Historical inductions, Old and New

I review prominent historical arguments against scientific realism to indicate how they display a systematic overshooting in the conclusions drawn from the historical evidence. The root of the overshooting can be located in some critical, undue presuppositions regarding realism. I will highlight these presuppositions in connection with both Laudan’s ‘Old induction’ and Stanford’s New induction, and then delineate a minimal realist view that does without the problematic presuppositions

Translog, a web browser for studying the expression divergence of homologous genes

<p>Abstract</p> <p>Background</p> <p>Increasing amount of data from comparative genomics, and newly developed technologies producing accurate gene expression data facilitate the study of the expression divergence of homologous genes. Previous studies have individually highlighted factors that contribute to the expression divergence of duplicate genes, e.g. promoter changes, exon structure heterogeneity, asymmetric histone modifications and genomic neighborhood conservation. However, there is a lack of a tool to integrate multiple factors and visualize their variety among homologous genes in a straightforward way.</p> <p>Results</p> <p>We introduce Translog (a web-based tool for Transcriptome comparison of homologous genes) that assists in the comparison of homologous genes by displaying the loci in three different views: promoter view for studying the sharing/turnover of transcription initiations, exon structure for displaying the exon-intron structure changes, and genomic neighborhood to show the macro-synteny conservation in a larger scale. CAGE data for transcription initiation are mapped for each transcript and can be used to study transcription turnover and expression changes. Alignment anchors between homologous loci can be used to define the precise homologous transcripts. We demonstrate how these views can be used to visualize the changes of homologous genes during evolution, particularly after the 2R and 3R whole genome duplication.</p> <p>Conclusion</p> <p>We have developed a web-based tool for assisting in the transcriptome comparison of homologous genes, facilitating the study of expression divergence.</p

The neighbourhood social environment and alcohol use among urban and rural Scottish adolescents

Funding for the Scottish Health Behaviour in School-aged Children was provided by NHS Scotland. This work was also supported by the 600th Anniversary Ph.D. Scholarship which was awarded to Gina Martin by the University of St Andrews.Objectives This research examined the relationship between neighbourhood social environmental characteristics and drinking outcomes among a sample of urban and rural adolescents. Methods From a sample of 1558 Scottish secondary schoolchildren, surveyed as part of the 2010 Health Behaviour in School-aged Children study, we modelled three drinking outcomes on a variety of neighbourhood conditions, including social cohesion, disorder, alcohol outlet density, deprivation, and urban/rurality. Nested and cross-classified multilevel logistic regressions were specified. Results An urban-to-rural gradient was found with non-urban adolescents exhibiting higher odds of having ever drank. Neighbourhood social cohesion related to having ever drank. Among drinkers, those living in accessible small towns had higher odds of weekly drinking and drunkenness compared to urban areas. Higher odds of drunkenness were also found in remote rural areas. Those residing in the least deprived areas had lower odds of weekly drinking. Conclusions In Scotland, inequalities exist in adolescent alcohol use by urban/rurality and neighbourhood social conditions. Findings support regional targeting of public health efforts to address inequalities. Future work is needed to develop and evaluate intervention and prevention approaches for neighbourhoods at risk.Publisher PDFPeer reviewe

Gene-Environment Interaction in the Etiology of Mathematical Ability Using SNP Sets

Mathematics ability and disability is as heritable as other cognitive abilities and disabilities, however its genetic etiology has received relatively little attention. In our recent genome-wide association study of mathematical ability in 10-year-old children, 10 SNP associations were nominated from scans of pooled DNA and validated in an individually genotyped sample. In this paper, we use a ‘SNP set’ composite of these 10 SNPs to investigate gene-environment (GE) interaction, examining whether the association between the 10-SNP set and mathematical ability differs as a function of ten environmental measures in the home and school in a sample of 1888 children with complete data. We found two significant GE interactions for environmental measures in the home and the school both in the direction of the diathesis-stress type of GE interaction: The 10-SNP set was more strongly associated with mathematical ability in chaotic homes and when parents are negative

Which patient will feel down, which will be happy? The need to study the genetic disposition of emotional states

Purpose In quality-of-life (QL) research, the genetic susceptibility of negative and positive emotions is frequently ignored, taken for granted, or treated as noise. The objectives are to describe: (1) the major findings of studies addressing the heritable and environmental causes of variation in negative and positive emotional states and (2) the major biological pathways of and genetic variants involved in these emotional states

The EpsE Flagellar Clutch Is Bifunctional and Synergizes with EPS Biosynthesis to Promote Bacillus subtilis Biofilm Formation

Many bacteria inhibit motility concomitant with the synthesis of an extracellular polysaccharide matrix and the formation of biofilm aggregates. In Bacillus subtilis biofilms, motility is inhibited by EpsE, which acts as a clutch on the flagella rotor to inhibit motility, and which is encoded within the 15 gene eps operon required for EPS production. EpsE shows sequence similarity to the glycosyltransferase family of enzymes, and we demonstrate that the conserved active site motif is required for EPS biosynthesis. We also screen for residues specifically required for either clutch or enzymatic activity and demonstrate that the two functions are genetically separable. Finally, we show that, whereas EPS synthesis activity is dominant for biofilm formation, both functions of EpsE synergize to stabilize cell aggregates and relieve selective pressure to abolish motility by genetic mutation. Thus, the transition from motility to biofilm formation may be governed by a single bifunctional enzyme

Adaptive Evolution and the Birth of CTCF Binding Sites in the Drosophila Genome

Changes in the physical interaction between cis-regulatory DNA sequences and proteins drive the evolution of gene expression. However, it has proven difficult to accurately quantify evolutionary rates of such binding change or to estimate the relative effects of selection and drift in shaping the binding evolution. Here we examine the genome-wide binding of CTCF in four species of Drosophila separated by between ~2.5 and 25 million years. CTCF is a highly conserved protein known to be associated with insulator sequences in the genomes of human and Drosophila. Although the binding preference for CTCF is highly conserved, we find that CTCF binding itself is highly evolutionarily dynamic and has adaptively evolved. Between species, binding divergence increased linearly with evolutionary distance, and CTCF binding profiles are diverging rapidly at the rate of 2.22% per million years (Myr). At least 89 new CTCF binding sites have originated in the Drosophila melanogaster genome since the most recent common ancestor with Drosophila simulans. Comparing these data to genome sequence data from 37 different strains of Drosophila melanogaster, we detected signatures of selection in both newly gained and evolutionarily conserved binding sites. Newly evolved CTCF binding sites show a significantly stronger signature for positive selection than older sites. Comparative gene expression profiling revealed that expression divergence of genes adjacent to CTCF binding site is significantly associated with the gain and loss of CTCF binding. Further, the birth of new genes is associated with the birth of new CTCF binding sites. Our data indicate that binding of Drosophila CTCF protein has evolved under natural selection, and CTCF binding evolution has shaped both the evolution of gene expression and genome evolution during the birth of new genes

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons