Biology subjects

Jones, S.

Publications and source records attributed to Jones, S..

8 recordsLinked to original sources

bioRxiv2018

Spatial organization of Clostridium difficile S-layer biogenesis

Surface layers (S-layers) are protective protein coats which form around all archaea and most bacterial cells. Clostridium difficile is a Gram-positive bacterium with an S-layer covering its peptidoglycan cell wall. The S-layer in C. difficile is constructed mainly of S-layer protein A (SlpA), which is a key virulence factor and an absolute requirement for disease. S-layer biogenesis is a complex multi-step process, disruption of which has severe consequences for the bacterium. We examined the subcellular localization of SlpA secretion and S-layer growth; observing formation of S-layer at specific sites that coincide with cell wall synthesis, while the secretion of SlpA from the cell is relatively delocalized. We conclude that this delocalized secretion of SlpA leads to a pool of precursor in the cell wall which is available to repair openings in the S-layer formed during cell growth or following damage.

microbiology↗

bioRxiv2018

Population sequencing reveals clonal diversity and ancestral inbreeding in the grapevine cultivar Chardonnay

Chardonnay is the basis of some of the worlds most iconic wines and its success is underpinned by a historic program of clonal selection. There are numerous clones of Chardonnay available that exhibit differences in key viticultural and oenological traits that have arisen from the accumulation of somatic mutations during centuries of asexual propagation. However, the genetic variation that underlies these differences remains largely unknown. To address this knowledge gap, a high-quality, diploid-phased Chardonnay genome assembly was produced from single-molecule real time sequencing, and combined with re-sequencing data from 15 different commercial Chardonnay clones. There were 1620 markers identified that distinguish the 15 Chardonnay clones. These markers were reliably used for clonal identification of validation genomic material, as well as in identifying a potential genetic basis for some clonal phenotypic differences. The predicted parentage of the Chardonnay haplomes was elucidated by mapping sequence data from the predicted parents of Chardonnay (Gouais blanc and Pinot noir) against the Chardonnay reference genome. This enabled the detection of instances of heterosis, with differentially-expanded gene families being inherited from the parents of Chardonnay. Most surprisingly however, the patterns of nucleotide variation present in the Chardonnay genome indicate that Pinot noir and Gouais blanc share an extremely high degree of kinship that has resulted in the Chardonnay genome displaying characteristics that are indicative of inbreeding.\n\nAuthor SummaryPhenotypic variation within a grapevine cultivar arises from an accumulation of mutations from serial vegetative propagation. Old cultivars such as Chardonnay have been propagated for centuries resulting in hundreds of available clones containing unique genetic mutations and a range of various phenotypic peculiarities. The genetic mutations can be leveraged as genetic markers and are useful in identifying specific clones for authenticity testing, or as breeding markers for new clonal selections where particular mutations are known to confer a phenotypic trait. We produced a high-quality genome assembly for Chardonnay, and using re-sequencing data for 15 popular clones, were able to identify a large selection of markers that are unique to at least one clone. We identified mutations that may confer phenotypic effects, and were able to identify clones from material independently sourced from nurseries and vineyards. The marker detection framework we describe for authenticity testing would be applicable to other grapevine cultivars or even other agriculturally important woody-plant crops that are vegetatively propagated such as fruit orchards. Finally, we show that the Chardonnay genome contains extensive evidence for parental inbreeding, such that its parents, Gouais blanc and Pinot noir, may even represent first-degree relatives.

genomics↗

bioRxiv2018

PI31 is an adaptor protein for proteasome transport in axons

Protein degradation by the ubiquitin-proteasome system (UPS) is critical for neuronal development, plasticity and function. Neurons utilize microtubule-dependent molecular motors to allocate proteasomes to synapses, but how proteasomes are coupled to motor proteins and how this transport is regulated to meet changing demand for protein breakdown remains largely unknown. We show that the conserved proteasome-binding protein PI31 serves as an adaptor to directly couple proteasomes with dynein light chain proteins (DYNLL1/2). Inactivation of PI31 inhibits proteasome motility in axons and disrupts synaptic protein homeostasis, structure and function. Moreover, phosphorylation of PI31 at a conserved site by p38 MAP kinase promotes binding to DYNLL1/2, and a non-phosphorable PI31 mutant impairs proteasome movement in axons, suggesting a mechanism to regulate loading of proteasomes onto motor proteins. Because mutations affecting PI31 activity are associated with human neurodegenerative diseases, impairment of PI31-mediated axonal transport of proteasomes may be the root cause of these disorders.

cell biology↗

bioRxiv2018

Data-Constrained Biophysical Modeling Of Human VIM To Assess Contributions Of Intrinsic Oscillatory Activity To Essential Tremor

Essential tremor (ET) is the most common movement disorder, in which the primary symptom is a prominent, involuntary 4-10 Hz rhythmic movement. The presence of tremor frequency oscillations (TFOs) in the ventral intermediate nucleus of the thalamus (VIM) is well-established, but it is often assumed that it is driven by cerebellar tremor frequency activity, while the role of intrinsic oscillatory activity in VIM is not clear. An improved understanding of the mechanisms of tremor and non-tremor frequency activity in VIM is critical to the development of improved pharmacological and neuromodulatory therapies. Starting from a canonical model of thalamus, we developed a biophysically-principled computational model of tremor field activity in the VIM, coupled with the thalamic reticular nucleus (TRN). We simulated TFOs in the model generated either by extrinsic tremor-periodic drive or intrinsic VIM-TRN interaction to understand whether these networks exhibited distinct biophysical properties, which may impact the efficacy of pharmacological or stimulation treatment for TFOs. Extrinsic and intrinsic TFOs in the model depended on T-type Ca2+ channels in different ways. Each also depended on GABA modulation in a site- and type-specific manner. These results suggested that efficacy of pharmacological manipulations may depend upon the mechanisms generating TFOs in VIM. Simulated non-tremor-related motor activity from cerebellum decreased extrinsic but increased intrinsic TFOs. Our results suggest that both mechanisms may be important to understand the emergence and cessation of TFOs in VIM and lead to experimentally testable predictions on how to modulate tremor frequency activity to improve treatment strategies for ET.\n\nSignificance StatementEssential Tremor (ET) is a movement disorder in which the primary symptom is a prominent, involuntary, and rhythmic shaking, often of the hands. Electrical activity in many areas of the brain exhibit rhythmicity related to the patients tremor. One such area resides in a structure called the thalamus, but it is not fully known what gives rise to tremor-related activity. We created a computational model of this activity, which suggested how to differentiate tremor mechanisms and how these differences may contribute to other impairments in ET. Knowledge of the biophysical mechanisms contributing to tremor can ultimately lead to improvements in treatments to alleviate symptoms of ET.

neuroscience↗

bioRxiv2018

Meta-analysis of genome-wide association studies for body fat distribution in 694,649 individuals of European ancestry

One in four adults worldwide are either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, is most informative for predicting risk of obesity sequellae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio adjusted for BMI (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

genetics↗

bioRxiv2018

Biological and clinical insights from genetics of insomnia symptoms

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying pathophysiological processes and causal relationships with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n=453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n=14,923 cases, 47,610 controls), physician diagnosed insomnia in Partners Biobank (n=2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n=83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis, phototransduction and muscle development pathways and of genes expressed in multiple brain regions, skeletal muscle and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary heart disease, depressive symptoms and subjective well-being.\n\nOne Sentence SummaryWe identify 57 genomic regions associated with insomnia pointing to the involvement of phototransduction and ubiquitination and potential causal links to CAD and depression.

genomics↗

bioRxiv2017

Genome-wide discovery of somatic coding and regulatory variants in Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Many known driver mutations are over-represented in one of its two molecular subgroups, knowledge of which has aided in the development of therapeutics that target these features. The heterogeneity of DLBCL determined through prior genomic analysis suggests an incomplete understanding of its molecular aetiology, with a limited diversity of genetic events having thus far been attributed to the activated B-cell (ABC) subgroup. Through an integrative genomic analysis we uncovered genes and non-coding loci that are commonly mutated in DLBCL including putative regulatory sequences. We implicate recurrent mutations in the 3UTR of NFKBIZ as a novel mechanism of oncogene deregulation and found small amplifications associated with over-expression of FC-{gamma} receptor genes. These results inform on mechanisms of NF-{kappa}B pathway activation in ABC DLBCL and may reveal a high-risk population of patients that might not benefit from standard therapeutics.

genomics↗

bioRxiv2016

Synthetic hypermutation: gene-drug mutation rate synergy reveals a translesion synthesis mechanism

Gene-gene or gene-drug interactions are typically quantified using fitness as readout because the data is continuous and easily measured in high-throughput. However, to what extent fitness captures the range of other phenotypes that show synergistic effects is usually unknown. Using Saccharomyces cerevisiae, and focusing on a matrix of DNA repair mutants and genotoxic drugs, we quantify 76 gene-drug interactions based on both mutation rate and fitness and find that these parameters are not necessarily overlapping. Independent of fitness defects we identified six cases of synthetic hypermutation, where the combined effect of the drug and mutant on mutation rate was greater than predicted. One example occurred when yeast lacking RAD1 were exposed to cisplatin and we characterized this interaction using whole-genome sequencing. Our sequencing results indicate mutagenesis by cisplatin in rad1{Delta} cells appeared to depend almost entirely on interstrand crosslinks at GpCpN motifs. Interestingly, our data suggests that the 3 base in these motifs templates the addition of the mutated base. This result differs from cisplatin mutation signatures in XPF-deficient C. elegans and supports a model in which translesion synthesis polymerases perform a slippage and realignment extension across from the damaged base. Accordingly, DNA polymerase {zeta} activity was essential for mutagenesis in cisplatin treated rad1{Delta} cells. Together these data reveal the potential to gain new mechanistic insights from non-fitness measures of gene-drug interactions and extend the use of mutation accumulation and whole-genome sequencing analysis to define DNA repair mechanisms.

genetics↗