Biology subjects

Smith, A. R.

Publications and source records attributed to Smith, A. R..

22 records · Page 2Linked to original sources

bioRxiv2020

Meta-analysis of epigenome-wide association studies in Alzheime's disease highlights 220 differentially methylated loci across cortex

Epigenome-wide association studies of Alzheimers disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimers disease (N=1,453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N=1,408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further > 600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

genomics↗

bioRxiv2020

Biotic and abiotic drivers of soil microbial functions across tree diversity experiments

AimSoil microorganisms are essential for the functioning of terrestrial ecosystems. Although soil microbial communities and functions may be linked to the tree species composition and diversity of forests, there has been no comprehensive study of how general potential relationships are and if these are context-dependent. A global network of tree diversity experiments (TreeDivNet) allows for a first examination of tree diversity-soil microbial function relationships across environmental gradients. LocationGlobal Major Taxa StudiedSoil microorganisms MethodsSoil samples collected from eleven tree diversity experiments in four biomes across four continents were used to measure soil basal respiration, microbial biomass, and carbon use efficiency using the substrate-induced respiration method. All samples were measured using the same analytical device in the same laboratory to prevent measurement bias. We used linear mixed-effects models to examine the effects of tree species diversity, environmental conditions, and their interactions on soil microbial functions. ResultsAcross biodiversity experiments, abiotic drivers, mainly soil water content, significantly increased soil microbial functions. Potential evapotranspiration (PET) increased, whereas soil C-to-N ratio (CN) decreased soil microbial functions under dry soil conditions, but high soil water content reduced the importance of other abiotic drivers. Tree species richness and phylogenetic diversity had overall similar, but weak and context-dependent (climate, soil abiotic variables) effects on soil microbial respiration. Positive tree diversity effects on soil microbial respiration were most pronounced at low PET, low soil CN, and high tree density. Soil microbial functions increased with the age of the experiment. Main conclusionsOur results point at the importance of soil water content for maintaining high levels of soil microbial functions and modulating effects of other environmental drivers. Moreover, overall tree diversity effects on soil microbial functions seem to be negligible in the short term (experiments were 1-18 years old). However, context-dependent tree diversity effects (climate, soil abiotic variables) have greater importance at high tree density, and significant effects of experimental age call for longer-term studies. Such systematic insights are key to better integrate soil carbon dynamics into the management of afforestation projects across environmental contexts, as todays reforestation efforts remain focused largely on aboveground carbon storage and are still dominated by less diverse forests stands of commercial species.

ecology↗

bioRxiv2019

Characterization of resistance to a potent D-peptide HIV entry inhibitor

BackgroundPIE12-trimer is a highly potent D-peptide HIV-1 entry inhibitor that broadly targets group M isolates. It specifically binds the three identical conserved hydrophobic pockets at the base of the gp41 N-trimer with sub-femtomolar affinity. This extremely high affinity for the transiently exposed gp41 trimer provides a reserve of binding energy (resistance capacitor) to combat resistance via stepwise accumulation of modest affinity-disrupting mutations. Viral passaging in the presence of escalating PIE12-trimer concentrations ultimately selected for PIE12-trimer resistant populations, but required an extremely extended timeframe (>1 year) in comparison to other entry inhibitors. Eventually, HIV developed resistance to PIE12-trimer by mutating Q577 in the gp41 pocket.\n\nResultsUsing deep sequence analysis, we identified three mutations at Q577 (R, N and K) in our two PIE12-trimer resistant pools. Each point mutant is capable of conferring the majority of PIE12-trimer resistance seen in the polyclonal pools. Surface plasmon resonance studies demonstrated substantial affinity loss between PIE12-trimer and the Q577R-mutated gp41 pocket. A high-resolution x-ray crystal structure of PIE12 bound to the Q577R pocket revealed the loss of two hydrogen bonds, the repositioning of neighboring residues, and a small decrease in buried surface area. The Q577 mutations in an NL4-3 backbone decreased viral growth rates. Fitness was ultimately rescued in resistant viral pools by a suite of compensatory mutations in gp120 and gp41, of which we identified seven candidates from our sequencing data.\n\nConclusionsThese data show that PIE12-trimer exhibits a high barrier to resistance, as extended passaging was required to develop resistant virus with normal growth rates. The primary resistance mutation, Q577R/N/K, found in the conserved gp41 pocket, substantially decreases inhibitor affinity but also damages viral fitness. Identified candidate compensatory mutations in gp160 will be the focus of future mechanistic studies.

microbiology↗

bioRxiv2017

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Alzheimers disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-{beta} (A{beta}) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of A{beta} and tau pathology (e.g. APP, PSEN1, PSEN2, MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.

genomics↗