Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Assembly of an interactive correlation network for the Arabidopsis genome using a novel heuristic clustering algorithm

Peer reviewedPublisher PD

Global isoform-specific transcript alterations and deregulated networks in clear cell renal cell carcinoma.

Extensive genome-wide analyses of deregulated gene expression have now been performed for many types of cancer. However, most studies have focused on deregulation at the gene-level, which may overlook the alterations of specific transcripts for a given gene. Clear cell renal cell carcinoma (ccRCC) is one of the best-characterized and most pervasive renal cancers, and ccRCCs are well-documented to have aberrant RNA processing. In the present study, we examine the extent of aberrant isoform-specific RNA expression by reporting a comprehensive transcript-level analysis, using the new kallisto-sleuth-RATs pipeline, investigating coding and non-coding differential transcript expression in ccRCC. We analyzed 50 ccRCC tumors and their matched normal samples from The Cancer Genome Altas datasets. We identified 7,339 differentially expressed transcripts and 94 genes exhibiting differential transcript isoform usage in ccRCC. Additionally, transcript-level coexpression network analyses identified vasculature development and the tricarboxylic acid cycle as the most significantly deregulated networks correlating with ccRCC progression. These analyses uncovered several uncharacterized transcripts, including lncRNAs FGD5-AS1 and AL035661.1, as potential regulators of the tricarboxylic acid cycle associated with ccRCC progression. As ccRCC still presents treatment challenges, our results provide a new resource of potential therapeutics targets and highlight the importance of exploring alternative methodologies in transcriptome-wide studies

Integration of disease-specific single nucleotide polymorphisms, expression quantitative trait loci and coexpression networks reveal novel candidate genes for type 2 diabetes.

Aims/hypothesisWhile genome-wide association studies (GWASs) have been successful in identifying novel variants associated with various diseases, it has been much more difficult to determine the biological mechanisms underlying these associations. Expression quantitative trait loci (eQTL) provide another dimension to these data by associating single nucleotide polymorphisms (SNPs) with gene expression. We hypothesised that integrating SNPs known to be associated with type 2 diabetes with eQTLs and coexpression networks would enable the discovery of novel candidate genes for type 2 diabetes.MethodsWe selected 32 SNPs associated with type 2 diabetes in two or more independent GWASs. We used previously described eQTLs mapped from genotype and gene expression data collected from 1,008 morbidly obese patients to find genes with expression associated with these SNPs. We linked these genes to coexpression modules, and ranked the other genes in these modules using an inverse sum score.ResultsWe found 62 genes with expression associated with type 2 diabetes SNPs. We validated our method by linking highly ranked genes in the coexpression modules back to SNPs through a combined eQTL dataset. We showed that the eQTLs highlighted by this method are significantly enriched for association with type 2 diabetes in data from the Wellcome Trust Case Control Consortium (WTCCC, p = 0.026) and the Gene Environment Association Studies (GENEVA, p = 0.042), validating our approach. Many of the highly ranked genes are also involved in the regulation or metabolism of insulin, glucose or lipids.Conclusions/interpretationWe have devised a novel method, involving the integration of datasets of different modalities, to discover novel candidate genes for type 2 diabetes

Genetic and Neuroanatomical Support for Functional Brain Network Dynamics in Epilepsy

Focal epilepsy is a devastating neurological disorder that affects an overwhelming number of patients worldwide, many of whom prove resistant to medication. The efficacy of current innovative technologies for the treatment of these patients has been stalled by the lack of accurate and effective methods to fuse multimodal neuroimaging data to map anatomical targets driving seizure dynamics. Here we propose a parsimonious model that explains how large-scale anatomical networks and shared genetic constraints shape inter-regional communication in focal epilepsy. In extensive ECoG recordings acquired from a group of patients with medically refractory focal-onset epilepsy, we find that ictal and preictal functional brain network dynamics can be accurately predicted from features of brain anatomy and geometry, patterns of white matter connectivity, and constraints complicit in patterns of gene coexpression, all of which are conserved across healthy adult populations. Moreover, we uncover evidence that markers of non-conserved architecture, potentially driven by idiosyncratic pathology of single subjects, are most prevalent in high frequency ictal dynamics and low frequency preictal dynamics. Finally, we find that ictal dynamics are better predicted by white matter features and more poorly predicted by geometry and genetic constraints than preictal dynamics, suggesting that the functional brain network dynamics manifest in seizures rely on - and may directly propagate along - underlying white matter structure that is largely conserved across humans. Broadly, our work offers insights into the generic architectural principles of the human brain that impact seizure dynamics, and could be extended to further our understanding, models, and predictions of subject-level pathology and response to intervention

Coordinated functional divergence of genes after genome duplication in Arabidopsis thaliana

Gene and genome duplications have been rampant during the evolution of flowering plants. Unlike small-scale gene duplications, whole-genome duplications (WGDs) copy entire pathways or networks, and as such create the unique situation in which such duplicated pathways or networks could evolve novel functionality through the coordinated sub-or neofunctionalization of its constituent genes. Here, we describe a remarkable case of coordinated gene expression divergence following WGDs in Arabidopsis thaliana. We identified a set of 92 homoeologous gene pairs that all show a similar pattern of tissue-specific gene expression divergence following WGD, with one homoeolog showing predominant expression in aerial tissues and the other homoeolog showing biased expression in tip-growth tissues. We provide evidence that this pattern of gene expression divergence seems to involve genes with a role in cell polarity and that likely function in the maintenance of cell wall integrity. Following WGD, many of these duplicated genes evolved separate functions through subfunctionalization in growth/development and stress response. Uncoupling these processes through genome duplications likely provided important adaptations with respect to growth and morphogenesis and defense against biotic and abiotic stress

Inhibition of activity of GABA transporter GAT1 by δ-opioid receptor

Analgesia is a well-documented effect of acupuncture. A critical role in pain sensation plays the nervous system, including the GABAergic system and opioid receptor (OR) activation. Here we investigated regulation of GABA transporter GAT1 by δOR in rats and in Xenopus oocytes. Synaptosomes of brain from rats chronically exposed to opiates exhibited reduced GABA uptake, indicating that GABA transport might be regulated by opioid receptors. For further investigation we have expressed GAT1 of mouse brain together with mouse δOR and μOR in Xenopus oocytes. The function of GAT1 was analyzed in terms of Na(+)-dependent [(3)H]GABA uptake as well as GAT1-mediated currents. Coexpression of δOR led to reduced number of fully functional GAT1 transporters, reduced substrate translocation, and GAT1-mediated current. Activation of δOR further reduced the rate of GABA uptake as well as GAT1-mediated current. Coexpression of μOR, as well as μOR activation, affected neither the number of transporters, nor rate of GABA uptake, nor GAT1-mediated current. Inhibition of GAT1-mediated current by activation of δOR was confirmed in whole-cell patch-clamp experiments on rat brain slices of periaqueductal gray. We conclude that inhibition of GAT1 function will strengthen the inhibitory action of the GABAergic system and hence may contribute to acupuncture-induced analgesia

Requirement for the coexpression of T3 and the T cell antigen receptor on a malignant human T cell line.

The association between T3 and the T cell antigen receptor was examined using the T3 bearing T cell leukemic line Jurkat. A monoclonal antibody, C305, was produced, which reacted with idiotypic-like determinants expressed on Jurkat. The molecule with which this antibody reacted was a disulfide-linked heterodimer of 90 kD, composed of polypeptides of 42 and 54 kD. Thus, C305 reacted with a molecule with characteristics of the putative T cell antigen receptor described by others. A series of mutants of Jurkat, induced with ethyl methane sulfonate or radiation, was selected for T3 or antigen receptor negativity. In every instance, there was a concomitant loss of both T3 and the antigen receptor as assessed by quantitative absorption, indirect immunofluorescence, and antibody plus complement-mediated cytotoxicity. The absence of antigen receptor molecules was confirmed on diagonal gels, excluding the possibility that conformational changes of the antigen receptor on such T3-negative mutants were responsible for the failure of such mutants to react with C305. Moreover, in a mutant that expressed a marked decrease in the level of T3 expression, there was a comparable decrease in the expression of antigen receptor determinants. These results suggest that there is an obligate requirement for the coexpression of T3 and the T cell antigen receptor. Furthermore, attempts to activate such mutants with the lectin phytohemagglutinin suggested that the expression of T3 and/or the antigen receptor was required for activation of these cells