EpiScanpy: integrated single-cell epigenomic analysis

EpiScanpy is a toolkit for the analysis of single-cell epigenomic data, namely single-cell DNA methylation and single-cell ATAC-seq data. To address the modality specific challenges from epigenomics data, epiScanpy quantifies the epigenome using multiple feature space constructions and builds a nearest neighbour graph using epigenomic distance between cells. EpiScanpy makes the many existing scRNA-seq workflows from scanpy available to large-scale single-cell data from other -omics modalities, including methods for common clustering, dimension reduction, cell type identification and trajectory learning techniques, as well as an atlas integration tool for scATAC-seq datasets. The toolkit also features numerous useful downstream functions, such as differential methylation and differential openness calling, mapping epigenomic features of interest to their nearest gene, or constructing gene activity matrices using chromatin openness. We successfully benchmark epiScanpy against other scATAC-seq analysis tools and show its outperformance at discriminating cell types. The authors present epiScanpy: a computational framework for the analysis of single-cell epigenomic data, both ATAC-seq and DNA methylation data, with examples for clustering, cell type identification, trajectory learning and atlas integration - and show its performance in distinguishing cell types

Effets de taille finie et dynamique dans les systèmes intégrables unidimensionnels

Many physical systems can be described by one-dimensional (1D) models. It is the case of ultra-cold atoms: under certain circumstances their dynamics occurs only in one dimension.During my PhD I studied some aspects of 1D integrable systems. First, I present a study on the ground state of a system of 2-component repulsive fermions in 1D under harmonic confinement. I use the Bethe ansatz solution to calculate the phase diagram of the system in the homogeneous case. Adding a harmonic confinement I show that the atoms are distributed in a two-shell structure: the partially polarised phase in the inner shell and the fully polarised phase at the edges of the trap.Next I study the finite size effects for the gap of the quasiparticle excitation spectrum in the 1D Hubbard model. Two type of corrections to the result of the thermodynamic limit are obtained: a power law correction inversely proportional to the size of the system L, due to gapless excitations, and an exponential correction on L related to the existence of gapped excitations. In the weakly interacting regime this last correction can become important.Finally I study the response of a highly excited 1D gas to a periodic modulation of the coupling constant. I consider the Lieb-Liniger model and the non-integrable model of a single mobile impurity in a Fermi gas. I show that the non-integrable system is sensitive to excitations with frequencies as low as the mean level spacing, whereas the threshold frequency in the integrable case is much larger. This effect can be used as a probe of integrability for mesoscopic 1D systems, and can be observed experimentally by measuring the heating rate of a parametrically excited gas.De nombreux systèmes physiques peuvent être décrits par des modèles unidimensionnels (1D). C'est le cas de certains gaz d'atomes ultrafroids: dans les bonnes conditions leur dynamique a lieu suivant une seule dimension spatiale.Je me suis intéressée à l'étude de quelques aspects des systèmes intégrables à 1D. D'abord je présente une étude de l'état fondamental d'un système de fermions 1D à 2 composants en interactions de contact répulsives. J'utilise l'ansatz de Bethe pour calculer le diagramme de phase du système homogène. Je prends ensuite en compte un piège harmonique et je montre que les atomes s'organisent en deux couches: une phase partiellement polarisée se trouve au centre du piège et une phase totalement polarisée aux bords.Ensuite j'étudie des corrections dues aux effets de taille finie au gap du spectre d'excitations du modèle d'Hubbard 1D. J'obtiens deux termes correctifs aux résultats de la limite thermodynamique: un en loi de puissances inverses en la taille du système L, et un second exponentiel en L. Dans le régime de faible interaction ce deuxième terme peut être important.Finalement j'étudie la réponse d'un système excité à la modulation temporelle de l'interaction entre atomes. Je considère le modèle de Lieb-Liniger et le modèle non-intégrable d'un gaz de fermions avec une impureté mobile. Je montre que le système non-intégrable est sensible à des excitations de fréquences de l'ordre de l'espacement moyen entre niveaux d'énergie, tandis que le système intégrable n'est excité que par des fréquences beaucoup plus grandes. Cet effet peut être utilisé comme test d'intégrabilité dans des systèmes mésoscopiques 1D et pourrait être observé expérimentalement

Signatures of Dobzhansky-Muller Incompatibilities in the Genomes of Recombinant Inbred Lines

In the construction of recombinant inbred lines (RILs) from two divergent inbred parents certain genotype (or epigenotype) combinations may be functionally "incompatible" when brought together in the genomes of the progeny, thus resulting in sterility or lower fertility. Natural selection against these epistatic combinations during inbreeding can change haplotype frequencies and distort linkage disequilibrium (LD) relations between loci on the same or on different chromosomes. These LD distortions have received increased experimental attention, because they point to genomic regions that may drive a Dobzhansky-Muller type of reproductive isolation and, ultimately, speciation in the wild. Here we study the selection signatures of two-locus epistatic incompatibility models and quantify their impact on the genetic composition of the genomes of two-way RILs obtained by selfing. We also consider the biases introduced by breeders when trying to counteract the loss of lines by selectively propagating only viable seeds. Building on our theoretical results, we develop model-based maximum-likelihood (ML) tests that can be applied to multilocus RIL genotype data to infer the precise mode of incompatibility as well as the relative fitness of incompatible loci. We illustrate this ML approach in the context of two published Arabidopsis thaliana RIL panels. Our work lays the theoretical foundation for studying more complex systems such as RILs obtained by sibling mating and/or from multiparental crosses

Finite size effects and dynamics in one-dimensional integrable systems

ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Rate, spectrum, and evolutionary dynamics of spontaneous epimutations

Stochastic changes in cytosine methylation are a source of heritable epigenetic and phenotypic diversity in plants. Using the model plant Arabidopsis thaliana, we derive robust estimates of the rate at which methylation is spontaneously gained (forward epimutation) or lost (backward epimutation) at individual cytosines and construct a comprehensive picture of the epimutation landscape in this species. We demonstrate that the dynamic interplay between forward and backward epimutations is modulated by genomic context and show that subtle contextual differences have profoundly shaped patterns of methylation diversity in A. thaliana natural populations over evolutionary timescales. Theoretical arguments indicate that the epimutation rates reported here are high enough to rapidly uncouple genetic from epigenetic variation, but low enough for new epialleles to sustain long-term selection responses. Our results provide new insights into methylome evolution and its population-level consequences

Ecological plant epigenetics: Evidence from model and non-model species, and the way forward

none25noneRichards, Christina L.; Alonso, Conchita; Becker, Claude; Bossdorf, Oliver; Bucher, Etienne; Colomé-Tatché, Maria; Durka, Walter; Engelhardt, Jan; Gaspar, Bence; Gogol-Döring, Andreas; Grosse, Ivo; van Gurp, Thomas P.; Heer, Katrin; Kronholm, Ilkka; Lampei, Christian; Latzel, Vít; Mirouze, Marie; Opgenoorth, Lars; Paun, Ovidiu; Prohaska, Sonja J.; Rensing, Stefan A.; Stadler, Peter F.; Trucchi, Emiliano; Ullrich, Kristian; Verhoeven, Koen J. F.Richards, Christina L.; Alonso, Conchita; Becker, Claude; Bossdorf, Oliver; Bucher, Etienne; Colomé-Tatché, Maria; Durka, Walter; Engelhardt, Jan; Gaspar, Bence; Gogol-Döring, Andreas; Grosse, Ivo; van Gurp, Thomas P.; Heer, Katrin; Kronholm, Ilkka; Lampei, Christian; Latzel, Vít; Mirouze, Marie; Opgenoorth, Lars; Paun, Ovidiu; Prohaska, Sonja J.; Rensing, Stefan A.; Stadler, Peter F.; Trucchi, Emiliano; Ullrich, Kristian; Verhoeven, Koen J. F

Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients

Background!#!The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system.!##!Methods!#!In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings.!##!Results!#!Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.!##!Conclusions!#!Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

Schulte-Schrepping J, Reusch N, Paclik D, et al. Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment. Cell. 2020;182(6):1419-1440.e23.Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19