Biology subjects

Hall, J.

Publications and source records attributed to Hall, J..

13 recordsLinked to original sources

bioRxiv2018

ASD Diagnosis in Adults: Phenotype and Genotype Findings from a Clinically-derived Cohort

BackgroundThe last decade has seen the development of services for adults presenting with symptoms of autism spectrum disorder (ASD) in the UK. Compared to children, little is known about the phenotypic and genetic characteristics of these patients.\n\nAimsThis e-cohort study aimed to examine the phenotypic and genetic characteristics of a clinically-presenting sample of adults diagnosed with ASD by specialist services.\n\nMethodsIndividuals diagnosed with ASD as adults were recruited by the National Centre for Mental Health and completed self-report questionnaires, interviews and provided DNA. 105 eligible individuals were matched to 76 healthy controls. We investigated the demographics, social history, comorbid psychiatric and physical disorders. Samples were genotyped, copy number variants (CNVs) were called and polygenic risk scores calculated.\n\nResults89.5% of individuals with ASD had at least one comorbid psychiatric diagnosis with comorbid depression (62.9%) and anxiety (55.2%) the most common. The ASD group experienced more neurological comorbidities than healthy controls, particularly migraine headache. They were less likely to have married or be in work and had more alcohol-related problems. There was a significantly higher load of autism common genetic variants in the adult ASD group compared to controls, but there was no difference in the rate of rare CNVs.\n\nConclusionsThis study provides important information about psychiatric comorbidity in adult ASD which may be used to inform clinical practice and patient counselling. It also suggests that the polygenic load of common ASD-associated variants may be important in conferring risk within non-intellectually disabled population of adults with ASD.

neuroscience↗

bioRxiv2018

Haploinsufficiency of the schizophrenia risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through a novel microglia dependent mechanism

Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult born hippocampal neurons due to reduced apoptosis, without altering proliferation. We confirm this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.

neuroscience↗

bioRxiv2018

Dynamic expression of risk genes for schizophrenia and bipolar disorder across development

AO_SCPCAPBSTRACTC_SCPCAPCommon genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between schizophrenia and bipolar disorder. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genes associated with schizophrenia have a strong bias towards increased expression in the prefrontal cortex during early midfetal development and early infancy, and decreased expression during late childhood which normalises in adolescence. Risk-associated genes for bipolar disorder shared this postnatal expression profile but did not exhibit a bias towards expression at any prenatal stage. These results emphasise the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the view that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.

neuroscience↗

bioRxiv2018

Genetic risk for schizophrenia and developmental delay is associated with shape and microstructure of midline white matter structures

Genomic copy number variants (CNVs) are amongst the most highly penetrant genetic risk factors for neuropsychiatric disorders. The scarcity of carriers of individual CNVs and their phenotypical heterogeneity limits investigations of the associated neural mechanisms and endophenotypes. We applied a novel design based on CNV penetrance for schizophrenia and developmental delay that allows us to identify structural sequelae that are most relevant to neuropsychiatric disorders. Our focus on brain structural abnormalities was based on the hypothesis that convergent mechanisms contributing to neurodevelopmental disorders would likely manifest in the macro- and microstructure of white matter and cortical and subcortical grey matter. 21 adult participants carrying neuropsychiatric risk CNVs (including those located at 22q11.2, 15q11.2, 1q21.1, 16p11.2, and 17q12) and 15 age- and gender matched controls underwent T1-weighted structural, diffusion and quantitative T1 relaxometry MRI.\n\nThe macro- and microstructural properties of the cingulum bundles were associated with penetrance for both developmental delay and schizophrenia, in particular curvature along the anterior-posterior axis (Sz: pcorr=0.026; DD: pcorr=0.035) and intracellular volume fraction (Sz: pcorr=0.019; DD: pcorr=0.064) Further principal component analysis showed alterations in the interrelationships between the volumes of several mid-line white matter structures (Sz: pcorr=0.055; DD, pcorr=0.027). In particular, the ratio of volumes in the splenium and body of the corpus callosum was significantly associated with both penetrance scores (Sz: p=0.037; DD; p=0.006). Our results are consistent with the notion that a significant alteration in developmental trajectories of mid-line white-matter structures constitutes a common neurodevelopmental aberration contributing to risk for schizophrenia and intellectual disability.

neuroscience↗

bioRxiv2018

Leveraging chromatin accessibility for transcriptional regulatory network inference in T Helper 17 Cells

Transcriptional regulatory networks (TRNs) provide insight into cellular behavior by describing interactions between transcription factors (TFs) and their gene targets. The Assay for Transposase Accessible Chromatin (ATAC)-seq, coupled with transcription-factor motif analysis, provides indirect evidence of chromatin binding for hundreds of TFs genome-wide. Here, we propose methods for TRN inference in a mammalian setting, using ATAC-seq data to influence gene expression modeling. We rigorously test our methods in the context of T Helper Cell Type 17 (Th17) differentiation, generating new ATAC-seq data to complement existing Th17 genomic resources (plentiful gene expression data, TF knock-outs and ChIP-seq experiments). In this resource-rich mammalian setting, our extensive benchmarking provides quantitative, genome-scale evaluation of TRN inference combining ATAC-seq and RNA-seq data. We refine and extend our previous Th17 TRN, using our new TRN inference methods to integrate all Th17 data (gene expression, ATAC-seq, TF KO, ChIP-seq). We highlight new roles for individual TFs and groups of TFs (\"TF-TF modules\") in Th17 gene regulation. Given the popularity of ATAC-seq, which provides high-resolution with low sample input requirements, we anticipate that application of our methods will improve TRN inference in new mammalian systems, especially in vivo, for cells directly from humans and animal models.

systems biology↗

bioRxiv2018

Is reading automatic? Are the ERP correlates of masked priming really lexical?

Humans have an almost unbounded ability to adapt their behaviour to perform different tasks. In the laboratory, this flexibility is sometimes viewed as a nuisance factor that prevents access to the underlying cognitive mechanisms of interest. For example, in order to study \"automatic\" lexical processing, psycholinguists have used masked priming or evoked potentials to measure \"automatic\" lexical processing. However, the pattern of masked priming can be radically altered by changing the task. In lexical decision, priming is observed for words but not for nonwords, yet in a same-different matching task, priming is observed for same responses but not for different responses, regardless of whether the target is a word or a nonword (Norris & Kinoshita, 2008). Here we show that evoked potentials are equally sensitive to the nature of required decision, with the neural activity normally associated with lexical processing being seen for both words and nonwords on same trials, and for neither on different trials. (150)

neuroscience↗

bioRxiv2017

Covalent linkage of the DNA repair template to the CRISPR/Cas9 complex enhances homology-directed repair

The CRISPR/Cas9 targeted nuclease technology allows the insertion of genetic modifications with single base-pair precision. The preference of mammalian cells to repair Cas9-induced DNA double-strand breaks via non-homologous end joining (NHEJ) rather than via homology-directed repair (HDR) however leads to relatively low rates of correctly edited loci. Here we demonstrate that covalently linking the DNA repair template to Cas9 increases the ratio of HDR over NHEJ up to 23-fold, and therefore provides advantages for clinical applications where high-fidelity repair is needed.

molecular biology↗

bioRxiv2017

The Smc5/6 complex belongs to a novel class of evolutionary-constrained restriction factors and is antagonized by all mammalian hepatitis B virus X proteins

Infection with Hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. HBVs (family Hepadnaviridae) have been associated with mammals for millions of years. Recently, the Smc5/6 complex, known for its essential housekeeping functions in genome maintenance, was identified as an antiviral restriction factor of human HBV. The virus has however developed a counteraction mechanism by degrading the complex via its regulatory HBx protein. Whether the antiviral activity of the Smc5/6 complex against hepadnaviruses is an important and evolutionary-conserved function is unknown. Here, we used a combined evolutionary and functional approach to address this question. We first performed phylogenetic and positive selection analyses of the six Smc5/6 complex subunits and found that they have been highly conserved in primates and mammals. Yet, the Smc6 subunit showed marks of adaptive evolution, potentially reminiscent of virus-host \"arms-race\" We then functionally tested the HBx from six very divergent hepadnaviruses now naturally infecting primates, rodents, and bats. Despite little sequence homology, we demonstrate that these HBx efficiently degraded mammalian Smc5/6 complexes, independently of the host species and of the sites under positive selection. Importantly, all also rescued the replication of an HBx-deficient HBV in primary human hepatocytes. These findings point to an evolutionary-conserved requirement for Smc5/6 inactivation by HBx, showing that the Smc5/6 antiviral activity has been an important defense mechanism against hepadnaviruses in mammals. Interestingly, Smc5/6 may further be a restriction factor of other yet unidentified viruses that have driven some of its adaptation.\n\nImportanceInfection with hepatitis B virus (HBV) led to 887000 human deaths in 2015. HBV has been co-evolving with mammals for millions of years. Recently, the Smc5/6 complex, known for its essential housekeeping functions, was identified as a restriction factor of human HBV antagonized by the regulatory HBx protein. Here, we address whether the antiviral activity of Smc5/6 is an important evolutionary-conserved function. We found that all six subunits of Smc5/6 have been conserved in primates with only Smc6 showing signatures of \"evolutionary arms-race\" Using evolutionary-guided functional assays that include infections of primary human hepatocytes, we demonstrate that HBx from very divergent mammalian HBVs could all efficiently antagonize Smc5/6, independently of the host species and sites under positive selection. These findings show that the Smc5/6 antiviral activity against HBV is an important function in mammals. It also raises the intriguing possibility that Smc5/6 restricts other, yet unidentified viruses.

microbiology↗

bioRxiv2017

Type III CRISPR-Cas systems generate cyclic oligoadenylate second messengers to activate Csm6 RNases

In many prokaryotes, type III CRISPR-Cas systems detect and degrade invasive genetic elements by an RNA-guided, RNA-targeting multisubunit interference complex that possesses dual RNase and DNase activities. The CRISPR-associated protein Csm6 additionally contributes to interference by functioning as a standalone ribonuclease that degrades invader RNA transcripts, but the mechanism linking invader sensing to Csm6 activity is not understood. Here we show that Csm6 proteins are activated through a second messenger generated by the type III interference complex. Upon target RNA binding by the type III interference complex, the Cas10 subunit converts ATP into a cyclic oligoadenylate product, which allosterically activates Csm6 by binding to its CARF domain. CARF domain mutations that abolish allosteric activation inhibit Csm6 activity in vivo, and mutations in the Cas10 Palm domain phenocopy loss of Csm6. Together, these results point to a hitherto unprecedented mechanism for regulation of CRISPR interference that bears striking conceptual similarity to oligoadenylate signalling in mammalian innate immunity.

biochemistry↗

bioRxiv2017

Development Of RNAseq Methodologies To Profile The In Vivo Transcriptome Of Bordetella pertussis During Murine Lung Infection

Bordetella pertussis is an obligate human respiratory pathogen that causes the disease whooping cough. A whole cell vaccine (DTP) was developed in the 1940s and was subsequently replaced in the 1990s with a protein-based subunit acellular vaccine (DTaP; tdap). Today, we are observing a resurgence of whooping cough due to evolution of the pathogen and waning vaccine immunity. The use of vaccines decreased the need for basic research on this pathogen. As a result, numerous questions on the basic pathogenesis of B. pertussis remain to be answered. Microarrays and more recently, RNA sequencing (RNAseq), have allowed the field to describe the in vitro gene expression profiles of the pathogen growing in both virulent and avirulent phases; however, no published studies have described an in vivo transcriptome of the pathogen. To address this need, we have designed and evaluated workflows to characterize the in vivo transcriptome of B. pertussis during infection of the murine lung. During our initial studies, we observed that only 0.014% of the ~100 million 2x50bp illumina reads corresponded to the pathogen, which is insufficient for analysis. Therefore, we developed a simple protocol to filter the bacteria out of the tissue homogenates and separate bacterial cells from the host tissue. RNA is then prepared, quantified, and the B. pertussis to host RNA ratio is determined. Here, we present the protocol and discuss the uses and next directions for which this RNAseq workflow can be applied. With this strategy we plan to fully characterize the B. pertussis transcriptome when the pathogen is infecting the murine lung in order to identify expressed genes that encode potential new vaccine antigens that will facilitate the development of the next generation of pertussis vaccines.

microbiology↗

bioRxiv2017

Diagnostic, Infection Timing and Incidence Surveillance Applications of High Dynamic Range Chemiluminescent HIV Immuno-Assay Platforms

BackgroundCustom staging assays, including the Sedia HIV-1 Limiting Antigen Avidity EIA (LAg) and avidity modifications of the Ortho VITROS anti-HIV-1+2 and Abbott ARCHITECT HIV Ag/Ab Combo assays, are used to identify recent infections in clinical settings and for cross-sectional HIV incidence estimation. However, the high dynamic range of chemiluminescent platforms allows differentiating recent and longstanding infection on signal intensity, and this raises the prospect of using unmodified diagnostic assays for infection timing and surveillance applications.\n\nMethodsWe tested a panel of 2,500 well-characterised specimens with estimable duration of HIV infection with the three assays and the unmodified ARCHITECT. Regression models were used to estimate mean durations of recent infection (MDRI), context-specific false-recent rates (FRR) and correlation between signal intensity and LAg measurements. A hypothetical epidemiological scenario was constructed to evaluate utility in surveillance applications.\n\nResultsOver a range of MDRIs (reflecting recency discrimination thresholds), a diluted ARCHITECT-based RITA produced lower FRRs than the VITROS platform (FRR {approx} 0.5% and 1.5% respectively at MDRI of 200 days) and the unmodified diagnostic ARCHITECT produces incidence estimates with comparable precision to LAg (RSE {approx} 17.5% and 15% respectively at MDRI of 200 days). ARCHITECT S/CO measurements were highly correlated with LAg ODn measurements (r = 0.80) and values below 200 are strongly predictive of LAg recency and duration of infection less than one year.\n\nConclusionsLow quantitative measurements from the unmodified ARCHITECT obviate the need for additional recency testing and its use is feasible in clinical staging and incidence surveillance applications.

epidemiology↗

bioRxiv2017

Accumulation of sensory evidence is impaired in Parkinson’s disease with visual hallucinations

Models of hallucinations across disorders emphasise an imbalance between sensory input and top-down influences over perception. However, the psychological and mechanistic correlates of this imbalance remain underspecified. Visual hallucinations in Parkinsons disease (PD) are associated with impairments in lower level visual processes and attention, accompanied by over activity and connectivity in higher-order association brain networks. PD therefore provides an attractive framework to explore the relative contributions of bottom-up versus top-down disturbances in hallucinations. Here, we characterised sensory processing in PD patients with and without visual hallucinations, and in healthy controls, by fitting a hierarchical drift diffusion model (hDDM) to an attentional task. The hDDM uses Bayesian estimates to decompose reaction time and response output into parameters reflecting drift rates of evidence accumulation, decision thresholds and non-decision time. We observed slower drift rates in PD patients with hallucinations, which were insensitive to changes in task demand. In contrast, wider decision boundaries and shorter non-decision times relative to controls were found in PD regardless of hallucinator status. Inefficient and less flexible sensory evidence accumulation emerge as unique features of PD hallucinators. We integrate these results with current models of hallucinations, suggesting that slow and inefficient sensory input in PD is less informative, and may therefore be down-weighted leading to an over reliance on top-down influences. Our findings provide a novel computational framework to better specify the impairments in dynamic sensory processing that are a risk factor for visual hallucinations.

neuroscience↗

bioRxiv2017

NMDAR hypofunction increases top-down influence on sensory processing

Converging evidence implicates NMDAR disruption in the pathogenesis of schizophrenia, a condition in which perceptual disturbances are prominent. To explore how NMDAR hypofunction causes perceptual symptoms we investigated activity in cortical sensory circuits in awake behaving mice during pharmacologically induced NMDAR hypofunction. We observed a reduction in sensory-driven activity in V1 while input from the anterior cingulate cortex simultaneously increased, suggesting NMDAR hypofunction may lead to altered perception by modifying the balance of top-down and bottom-up processing.

neuroscience↗