Using DNA from mothers and children to study parental investment in children's educational attainment, bioRxiv, 2018-12-10
This study tested implications of new genetic discoveries for understanding the association between parental investment and children's educational attainment. A novel design matched genetic data from 860 British mothers and their children with home-visit measures of parenting the E-Risk Study. Three findings emerged. First, both mothers' and children's education-associated genetics, summarized in a genome-wide polygenic score, predicted parenting -- a gene-environment correlation. Second, accounting for genetic influences slightly reduced associations between parenting and children's attainment -- indicating some genetic confounding. Third, mothers' genetics influenced children's attainment over and above genetic mother-to-child transmission, via cognitively-stimulating parenting -- an environmentally-mediated effect. Findings imply that, when interpreting parents' effects on children, environmentalists must consider genetic transmission, but geneticists must also consider environmental transmission.
biorxiv genetics 100-200-users 2018Assignment of virus and antimicrobial resistance genes to microbial hosts in a complex microbial community by combined long-read assembly and proximity ligation, bioRxiv, 2018-12-09
AbstractThe characterization of microbial communities by metagenomic approaches has been enhanced by recent improvements in short-read sequencing efficiency and assembly algorithms. We describe the results of adding long-read sequencing to the mix of technologies used to assemble a highly complex cattle rumen microbial community, and compare the assembly to current short read-based methods applied to the same sample. Contigs in the long-read assembly were 7-fold longer on average, and contained 7-fold more complete open reading frames (ORF), than the short read assembly, despite having three-fold lower sequence depth. The linkages between long-read contigs, provided by proximity ligation data, supported identification of 188 novel viral-host associations in the rumen microbial community that suggest cross-species infectivity of specific viral strains. The improved contiguity of the long-read assembly also identified 94 antimicrobial resistance genes, compared to only seven alleles identified in the short-read assembly. Overall, we demonstrate a combination of experimental and computational methods that work synergistically to improve characterization of biological features in a highly complex rumen microbial community.
biorxiv microbiology 0-100-users 2018Atomic Level Characterisation of Millisecond-Time Scale Protein Motions through a Combined Molecular Simulations and NMR Approach, bioRxiv, 2018-12-09
AbstractAdvances in biomolecular sciences are closely linked to our ability to chart the energy landscapes of biomolecules with atomic details. Here we validate a new paradigm to characterise thermodynamics and kinetics of millisecond timescale conformational transitions between ground state and transient excited states in the enzyme cyclophilin A (CypA). We describe a novel methodology that combines molecular dynamics simulations and Markov State modelling with NMR measurements to provide atomic-level insights into the nature of CypA transient conformational states. The computed conformational ensembles also enabled the predictive design and experimental validation of a single-site mutant that dramatically perturbs millisecond timescale loop motions, converting a CypA excited state into the ground state. The resulting models open up new horizons for targeting CypA with inhibitors and pave the way towards rational design of protein energy landscapes for protein engineering and drug discovery purposes.
biorxiv biophysics 0-100-users 2018Dynamic design manipulation of millisecond timescale motions on the energy landscape of Cyclophilin A, bioRxiv, 2018-12-09
AbstractProteins need to interconvert between many conformations in order to function, many of which are formed transiently, and sparsely populated. Particularly when the lifetimes of these states approach the millisecond timescale, identifying the relevant structures and the mechanism by which they inter-convert remains a tremendous challenge. Here we introduce a novel combination of accelerated MD (aMD) simulations and Markov State modelling (MSM) to explore these ‘excited’ conformational states. Applying this to the highly dynamic protein CypA, a protein involved in immune response and associated with HIV infection, we identify five principally populated conformational states and the atomistic mechanism by which they interconvert. A rational design strategy predicted that the mutant D66A should stabilise the minor conformations and substantially alter the dynamics whereas the similar mutant H70A should leave the landscape broadly unchanged. These predictions are confirmed using CPMG and R1ρ solution state NMR measurements. By accurately and reliably exploring functionally relevant, but sparsely populated conformations with milli-second lifetimes in silico, our aMDMSM method has tremendous promise for the design of dynamic protein free energy landscapes for both protein engineering and drug discovery.
biorxiv biophysics 0-100-users 2018Chemogenetic ligands for translational neurotheranostics, bioRxiv, 2018-12-08
AbstractDesigner Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for precision medicine-based clinical theranostics. DREADD ligands developed to date are not appropriate for such translational applications. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine. The second-generation DREADD agonist, Compound 21 (C21), was developed to overcome these limitations. We found that C21 has low brain penetrance, weak affinity, and low in vivo DREADD occupancy. To address these drawbacks, we developed two new DREADD agonists, JHU37152 and JHU37160, and the first dedicated positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons and at their long-range projections, enabling for the first time, noninvasive and longitudinal neuronal projection mapping and potential for neurotheranostic applications.
biorxiv neuroscience 0-100-users 2018Fast and accurate large multiple sequence alignments using root-to-leave regressive computation, bioRxiv, 2018-12-08
AbstractInferences derived from large multiple alignments of biological sequences are critical to many areas of biology, including evolution, genomics, biochemistry, and structural biology. However, the complexity of the alignment problem imposes the use of approximate solutions. The most common is the progressive algorithm, which starts by aligning the most similar sequences, incorporating the remaining ones following the order imposed by a guide-tree. We developed and validated on protein sequences a regressive algorithm that works the other way around, aligning first the most dissimilar sequences. Our algorithm produces more accurate alignments than non-regressive methods, especially on datasets larger than 10,000 sequences. By design, it can run any existing alignment method in linear time thus allowing the scale-up required for extremely large genomic analyses.One Sentence SummaryInitiating alignments with the most dissimilar sequences allows slow and accurate methods to be used on large datasets
biorxiv bioinformatics 200-500-users 2018