Biology subjects

Wood, A.

Publications and source records attributed to Wood, A..

29 records · Page 2Linked to original sources

bioRxiv2019

Identification of a major QTL and associated marker for high arabinoxylan fibre in white wheat flour

Dietary fibre (DF) has multiple health benefits, and wheat products are major sources of DF for human health. However, DF is depleted in white flour, which is most widely consumed, compared to wholegrain. The major type of DF in white wheat flour is the cell wall polysaccharide arabinoxylan (AX). Previous studies have identified the Chinese wheat cultivar Yumai 34 as having unusually high contents of AX in both water-soluble and insoluble forms. We have therefore used populations generated from crosses between Yumai 34 and four other wheat cultivars, three with average contents of AX (Ukrainka, Altigo and Claire) and one also having unusually high AX (Valoris), in order to map QTLs for soluble AX (determined as relative viscosity) of aqueous extracts of wholemeal flours) and total AX (determined by enzyme fingerprinting of white flour). A number of QTL were mapped, but most were only detected in one or two crosses. However, all four crosses showed strong QTLs for high RV/total AX on chromosome 1B, with Yumai 34 being the increasing parent, and a KASP marker for the high AX Yumai 34 allele was validated by analysis of high AX lines derived from Yumai 34 but selected by biochemical analysis. A QTL for RV was mapped on chromosome 6B in Yumai 34 x Valoris, with Valoris being the increasing allele, which was consistent with the observation of transgressive segregation for this trait. The data indicate that breeding can be used to develop wheat with high AX fibre in white flour.

genetics↗

bioRxiv2019

Maximum likelihood method quantifies the overall contribution of gene-environment interaction to complex traits: an application to obesity traits

As genome-wide association studies (GWAS) increased in size, numerous gene-environment interactions (GxE) have been discovered, many of which however explore only one environment at a time and may suffer from statistical artefacts leading to biased interaction estimates. Here we propose a maximum likelihood method to estimate the contribution of GxE to complex traits taking into account all interacting environmental variables at the same time, without the need to measure any. This is possible because GxE induces fluctuations in the conditional trait variance, the extent of which depends on the strength of GxE. The approach can be applied to continuous outcomes and for single SNPs or genetic risk scores (GRS). Extensive simulations demonstrated that our method yields unbiased interaction estimates and excellent confidence interval coverage. We also offer a strategy to distinguish specific GxE from general heteroscedasticity (scale effects). Applying our method to 32 complex traits in the UK Biobank reveals that for body mass index (BMI) the GRSxE explains an additional 1.9% variance on top of the 5.2% GRS contribution. However, this interaction is not specific to the GRS and holds for any variable similarly correlated with BMI. On the contrary, the GRSxE interaction effect for leg impedance [Formula] is significantly (P < 10-56) larger than it would be expected for a similarly correlated variable [Formula]. We showed that our method could robustly detect the global contribution of GxE to complex traits, which turned out to be substantial for certain obesity measures.

epidemiology↗

bioRxiv2019

Integrated phylogenomic analyses reveal recurrent ancestral large-scale duplication events in mosses

O_LIMosses (Bryophyta) are a key group occupying important phylogenetic position for understanding land plant (embryophyte) evolution. The class Bryopsida represents the most diversified lineage and contains more than 95% of the modern mosses, whereas the other classes are by nature species-poor. The phylogeny of mosses remains elusive at present.\nC_LIO_LIRecurrent whole genome duplications have shaped the evolution trajectory of angiosperms, but little is known about the genome evolutionary history in mosses. It remains to be answered if there existed a historical genome duplication event associated with the species radiation of class Bryopsida.\nC_LIO_LIHere, the high-confidence moss phylogeny was generated covering major moss lineages. Two episodes of ancient genomic duplication events were elucidated by phylogenomic analyses, one in the ancestry of all mosses and another before the separation of the Bryopsida, Polytrichopsida and Tetraphidopsida, with estimated ages of the gene duplications clustered around 329 and 182 million year ago, respectively.\nC_LIO_LIThe third episode of polyploidy event (termed {psi}) was tightly associated with the early diversification of Bryopsida with an estimated age of ~87 million years. By scrutinizing the phylogenetic timing of duplicated syntelogs in Physcomitrella patens, the WGD1 and WGD2 events were confidently re-recognized as the {psi} event and the Funarioideae duplication event (~65 mya), respectively. Together, our findings unveiled four episodes of polyploidy events in the evolutionary past of Physcomitrella patens.\nC_LI

evolutionary biology↗

bioRxiv2019

A model for the spatio-temporal design of gene regulatory circuits

The design of increasingly complex gene regulatory networks relies upon mathematical modelling to link the gap that goes from conceptualisation to implementation. An overarching challenge is to update modelling abstractions and assumptions as new mechanistic information arises. Although models of bacterial gene regulation are often based on the assumption that the role played by intracellular physical distances between genetic elements is negligible, it has been shown that bacteria are highly ordered organisms, compartmentalizing their vital functions in both time and space. Here, we analysed the dynamical properties of regulatory interactions by explicitly modelling spatial constraints. Key to the model is the combined search by a regulator for its target promoter via 1D sliding along the chromosome and 3D diffusion through the cytoplasm. Moreover, this search was coupled to gene expression dynamics, with special attention to transcription factor-promoter interplay. As a result, promoter activity within the model depends on its physical separation from the regulator source. Simulations showed that by modulating the distance between DNA components in the chromosome, output levels changed accordingly. Finally, previous experimental results with engineered bacteria in which this distance was minimized or enlarged were successfully reproduced by the model. This suggests that the spatial specification of the circuit alone can be exploited as a design parameter to select programmable output levels.

synthetic biology↗

bioRxiv2018

Stringent response-mediated control of rRNA processing via the ribosomal assembly GTPase Era

P-loop GTPases are widely conserved across all domains of life. These enzymes act as molecular switches, cycling between inactive GDP-bound, and active GTP-bound states. Our previous work identified the Staphylococcus aureus GTPase Era as a binding target for the stringent response alarmone (p)ppGpp. Here we show that, unlike in Escherichia coli, Era is not essential in S. aureus but is important for 30S ribosomal subunit assembly. We employ bacterial two-hybrid and split luciferase approaches to show that Era interacts with the endonuclease YbeY, a protein of unknown function YbeZ, and the DEAD-box RNA helicase CshA in E. coli and natively in S. aureus. We determine that both Era and CshA are cold shock proteins required for virulence and rRNA processing. Era and CshA also form direct interactions with the (p)ppGpp synthetase RSH, an interaction required for controlling (p)ppGpp levels in response to cold shock. Taken together, we conclude that Era acts as an intermediary protein, directing enzymes involved in rRNA maturation to their site of action, an activity which, under stress, is controlled by the stringent response.

microbiology↗

bioRxiv2018

Complement 3 signaling is necessary for the developmental refinement of olfactory bulb circuitry

The olfactory system depends upon organizational maps that are developmentally refined and maintained, however the cellular and molecular mechanisms that underlie these processes are unknown. Studies have shown that microglia and complement molecules are important for the developmental refinement of circuitry within the visual system, thus we asked whether they played a similar role in the olfactory system through the formation of the olfactory bulb (OB) maps, the glomerular and intrabulbar maps. Our findings revealed that microglia in mature animals engulf olfactory sensory neuron (OSN) axons and the synaptic terminals of tufted cells in the glomerular and intrabulbar maps respectively, suggesting microglia could anatomically shape the mature OB circuitry. To determine the mechanisms underlying this axonal pruning activity we used complement 3 (C3) and complement receptor 3 (CR3) knockout mice to investigate if C3 signaling was necessary for precise OB map development. Our results demonstrate that glomerular and intrabulbar map disorganization as typically present in early postnatal mice persists into adulthood when C3 signaling is disrupted. These data clearly establish the C3/CR3 pathway as necessary for the proper developmental refinement of both olfactory maps. We further present the olfactory system as a unique platform to study the role of glia in the development and adult refinement of regenerating circuits.

neuroscience↗

bioRxiv2018

The unsolved problem of otitis media in indigenous populations: A systematic review of upper respiratory and middle ear microbiota in indigenous children

BackgroundOtitis media (OM) imposes a great burden of disease in indigenous populations around the world, despite a variety of treatment and prevention programs. Improved understanding of the pathogenesis of OM in indigenous populations is required to advance treatment and reduce prevalence. We conducted a systematic review of the literature exploring upper airway and middle ear microbiota in relation to OM in indigenous children.\n\nMethodsPapers targeting microbiota in relation to OM in children <18 years indigenous to Australia, New Zealand, North America, and Greenland were sought. MEDLINE, CINAHL, EMBASE, Cochrane Library, and Informit databases were searched using key words. Two independent reviewers screened titles, abstracts, and then full-text papers against inclusion criteria according to PRISMA guidelines.\n\nResultsTwenty-five papers considering indigenous Australian, Alaskan and Greenlandic children were included. There were high rates of nasopharyngeal colonization with the three main otopathogens (Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis) in indigenous children with OM. Middle ear samples had lower rates of otopathogen detection, although detection rates increased when molecular methods were used. Pseudomonas aeruginosa and Staphylococcus aureus were commonly detected in middle ear discharge of children with chronic suppurative OM. There was significant heterogeneity between studies, particularly in microbiological methods, which were largely limited to culture-based detection of the main otopathogens.\n\nConclusionsThere are high rates of otopathogen colonization in indigenous children with OM. Chronic suppurative OM appears to be associated with a different microbial profile. Beyond the main otopathogens, the data are limited. Further research is required to explore the entire upper respiratory tract/ middle ear microbiota in relation to OM, with the inclusion of healthy indigenous peers as controls.

microbiology↗

bioRxiv2018

Heterogeneity of Long-History Migration Predicts Smiling, Laughter and Positive Emotion Across the Globe and Within the United States

Recent findings demonstrate that heterogeneity of long-history migration predicts present-day emotion behaviors and norms. Residents of countries characterized by high ancestral diversity display emotion expressions that are easier to decode by observers, endorse norms of higher emotion expressivity, and smile more in response to certain stimuli than residents of countries that lack ancestral diversity. We build on the extant findings and investigate historical heterogeneity as a predictor of daily smiling, laughter, and positive emotion across the worlds countries and the states of the United States. Study 1 finds that historical heterogeneity is positively associated with self-reports of smiling, laughter, and positive emotions in the Gallup World Poll when controlling for GDP and current present-day population diversity. Study 2 extends the findings to effects of long-history migration within the United States. We estimated the average percentage of foreign-born citizens in each state between 1850 and 2010 based on US Census information as an indicator of historical heterogeneity. Consistent with the world findings of Study 1, historical heterogeneity predicted smiling, laughter, and positive, but not negative, emotion. The relationships remained significant when controlling for per capita income and present-day diversity of population of each state. Together, the findings further demonstrate the important role of long-history migration in shaping emotion cultures of countries and states, which persist beyond the original socio-ecological conditions, and open promising avenues for cross-cultural research.

evolutionary biology↗

bioRxiv2018

An immortalised mesenchymal stem cell line maintains mechano-responsive behaviour and can be used as a reporter of substrate stiffness

The mechanical environment can influence cell behaviour, including changes to transcriptional and proteomic regulation, morphology and, in the case of stem cells, commitment to lineage. However, current tools for characterizing substrates mechanical properties, such as atomic force microscopy (AFM), often do not fully recapitulate the length and time scales over which cells feel substrates. Here, we show that an immortalised, clonal line of human mesenchymal stem cells (MSCs) maintained responsiveness to substrate mechanics observed in primary cells, and could be used as a reporter of stiffness. MSCs were cultured on soft and stiff polyacrylamide hydrogels. In both primary and immortalised MSCs, stiffer substrates promoted increased cell spreading, expression of lamin-A/C and translocation of mechano-sensitive proteins YAP1 and MKL1 to the nucleus. Stiffness was also found to regulate transcriptional markers of lineage. A GFP-YAP / RFP-H2B reporter construct was designed and virally delivered to the immortalised MSCs for in situ detection of substrate stiffness. MSCs with stable expression of the reporter showed GFP-YAP to be increasingly co-localized with nuclear RFP-H2B on stiffer substrates, enabling development of a cellular reporter of substrate stiffness. This will facilitate mechanical characterisation of new materials developed for applications in tissue engineering and regenerative medicine.

bioengineering↗

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

ProGeM: A framework for the prioritisation of candidate causal genes at molecular quantitative trait loci

Quantitative trait locus (QTL) mapping of molecular phenotypes such as metabolites, lipids, and proteins through genome-wide association studies (GWAS) represents a powerful means of highlighting molecular mechanisms relevant to human diseases. However, a major challenge of this approach is to identify the causal gene(s) at the observed QTLs. Here we present a framework for the \"Prioritisation of candidate causal Genes at Molecular QTLs\" (ProGeM), which incorporates biological domain-specific annotation data alongside genome annotation data from multiple repositories. We assessed the performance of ProGeM using a reference set of 227 previously reported and extensively curated metabolite QTLs. For 98% of these loci, the expert-curated gene was one of the candidate causal genes prioritised by ProGeM. Benchmarking analyses revealed that 69% of the causal candidates were nearest to the sentinel variant at the investigated molecular QTLs, indicating that genomic proximity is the most reliable indicator of \"true positive\" causal genes. In contrast, cis-gene expression QTL data led to three false positive candidate causal gene assignments for every one true positive assignment. We provide evidence that these conclusions also apply to other molecular phenotypes, suggesting that ProGeM is a powerful and versatile tool for annotating molecular QTLs. ProGeM is freely available via GitHub.

bioinformatics↗