypes. If different genes play a role across sex, GWA studies should consider the effect of genetic variants separately in men and women, which affects statistical power. Twin and family studies offer an opportunity to compare resemblance between opposite-sex family members to the resemblance between same-sex relatives, thereby presenting a test of quantitative and qualitative sex differences in the genetic architecture of complex traits. We analyzed data on lifestyle, personality, psychiatric disorder, health, growth, development and metabolic traits in dizygotic (DZ) same-sex and opposite-sex twins, as these siblings are perfectly matched for age and prenatal exposures. Sample size varied from slightly over 300 subjects for measures of brain function such as EEG power to over 30,000 subjects for childhood psychopathology and birth weight. For most phenotypes, sample sizes were large, with an average sample size of 9027 individuals. By testing whether the resemblance in DZ opposite-sex pairs is the same as in DZ same-sex pairs, we obtain evidence for genetic qualitative sex-differences in the genetic architecture of complex traits for 4% of phenotypes. We conclude that for most traits that were examined, the current evidence is that same the genes are operating in men and women

Similarities in drinking behavior of twin's friends: moderation of heritability of alcohol use

Previous research has indicated that friends' drinking may influence alcohol use in adolescents and young adults. We explored whether similarities in the drinking behavior of friends of twins influence the genetic architecture of alcohol use in adolescence and young adulthood. Survey data from The Netherlands Twin Register were available for 1,526 twin pairs aged 16-25 years. We categorized the twin pairs as concordant (both report similar alcohol use in their friends) or discordant for the alcohol use of their friends. Genetic moderator models were tested by carrying out multi-group analyzes in Mplus. Findings showed a significant moderation effect. Genetic factors were more and common environment less important in the explanation of variation in alcohol use in twins discordant for alcohol use of friends than in twins concordant for alcohol use of friend

A population-based study of anxiety as a precursor for depression in childhood and adolescence

BACKGROUND: Anxiety and depression co-occur in children and adolescents with anxiety commonly preceding depression. Although there is some evidence to suggest that the association between early anxiety and later depression is explained by a shared genetic aetiology, the contribution of environmental factors is less well examined and it is unknown whether anxiety itself is a phenotypic risk factor for later depression. These explanations of the association between early anxiety and later depression were evaluated. METHODS: Anxiety and depressive symptoms were assessed longitudinally in a U.K. population-based sample of 676 twins aged 5–17 at baseline. At baseline, anxiety and depression were assessed by parental questionnaire. Depression was assessed three years later by parental and adolescent questionnaire. RESULTS: Shared genetic effects between early anxiety and later depression were found. A model of a phenotypic risk effect from early anxiety on later depression provided a poor fit to the data. However, there were significant genetic effects specific to later depression, showing that early anxiety and later depression do not index entirely the same genetic risk. CONCLUSIONS: Anxiety and depression are associated over time because they share a partly common genetic aetiology rather than because the anxiety phenotype leads to later depression

Detecting Specific Genotype by Environment Interactions Using Marginal Maximum Likelihood Estimation in the Classical Twin Design

Considerable effort has been devoted to the analysis of genotype by environment (G × E) interactions in various phenotypic domains, such as cognitive abilities and personality. In many studies, environmental variables were observed (measured) variables. In case of an unmeasured environment, van der Sluis et al. (2006) proposed to study heteroscedasticity in the factor model using only MZ twin data. This method is closely related to the Jinks and Fulker (1970) test for G × E, but slightly more powerful. In this paper, we identify four challenges to the investigation of G × E in general, and specifically to the heteroscedasticity approaches of Jinks and Fulker and van der Sluis et al. We propose extensions of these approaches purported to solve these problems. These extensions comprise: (1) including DZ twin data, (2) modeling both A × E and A × C interactions; and (3) extending the univariate approach to a multivariate approach. By means of simulations, we study the power of the univariate method to detect the different G × E interactions in varying situations. In addition, we study how well we could distinguish between A × E, A × C, and C × E. We apply a multivariate version of the extended model to an empirical data set on cognitive abilities

Sex-specific genetic effects influence variation in body composition

Aims/hypothesis: Despite well-known sex differences in body composition it is not known whether sex-specific genetic or environmental effects contribute to these differences. Methods: We assessed body composition in 2,506 individuals, from a young Dutch genetic isolate participating in the Erasmus Rucphen Family study, by dual-energy X-ray absorptiometry and anthropometry. We used variance decomposition procedures to partition variation of body composition into genetic and environmental components common to both sexes and to men and women separately and calculated the correlation between genetic components in men and women. Results: After accounting for age

Comparative genomics of Escherichia coli isolated from patients with inflammatory bowel disease

<p>Abstract</p> <p>Background</p> <p>Inflammatory bowel disease (IBD) is used to describe a state of idiopathic, chronic inflammation of the gastrointestinal tract. The two main phenotypes of IBD are Crohn's disease (CD) and ulcerative colitis (UC). The major cause of IBD-associated mortality is colorectal cancer. Although both host-genetic and exogenous factors have been found to be involved, the aetiology of IBD is still not well understood. In this study we characterized thirteen <it>Escherichia coli </it>strains from patients with IBD by comparative genomic hybridization employing a microarray based on 31 sequenced <it>E. coli </it>genomes from a wide range of commensal and pathogenic isolates.</p> <p>Results</p> <p>The IBD isolates, obtained from patients with UC and CD, displayed remarkably heterogeneous genomic profiles with little or no evidence of group-specific determinants. No IBD-specific genes were evident when compared with the prototypic CD isolate, LF82, suggesting that the IBD-inducing effect of the strains is multifactorial. Several of the IBD isolates carried a number of extraintestinal pathogenic <it>E. coli </it>(ExPEC)-related virulence determinants such as the <it>pap</it>, <it>sfa</it>, <it>cdt </it>and <it>hly </it>genes. The isolates were also found to carry genes of ExPEC-associated genomic islands.</p> <p>Conclusions</p> <p>Combined, these data suggest that <it>E. coli </it>isolates obtained from UC and CD patients represents a heterogeneous population of strains, with genomic profiles that are indistinguishable to those of ExPEC isolates. Our findings indicate that IBD-induction from <it>E. coli </it>strains is multifactorial and that a range of gene products may be involved in triggering the disease.</p

Stage-associated overexpression of the ubiquitin-like protein, ISG15, in bladder cancer

Bladder cancer is among the most prevalent malignancies, and is characterised by frequent tumour recurrences and localised inflammation, which may promote tissue invasion and metastasis. Microarray analysis was used to compare gene expression in normal bladder urothelium with that in tumours at different stages of progression. The innate immune response gene, interferon-stimulated gene 15 kDa (ISG15, GIP2), was highly expressed at all stages of bladder cancer as compared to normal urothelium. Western blotting revealed a tumour-associated expression of ISG15 protein. ISG15 exhibited a stage-associated expression, with significantly (P<0.05) higher levels of ISG15 protein in muscle-invasive T2–T4 tumours, compared with normal urothelium. Although ISG15 is involved in the primary immune response, ISG15 expression did not correlate with bladder inflammation. However, immunohistochemical staining revealed expression of ISG15 protein in both cancer cells and stromal immune cells. Interestingly, a significant fraction of ISG15 protein was localised to the nuclei of tumour cells, whereas no nuclear ISG15 staining was observed in ISG15-positive stromal cells. Taken together, our findings identify ISG15 as a novel component of bladder cancer-associated gene expression

Epistasis: Obstacle or Advantage for Mapping Complex Traits?

Identification of genetic loci in complex traits has focused largely on one-dimensional genome scans to search for associations between single markers and the phenotype. There is mounting evidence that locus interactions, or epistasis, are a crucial component of the genetic architecture of biologically relevant traits. However, epistasis is often viewed as a nuisance factor that reduces power for locus detection. Counter to expectations, recent work shows that fitting full models, instead of testing marker main effect and interaction components separately, in exhaustive multi-locus genome scans can have higher power to detect loci when epistasis is present than single-locus scans, and improvement that comes despite a much larger multiple testing alpha-adjustment in such searches. We demonstrate, both theoretically and via simulation, that the expected power to detect loci when fitting full models is often larger when these loci act epistatically than when they act additively. Additionally, we show that the power for single locus detection may be improved in cases of epistasis compared to the additive model. Our exploration of a two step model selection procedure shows that identifying the true model is difficult. However, this difficulty is certainly not exacerbated by the presence of epistasis, on the contrary, in some cases the presence of epistasis can aid in model selection. The impact of allele frequencies on both power and model selection is dramatic