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Maintaining centrosomes and cilia
Full text linkThe deposited item is a review and has been submitted to peer review. This publication hasn't any creative commons license associated. There is no public supplementary material available for this publication.Centrosomes and cilia are present in organisms from all branches of the eukaryotic tree of life. These structures are composed of microtubules and various other proteins, and are required for a plethora of cell processes such as structuring the cytoskeleton, sensing the environment, and motility. Deregulation of centrosome and cilium components leads to a wide range of diseases, some of which are incompatible with life. Centrosomes and cilia are thought to be very stable and can persist over long periods of time. However, these structures can disappear in certain developmental stages and diseases. Moreover, some centrosome and cilia components are quite dynamic. While a large body of knowledge has been produced regarding the biogenesis of these structures, little is known about how they are maintained. In this Review, we propose the existence of specific centrosome and cilia maintenance programs, which are regulated during development and homeostasis, and when deregulated can lead to disease.Fundação para a Ciência e a Tecnologia grants: (SFRH/BPD/79680/2011, SFRH/BD/52176/2013); ERC grant: (ERC-2015-CoG - 683258_CentrioleBirthDeath).info:eu-repo/semantics/publishedVersio
Polygenicity and Epistasis Underlie Fitness-Proximal Traits in the Caenorhabditis elegans Multiparental Experimental Evolution (CeMEE) Panel
Full text linkThe deposited article is a pre-print version and it has not been submitted to peer reviewing. This article version was provided by bioRxiv and is the preprint first posted online Mar. 26, 2017. This publication hasn't any creative commons license associated. The deposited article version contains attached the supplementary materials within the pdf.Understanding the genetic basis of complex traits remains a major challenge in biology. Polygenicity, phenotypic plasticity and epistasis contribute to phenotypic variance in ways that are rarely clear. This uncertainty can be problematic for estimating heritability, for predicting individual phenotypes from genomic data, and for parameterizing models of phenotypic evolution. Here we report an advanced recombinant inbred line (RIL) quantitative trait locus (QTL) mapping panel for the hermaphroditic nematode Caenorhabditis elegans, the C. elegans multiparental experimental evolution (CeMEE) panel. The CeMEE panel, comprising 507 RILs at present, was created by hybridization of 16 wild isolates, experimental evolution for 140-190 generations, and inbreeding by selfing for 13-16 generations. The panel contains 22% of single nucleotide polymorphisms known to segregate in natural populations, and complements existing C. elegans mapping resources by providing fine resolution and high nucleotide diversity across >95% of the genome. We apply it to study the genetic basis of two fitness components, fertility and hermaphrodite body size at time of reproduction, with high broad sense heritability in the CeMEE. While simulations show we should detect common alleles with additive effects as small as 5%, at gene-level resolution, the genetic architectures of these traits does not feature such alleles. We instead find that a significant fraction of trait variance, approaching 40% for fertility, can be explained by sign epistasis with main effects below the detection limit. In congruence, phenotype prediction from genomic similarity, while generally poor (r2 < 10%), requires modeling epistasis for optimal accuracy, with most variance attributed to the rapidly evolving chromosome arms.National Science Foundation grant: (PHY-1125915); National Institutes of Health grants: (R25-GM-067110, R01-GM-089972, R01-GM-121828); Gordon and Betty Moore Foundation grant: (2919.01); Human Frontiers Science Program (RGP0045/2010); European Research Council grant: (FP7/2007-2013/243285); Agence Nationale de la Recherche grant: (ANR-14-ACHN-0032-01).info:eu-repo/semantics/publishedVersio
Tolerogenic insulin peptide therapy precipitates type 1 diabetes
Full text linkThe deposited article version contains attached the supplementary materials within the pdf.Daniel et al. (https://doi.org/10.1084/jem.20110574) have previously published in JEM a study on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Our study now challenges these results and shows that osmotic pump delivery of the modified insulin peptide R22E did not prevent hyperglycemia, accelerated disease onset, increased its incidence, and worsened insulitis.European Union’s (EU FP7) Large-Scale Focused Collaborative Research Project on Natural Immunomodulators as Novel Immunotherapies for Type 1 Diabetes grant: (NAIMIT, 241447).info:eu-repo/semantics/publishedVersio
Recurrent Reverse Evolution Maintains Polymorphism after Strong Bottlenecks in Commensal Gut Bacteria
Full text linkThe deposited article is a post-print version and has been submitted to peer review.This deposit is composed by the main article plus the supplementary materials of the publication.The evolution of new strains within the gut ecosystem is poorly understood. We used a natural but controlled system to follow the emergence of intraspecies diversity of commensal Escherichia coli, during three rounds of adaptation to the mouse gut (∼1,300 generations). We previously showed that, in the first round, a strongly beneficial phenotype (loss-of-function for galactitol consumption; gat-negative) spread to >90% frequency in all colonized mice. Here, we show that this loss-of-function is repeatedly reversed when a gat-negative clone colonizes new mice. The regain of function occurs via compensatory mutation and reversion, the latter leaving no trace of past adaptation. We further show that loss-of-function adaptive mutants reevolve, after colonization with an evolved gat-positive clone. Thus, even under strong bottlenecks a regime of strong-mutation-strong-selection dominates adaptation. Coupling experiments and modeling, we establish that reverse evolution recurrently generates two coexisting phenotypes within the microbiota that can or not consume galactitol (gat-positive and gat-negative, respectively). Although the abundance of the dominant strain, the gat-negative, depends on the microbiota composition, gat-positive abundance is independent of the microbiota composition and can be precisely manipulated by supplementing the diet with galactitol. These results show that a specific diet is able to change the abundance of specific strains. Importantly, we find polymorphism for these phenotypes in indigenous Enterobacteria of mice and man. Our results demonstrate that natural selection can greatly overwhelm genetic drift at structuring the strain diversity of gut commensals and that competition for limiting resources may be a key mechanism for maintaining polymorphism in the gut.This research received funding from the European Research Council (ERC): ERC-StG-ECOADAPT; University of Cologne-Instituto Gulbenkian de Ciência, under SFB of DFG.info:eu-repo/semantics/publishedVersio
CREM variant rs17583959 conferred susceptibility to T1D risk in the Tunisian families
No full textThis deposit is composed by a publication in which the IGC's authors have had the role of collaboration (it's a collaboration publication). This type of deposit in ARCA is in restrictedAccess (it can't be in open access to the public), and can only be accessed by two ways: either by requesting a legal copy from the author (the email contact present in this deposit) or by visiting the following link: https://www.sciencedirect.com/science/article/pii/S0165247816302711?via%3Dihub#sec0035This publication hasn't any creative commons license associated.There is no public supplementary material available.Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the destruction of insulin-producing pancreatic β-cells by autoreactive T cells. Studies in animal models, such as the non-obese diabetic (NOD) mouse reveal that this disease is under the control of several genes that encode molecules implicated in regulation of transcription factors and in T cell activation. In order to underline the role of the genes involved in this regulation pathways, we investigated, using the Sequenom MassARRAY platform, 13 single-nucleotide polymorphisms (SNPs) belonging to CREM, IRF5, STAT4, and STAT5a/b genes in 59 T1D Tunisian families. In the current study, we identified an association with rs17583959 (allele G; Z score=2.27; p=0.02; Genotype GG: score=1.96; p=0.04) of CREM gene. In LD analysis a strong LD between the 3 CREM variants (Block 1) was detected; rs2384352 was in complete LD with rs1148247. When haplotypes were constructed between CREM polymorphisms (rs1148247, rs17583959, rs2384352), AGA haplotype (H2) was significantly over-transmitted from parents to affected offspring (Z score=2.988; P=0.002) and may confer a risk for T1D disease. Whereas, AAG haplotype (H5) (Z score=-2.000; p=0.045) was less transmitted than expected to affected children suggesting its protective effect against T1D pathology. No significant association in IRF5, STAT4, and STAT5a/b genes were observed. In conclusion, this study shows an eventually involvement of CREM gene in the development of T1D pathology in Tunisian families. These facts are consistent with a major role for transcription factor genes involved in the immune pathways in the control of autoimmunity. Further researches of association and functional analysis across populations are needed to confirm these findings.There are no funders and sponsors indicated explicitly in the document.info:eu-repo/semantics/publishedVersio
A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages
Full text linkConditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood-brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood-brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.Fundação para a Ciência e Tecnologia grant: (PTDC/BIM-MET/3750/2014); European Molecular Biology Organization (EMBO); European Community’s Seventh Framework Programme (FP7/2007-2013) under agreement no. (281854—the ObERStress project); MINECO co-funded by the FEDER Program of EU: (ML: SAF20015-71026-R); Xunta de Galicia grant: (ML: 2015-CP079); Instituto Gulbenkian de Ciência; Royal Society University.info:eu-repo/semantics/publishedVersio
Quantitative proteomics screen identifies a substrate repertoire of rhomboid protease RHBDL2 in human cells and implicates it in epithelial homeostasis
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publication.Rhomboids are intramembrane serine proteases conserved in all kingdoms of life. They regulate epidermal growth factor receptor signalling in Drosophila by releasing signalling ligands from their transmembrane tethers. Their functions in mammals are poorly understood, in part because of the lack of endogenous substrates identified thus far. We used a quantitative proteomics approach to investigate the substrate repertoire of rhomboid protease RHBDL2 in human cells. We reveal a range of novel substrates that are specifically cleaved by RHBDL2, including the interleukin-6 receptor (IL6R), cell surface protease inhibitor Spint-1, the collagen receptor tyrosine kinase DDR1, N-Cadherin, CLCP1/DCBLD2, KIRREL, BCAM and others. We further demonstrate that these substrates can be shed by endogenously expressed RHBDL2 and that a subset of them is resistant to shedding by cell surface metalloproteases. The expression profiles and identity of the substrates implicate RHBDL2 in physiological or pathological processes affecting epithelial homeostasis.Academy of Sciences of the Czech Republic grant: (Purkyne Fellowship); EMBO grant: (Installation Grant no. 2329); Ministry of Education, Youth and Sports of the Czech Republic grants: (projects no. LK11206 and LO1302); Marie Curie Career Integration grant: (project no. 304154); National Subvention for Development of Research Organisations grant: (RVO: 61388963); Institute of Organic Chemistry and Biochemistry; Fundação Calouste Gulbenkian; Worldwide Cancer Research grant: (14–1289); Marie Curie Career Integration grant: (project no. 618769); Fundação para a Ciência e Tecnologica (FCT, PTDC/BEX-BCM/3015/2014); European Crohn’s and Colitis organization (ECCO); COST BM1406; Wellcome Trust grant: (101035/Z/13/Z); Medical Research Council grant: (programme number MC_U105178780).info:eu-repo/semantics/publishedVersio
The genetic legacy of Zoroastrianism in Iran and India: Insights into population structure, gene flow and selection.
Full text linkThe deposited article version is a "Pre-print version" provided by Biorxiv posted online on April 18, 2017 - 12:26, and it contains attached the supplementary materials within the pdf.Zoroastrianism is one of the oldest extant religions in the world, originating in Persia (present-day Iran) during the second millennium BCE. Historical records indicate that migrants from Persia brought Zoroastrianism to India, but there is debate over the timing of these migrations. Here we present genome-wide autosomal, Y chromosome, and mitochondrial DNA data from Iranian and Indian Zoroastrians and neighboring modern-day Indian and Iranian populations and conduct a comprehensive genome-wide genetic analysis in these groups. Using powerful haplotype-based techniques, we find that Zoroastrians in Iran and India have increased genetic homogeneity relative to other sampled groups in their respective countries, consistent with their current practices of endogamy. Despite this, we infer that Indian Zoroastrians (Parsis) intermixed with local groups sometime after their arrival in India, dating this mixture to 690–1390 CE and providing strong evidence that Iranian Zoroastrian ancestry was maintained primarily through the male line. By making use of the rich information in DNA from ancient human remains, we also highlight admixture in the ancestors of Iranian Zoroastrians dated to 570 BCE–746 CE, older than admixture seen in any other sampled Iranian group, consistent with a long-standing isolation of Zoroastrians from outside groups. Finally, we report results, and challenges, from a genome-wide scan to identify genomic regions showing signatures of positive selection in present-day Zoroastrians that might correlate to the prevalence of particular diseases among these communities.BBSRC grant: (BB/L009382/1); Wellcome Trust and the Royal Society Sir Henry Dale Fellowship: (098386/Z/12/Z); National Institute for Health Research University College London Hospitals Biomedical Research Centre; Wellcome Trust Senior Investigator Award grant: (100719/Z/12/Z); EPSRC grant: (EP/F500351/1).info:eu-repo/semantics/acceptedVersio
The Combined Effect of Oseltamivir and Favipiravir on Influenza A Virus Evolution
Full text linkThis deposit is composed by the main article plus the supplementary materials of the publication.Influenza virus inflicts a heavy death toll annually and resistance to existing antiviral drugs has generated interest in the development of agents with novel mechanisms of action. Favipiravir is an antiviral drug that acts by increasing the genome-wide mutation rate of influenza A virus (IAV). Potential synergistic benefits of combining oseltamivir and favipiravir have been demonstrated in animal models of influenza, but the population-level effects of combining the drugs are unknown. In order to elucidate the underlying evolutionary processes at play, we performed genome-wide sequencing of IAV experimental populations subjected to serial passaging in vitro under a combined protocol of oseltamivir and favipiravir. We describe the interplay between mutation, selection, and genetic drift that ultimately culminates in population extinction. In particular, selective sweeps around oseltamivir resistance mutations reduce genome-wide variation while deleterious mutations hitchhike to fixation given the increased mutational load generated by favipiravir. This latter effect reduces viral fitness and accelerates extinction compared with IAV populations treated with favipiravir alone, but risks spreading both established and newly emerging mutations, including possible drug resistance mutations, if transmission occurs before the viral populations are eradicated.Office of the Assistant Secretary of Defense for Health Affairs - Peer Reviewed Medical Research Program grant: (W81XWH-15-1-0317); Defense Advanced Research Projects Agency (DARPA) Prophecy Program; Defense Sciences Office (DSO), Contract No. HR0011-11-C-0095, and D13AP00041; MediVector; European Research Council (ERC); Fuji Films; Department of Defense.info:eu-repo/semantics/publishedVersio
Early and Real-Time Detection of Seasonal Influenza Onset
Full text linkData are available as supplementary materials. Some of the data is not supported by the repository, so the upload of data is not complete. For the complete data, please visit the publisher version of the article.Every year, influenza epidemics affect millions of people and place a strong burden on health care services. A timely knowledge of the onset of the epidemic could allow these services to prepare for the peak. We present a method that can reliably identify and signal the influenza outbreak. By combining official Influenza-Like Illness (ILI) incidence rates, searches for ILI-related terms on Google, and an on-call triage phone service, Saúde 24, we were able to identify the beginning of the flu season in 8 European countries, anticipating current official alerts by several weeks. This work shows that it is possible to detect and consistently anticipate the onset of the flu season, in real-time, regardless of the amplitude of the epidemic, with obvious advantages for health care authorities. We also show that the method is not limited to one country, specific region or language, and that it provides a simple and reliable signal that can be used in early detection of other seasonal diseases.Fundação para a Ciência e para a Tecnologia; Welcome grant: (DFRH WIIA 60 2011); Marie Curie Actions.info:eu-repo/semantics/publishedVersio