Predicting antigen-specificity of single T-cells based on TCR CDR3 regions, bioRxiv, 2019-08-14
It has recently become possible to assay T-cell specificity with respect to large sets of antigens as well as T-cell receptor sequence in high-throughput single-cell experiments. We propose multiple sequence-data specific deep learning approaches to impute TCR to epitope specificity to reduce the complexity of new experiments. We found that models that treat antigens as categorical variables outperform those which model the TCR and epitope sequence jointly. Moreover, we show that variability in single-cell immune repertoire screens can be mitigated by modeling cell-specific covariates.
biorxiv bioinformatics 0-100-users 2019Myristate as a carbon and energy source for the asymbiotic growth of the arbuscular mycorrhizal fungus Rhizophagus irregularis, bioRxiv, 2019-08-11
AbstractArbuscular mycorrhiza (AM) is one of the most widespread mutualistic symbioses, which is formed between the majority of land plants and soil-borne fungi belonging to Glomeromycotina. AM fungi are obligate symbionts that cannot complete their natural life cycle without a host. Recent evidence suggests that lipids synthesized by a host are transferred to AM fungi that possess no fatty acid synthase genes in their genome and that mutations in lipid biosynthesis-related genes of the host lead the symbiotic interaction to fail (1–3). We hypothesized that lipids derived from plants are crucial for AM fungal growth and reproduction. In this study, we evaluated whether AM fungi can grow on medium supplied with fatty acids under asymbiotic conditions without the host. Myristate led to an extensive hyphal growth of Rhizophagus irregularis and an increase in biomass production. Other examined fatty acids showed no effect on biomass production. Myristate also induced secondary spore formation. The myristate-induced spores can germinate, colonize carrot hairy roots, and form the next generation of mature daughter spores. A fluorescently labeled fatty acid probe was taken up by branched hyphae of AM fungi. Tracer experiments using 13C-labeled myristic acid showed that myristate and its metabolites were utilized for the synthesis of triacylglycerol and cell wall components of AM fungi. Furthermore, myristate activated ATP generation in the fungal hyphae. Here we demonstrate that myristate is utilized as a carbon and energy source for biomass production and sporulation under asymbiotic conditions.
biorxiv microbiology 0-100-users 2019Assessment of Polygenic Architecture and Risk Prediction based on Common Variants Across Fourteen Cancers, bioRxiv, 2019-08-10
AbstractWe analyzed summary-level data from genome-wide association studies (GWAS) of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) contributing to risk, as well as the distribution of their associated effect sizes. All cancers evaluated showed polygenicity, involving at a minimum thousands of independent susceptibility variants. For some malignancies, particularly chronic lymphoid leukemia (CLL) and testicular cancer, there are a larger proportion of variants with larger effect sizes than those for other cancers. In contrast, most variants for lung and breast cancers have very small associated effect sizes. For different cancer sites, we estimate a wide range of GWAS sample sizes, required to explain 80% of GWAS heritability, varying from 60,000 cases for CLL to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores, compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that polygenic risk scores have substantial potential for risk stratification for relatively common cancers such as breast, prostate and colon, but limited potential for other cancer sites because of modest heritability and lower disease incidence.
biorxiv genetics 0-100-users 2019WAPL maintains dynamic cohesin to preserve lineage specific distal gene regulation, bioRxiv, 2019-08-10
SUMMARYThe cohesin complex plays essential roles in sister chromatin cohesin, chromosome organization and gene expression. The role of cohesin in gene regulation is incompletely understood. Here, we report that the cohesin release factor WAPL is crucial for maintaining a pool of dynamic cohesin bound to regions that are associated with lineage specific genes in mouse embryonic stem cells. These regulatory regions are enriched for active enhancer marks and transcription factor binding sites, but largely devoid of CTCF binding sites. Stabilization of cohesin, which leads to a loss of dynamic cohesin from these regions, does not affect transcription factor binding or active enhancer marks, but does result in changes in promoter-enhancer interactions and downregulation of genes. Acute cohesin depletion can phenocopy the effect of WAPL depletion, showing that cohesin plays a crucial role in maintaining expression of lineage specific genes. The binding of dynamic cohesin to chromatin is dependent on the pluripotency transcription factor OCT4, but not NANOG. Finally, dynamic cohesin binding sites are also found in differentiated cells, suggesting that they represent a general regulatory principle. We propose that cohesin dynamically binding to regulatory sites creates a favorable spatial environment in which promoters and enhancers can communicate to ensure proper gene expression.HIGHLIGHTS<jatslist list-type=order><jatslist-item>The cohesin release factor WAPL is crucial for maintaining a pluripotency-specific phenotype.<jatslist-item><jatslist-item>Dynamic cohesin is enriched at lineage specific loci and overlaps with binding sites of pluripotency transcription factors.<jatslist-item><jatslist-item>Expression of lineage specific genes is maintained by dynamic cohesin binding through the formation of promoter-enhancer associated self-interaction domains.<jatslist-item><jatslist-item>CTCF-independent cohesin binding to chromatin is controlled by the pioneer factor OCT4.<jatslist-item>
biorxiv genomics 0-100-users 2019Serosolver an open source tool to infer epidemiological and immunological dynamics from serological data, bioRxiv, 2019-08-09
AbstractWe present a flexible, open source R package designed to obtain additional biological and epidemiological insights from commonly available serological datasets. Analysis of serological responses against pathogens with multiple strains such as influenza pose a specific statistical challenge because observed antibody responses measured in serological assays depend both on unobserved prior infections and the resulting cross-reactive antibody dynamics that these infections generate. We provide a general modelling framework to jointly infer these two typically confounded biological processes using antibody titres against current and historical strains. We do this by linking latent infection dynamics with a mechanistic model of antibody dynamics that generates expected antibody titres over time. This makes it possible to use observations of antibodies in serological assays to infer an individual’s infection history as well as the parameters of the antibody process model. Our aim is to provide a flexible inference package that can be applied to a range of datasets studying different viruses over different timescales. We present two case studies to illustrate how our model can infer key immunological parameters, such as antibody titre boosting, waning and cross-reaction, and well as latent epidemiological processes such as attack rates and age-stratified infection risk.
biorxiv immunology 0-100-users 2019NAD+ repletion rescues female fertility during reproductive ageing, bioRxiv, 2019-08-03
AbstractFemale infertility is a common and devastating condition with life-long health, emotional and social consequences. There is currently no pharmacological therapy for preserving oocyte quality during aging, which is the strongest risk factor for infertility. This leads to an age dependent decline in natural conception and IVF success rates (1). Here, we show that this is due in part to declining levels of the metabolic cofactor nicotinamide adenine dinucleotide (NAD+), and that restoring NAD+ levels with its metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality and quantity in aged animals, leading to improved fertility. These benefits extend to the developing embryo, where NMN supplementation in embryo culture media following IVF enhances blastocyst formation in older mice. The NAD+ dependent deacylase SIRT2 is sufficient, but not essential, to recapitulate the benefits of in vivo NMN treatment, and transgenic overexpression of SIRT2 maintains oocyte spindle assembly, accurate chromosome segregation, decreased oxidative stress and overall fertility with ageing. Pharmacological elevation of NAD+ may be an effective, non-invasive strategy for restoring and maintaining female fertility during ageing, and for improving the success of IVF.
biorxiv developmental-biology 0-100-users 2019