Biology subjects

Lynch, J.

Publications and source records attributed to Lynch, J..

7 recordsLinked to original sources

bioRxiv2018

Phosphorylation of the alpha2 glycine receptor induces an extracellular conformational change and slows the rise and decay rates of glycinergic synaptic currents

The 2 glycine receptor (GlyR) is a pentameric ligand-gated anion channel that plays a key role in cortical interneuron migration and in the differentiation of cortical progenitor cells into functional neurons. It also mediates tonic inhibitory chloride currents in adult forebrain neurons. Disruption of 2 GlyR gene expression or receptor function results in the aberrant functioning of neuronal circuits which contributes to the pathophysiology of schizophrenia, autism and epilepsy. This implicates the 2 GlyR as a possible therapeutic target for a range of neurological disorders. However, despite its therapeutic potential, little is known about the mechanisms by which 2 GlyRs are functionally modulated. To address this, we investigated whether the 2 GlyR is modulated by phosphorylation at a serine residue (S341) within the same PKA consensus sequence (R-E-S-R) that houses the 3 GlyR S346 residue that is known to be phosphorylated by PKA. Resolving this question might uncover a novel means of physiologically, pathologically or therapeutically modulating 2 GlyRs. We show using voltage-clamp fluorometry that forskolin-induced phosphorylation of S341 induces a conformational change in the glycine binding site. We also employed glycinergic artificial synapses to demonstrate that the S341E phospho-mimetic mutation slows the rise and decay rates of 2-mediated glycinergic inhibitory postsynaptic currents. These results suggest that PKA phosphorylation alters the structural and functional properties of the 2 GlyR. This information may help to identify new mechanisms by which 2 GlyRs may be pathologically modified or therapeutically targeted for the treatment of neurological disorders.

neuroscience↗

bioRxiv2018

The controlled direct effect of temperament at 2-3 years on cognitive and academic outcomes at 6-7 years

There is widespread interest in temperament and its impact upon cognitive and academic outcomes. Parents adjust their parenting according to their childs temperament, however, previous studies have not accounted for parenting while estimating the association between temperament and academic outcomes. We examined the controlled direct effect of temperament (2-3 years) on cognitive and academic outcomes (6-7 years) when mediation by parenting practices (4-5 years) was held constant. Participants were from the Longitudinal Study of Australian Children (n=5107). Cognitive abilities were measured by the Peabody Picture Vocabulary Test (verbal) and the Matrix Reasoning test (non-verbal). Literacy and numeracy were reported by teachers using the Academic Rating Scale. Mothers reported childrens temperament using the Short Temperament Scale for Toddlers (subscales: reactivity, approach, and persistence). Parenting practices included items about engagement in activities with children. Marginal structural models with inverse probability of treatment weights were used to estimate the controlled direct effect of temperament, when setting parenting to the mean. All temperament subscales were associated with cognitive abilities, with persistence showing the largest controlled direct effect on verbal ({beta}=0.58; 95%CI 0.27, 0.89) and non-verbal ({beta}=0.19; 0.02, 0.34) abilities. Higher persistence was associated with better literacy ({beta}=0.08; 0.03, 0.13) and numeracy ({beta}=0.08; 0.03, 0.13), and higher reactivity with lower literacy ({beta}=-0.08; -0.11, -0.05) and numeracy ({beta}=-0.07; -0.10, -0.04). There was little evidence that temperamental approach influenced literacy or numeracy. Overall, there was a small controlled direct effect of temperament on cognitive and academic outcomes after accounting for parenting and confounders.

epidemiology↗

bioRxiv2018

Ankyrin domain encoding genes resulting from an ancient horizontal transfer are functionally integrated into developmental gene regulatory networks in the wasp Nasonia

BackgroundHow and why regulatory networks incorporate additional components, and how novel genes are maintained and functionally integrated into developmental processes are two important and intertwined questions whose answers have major implications for the evolution of development. We recently described a set of novel genes with robust and unique expression patterns along the dorsal-ventral axis of the embryo of the wasp Nasonia. Given the unique evolutionary history of these genes, and their apparent integration in to the dorsal-ventral (DV) patterning network, they are collectively an excellent model to study the evolution of regulatory networks, and the fates of novel genes.\n\nResultsWe have found that the novel DV genes are part of a large family of rapidly duplicating and diverging ankyrin domain encoding genes that originated most likely by horizontal transfer from Wolbachia in a common ancestor of the wasp superfamilly Chalcidoidea. We tested the function of those ankyrin encoding genes expressed along the DV axis and found that they participate in early embryonic DV patterning. We also developed a new wasp model system (Melittobia) and found that some functional integration of ankyrin genes have been preserved for over 90 million years, while others are lineage specific.\n\nConclusionsOur results indicate that regulatory networks can incorporate novel genes that then become necessary for stable and repeatable outputs. Even modest role in developmental networks may be enough to allow novel or duplicate genes to be maintained in the genome and become fully integrated network components.

developmental biology↗

bioRxiv2018

Wheat shovelomics II: Revealing relationships between root crown traits and crop growth

Optimization of root system architecture represents an important goal in wheat breeding. Adopting new field methods for root phenotyping is key to delivering this goal. A novel shovelomics method was applied for phenotyping root crown traits to characterize the Savannah x Rialto doubled-haploid (DH) population in two field experiments under irrigated and rain-fed conditions. Trait validation was carried out through soil coring on a subset of 14 DH lines and the two parents. We observed that drought reduced grain yield per plant by 21.0%. Under rain-fed conditions, nodal root angle and roots shoot-1 were positively associated with root length density (RLD) at 40-60 cm depth; RLD was also positively correlated with grain yield. Nodal root angle and roots shoot-1 were also positively associated with canopy stay green and grain yield under rain-fed conditions. We conclude that shovelomics is a valuable technique for quantifying genetic variation in nodal root traits in wheat, revealing nodal root angle and root number per shoot provide useful selection criteria in breeding programs aimed at improving drought tolerance in wheat.\n\nHighlightNodal root angle and number shoot-1 measured using shovelomics were positively associated with root density at depth and yield under drought in a Savanah x Rialto wheat DH population.

plant biology↗

bioRxiv2017

BugBase Predicts Organism Level Microbiome Phenotypes

Shotgun metagenomics and marker gene amplicon sequencing can be used to directly measure or predict the functional repertoire of the microbiota en masse, but current methods do not readily estimate the functional capability of individual microorganisms. Here we present BugBase, an algorithm that predicts organism-level coverage of functional pathways as well as biologically interpretable phenotypes such as oxygen tolerance, Gram staining and pathogenic potential, within complex microbiomes using either whole-genome shotgun or marker gene sequencing data. We find BugBases organism-level pathway coverage predictions to be statistically higher powered than current bag-of-genes approaches for discerning functional changes in both host-associated and environmental microbiomes.

bioinformatics↗

bioRxiv2017

Do early life non-cognitive skills matter?A systematic review and meta-analysis of early life effects on academic achievement, psychosocial, language and cognitive, and health outcomes

BackgroundSuccess in school and the labour market is due to more than just high intelligence. Associations between traits such as attention, self-regulation, and perseverance in childhood, and later outcomes have been investigated by psychologists, economists, and epidemiologists. Such traits have been loosely referred to as \"non-cognitive\" skills. There has been no attempt to systematically assess the relative importance of non-cognitive skills in early life on later outcomes.\n\nMethodsThe systematic review protocol was registered with the International Prospective Register for Systematic Reviews (PROSPERO, CRD42013006566) in December 2013. We systematically reviewed electronic databases covering psychology, education, health and economics for articles published from database conception until September 2015. Titles and abstracts were screened for eligibility, and from eligible articles data was extracted on study design, sample type and size, age of participants at exposure and outcome, loss to follow up, measurement of exposure and outcome, type of intervention and comparison group, confounding adjustment and results. Where possible we extracted a standardised effect size. We reviewed all studies and rated their evidence quality as better, weak, or poor on the basis of study design and potential for confounding, selection and measurement bias.\n\nResultsWe reviewed 375 studies and provided interpretation of results from 142 (38%) better quality studies comprising randomised controlled trials, quasi-experimental, fixed effects including twin studies, longitudinal and some cross-sectional designs that made reasonable attempts to control confounding. In the academic achievement category outcomes were reported in 78 publications of better quality studies which were consistent with 0.1-0.2 SD effects.\n\nPsychosocial outcomes were reported in 65 better quality studies consistent with effects of 0.3-0.4 SD. For the language and cognitive category there were 42 publications reporting better quality studies consistent with effects of 0.3-0.4 SD. For physical health, results across only eight better quality studies were inconsistent but centred around zero. Analysis of funnel plots consistently showed asymmetric distributions, raising the potential of small study bias which may inflate these observed effects.\n\nConclusionsThe evidence under-pinning the importance of non-cognitive skills for life success is diverse and inconsistent. Nevertheless, there is tentative evidence from published studies that non-cognitive skills associate with modest improvements in academic achievement, psychosocial, and language and cognitive outcomes with effects in the range of 0.2-0.4 SD. The quality of evidence under-pinning this field is generally low with more than a third of studies making little or no attempt to control even the most basic confounding (endogeneity) bias. The evidence could be improved by adequately powering studies, and using procedures and tools that improve the conduct and reporting of RCTs and observational studies. Interventions designed to develop childrens non-cognitive skills could potentially improve opportunities, particularly for disadvantaged children. The inter-disciplinary researchers interested in these skills should take a more rigorous approach to determine which interventions are most effective.

epidemiology↗

bioRxiv2016

HOMINID: A framework for identifying associations between host genetic variation and microbiome composition

Recent studies have uncovered a strong effect of host genetic variation on the composition of host-associated microbiota. Here, we present HOMINID, a computational approach based on Lasso linear regression, that given host genetic variation and microbiome composition data, identifies host SNPs that are correlated with microbial taxa abundances. Using simulated data we show that HOMINID has accuracy in identifying associated SNPs, and performs better compared to existing methods. We also show that HOMINID can accurately identify the microbial taxa that are correlated with associated SNPs. Lastly, by using HOMINID on real data of human genetic variation and microbiome composition, we identified 13 human SNPs in which genetic variation is correlated with microbiome taxonomic composition across body sites. In conclusion, HOMINID is a powerful method to detect host genetic variants linked to microbiome composition, and can facilitate discovery of mechanisms controlling host-microbiome interactions.\n\nAvailability and implementationSoftware, code, tutorial, installation and setup details, and synthetic data are available in the project homepage: https://github.com/blekhmanlab/hominid.\n\nReal dataset used here is from Blekhman et al. (Blekhman et al. 2015); 16S rRNA gene sequence data and OTU tables are available on the HMP DACC website (www.hmpdacc.org), and host genetic data are deposited in dbGaP under project number phs000228.

genomics↗