Biology subjects

Liston, A.

Publications and source records attributed to Liston, A..

30 records · Page 2Linked to original sources

bioRxiv2020

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

Interleukin 2 (IL-2) is a key homeostatic cytokine, with potential therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical application has been hampered by pleiotropic functionality and wide-spread receptor expression, with unexpected adverse events during trials. To characterize the IL-2 homeostatic network, we developed a novel mouse strain allowing IL-2 production to be diverted. Rewiring of IL-2 production to diverse leukocyte sources allowed the identification of contextual influences over IL-2 impact. Network analysis identified a priority access for Tregs, and a competitive fitness cost induced among both Tregs and conventional CD4 T cells for IL-2 production. CD8 T cells and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified the Treg circuit, while IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells. The former was associated with an unexpected concentration of rare CD8+ Tregs in B cell zones, while the latter drove a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain unexpected adverse effects observed during clinical trials of exogenous IL-2. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

immunology↗

bioRxiv2020

A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice

The spread of SARS-CoV-2 has caused a global pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection, and may enable the relaxation of social distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection, therefore it is desirable that any new vaccine candidates should elicit a robust immune response in older adults. Here, we test the immunogenicity of the adenoviral vectored vaccine ChAdOx1 nCoV-19 (AZD-1222) in aged mice. We find that a single dose of this vaccine induces cellular and humoral immunity in aged mice, but at a reduced magnitude than in younger adult mice. Furthermore, we report that a second dose enhances the immune response to this vaccine in aged mice, indicating that a primeboost strategy may be a rational approach to enhance immunogenicity in older persons.

immunology↗

bioRxiv2020

Analysis of paralogs in target enrichment data pinpoints multiple ancient polyploidy events in Alchemilla s.l. (Rosaceae)

Target enrichment is becoming increasingly popular for phylogenomic studies. Although baits for enrichment are typically designed to target single-copy genes, paralogs are often recovered with increased sequencing depth, sometimes from a significant proportion of loci, especially in groups experiencing whole-genome duplication (WGD) events. Common approaches for processing paralogs in target enrichment datasets include random selection, manual pruning, and mainly, the removal of entire genes that show any evidence of paralogy. These approaches are prone to errors in orthology inference or removing large numbers of genes. By removing entire genes, valuable information that could be used to detect and place WGD events is discarded. Here we use an automated approach for orthology inference in a target enrichment dataset of 68 species of Alchemilla s.l. (Rosaceae), a widely distributed clade of plants primarily from temperate climate regions. Previous molecular phylogenetic studies and chromosome numbers both suggested ancient WGDs in the group. However, both the phylogenetic location and putative parental lineages of these WGD events remain unknown. By taking paralogs into consideration, we identified four nodes in the backbone of Alchemilla s.l. with an elevated proportion of gene duplication. Furthermore, using a gene-tree reconciliation approach we established the autopolyploid origin of the entire Alchemilla s.l. and the nested allopolyploid origin of four major clades within the group. Here we showed the utility of automated tree-based orthology inference methods, previously designed for genomic or transcriptomic datasets, to study complex scenarios of polyploidy and reticulate evolution from target enrichment datasets.

evolutionary biology↗

bioRxiv2020

AutoSpill: a method for calculating spillover coefficients in high-parameter flow cytometry

Compensating in classical flow cytometry or unmixing in spectral systems is an unavoidable challenge in the data analysis of fluorescence-based flow cytometry. In both cases, spillover coefficients are estimated for each fluorophore using single-color controls. This approach has remained essentially unchanged since its inception, and is increasingly limited in its ability to deal with high-parameter flow cytometry. Here, we present AutoSpill, a novel approach for calculating spillover coefficients or spectral signatures of fluorophores. The approach combines automated gating of cells, calculation of an initial spillover matrix based on robust linear regression, and iterative refinement to reduce error. Moreover, autofluorescence can be compensated out, by processing it as an endogenous dye in an unstained control. AutoSpill uses single-color controls and is compatible with common flow cytometry software, but it differs in two key aspects from current methods: (1) it is much less demanding in the preparation of controls, as it does not require the presence of well-defined positive and negative populations, and (2) it does not require manual tuning of the spillover matrix, as the algorithm iteratively computes the tuning, producing an optimal compensation matrix. Another algorithm, AutoSpread, complements this approach, providing a robust estimate of the Spillover Spreading Matrix (SSM), while avoiding the need for well-defined positive and negative populations. Together, AutoSpill and AutoSpread provide a superior solution to the problem of fluorophore spillover, allowing simpler and more robust workflows in high-parameter flow cytometry.

immunology↗

bioRxiv2020

Intrinsic defects in lymph node stromal cells underpin poor germinal center responses during aging

The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center response, which generates long-lived antibody-secreting cells that provide protection against (re)infection. Despite intensive investigation into the effect of age on the lymphoid compartment, the primary cellular defect that causes impaired germinal centers in aging has not been identified. Herein we demonstrate that aging reduces the capacity of germinal center-associated stromal cells to respond to vaccination. Heterochronic parabiosis and mathematical modeling demonstrate that a poor stromal cell response limits the size of the germinal center. This study reveals that age-associated defects in stromal cells are a significant barrier to efficacious vaccine responses in older individuals.

immunology↗

bioRxiv2019

Target Capture Sequencing Unravels Rubus Evolution

BackgroundRubus (Rosaceae) comprises more than 500 species with additional commercially cultivated raspberries and blackberries. The most recent (> 100 years old) global taxonomic treatment of the genus defined 12 subgenera; two subgenera were subsequently described and some species were rearranged. Intra- and interspecific ploidy levels and hybridization make phylogenetic estimation of Rubus challenging. Our objectives were to: estimate the phylogeny of 94 geographically diverse species and 3 cultivars using chloroplast DNA sequences and target capture of approximately 1,000 low copy nuclear genes; estimate divergence times between major Rubus clades; and examine the historical biogeography of species diversification.\n\nResultsTarget capture sequencing identified eight major groups within Rubus. Subgenus Orobatus and Subg. Anoplobatus were monophyletic, while other recognized subgenera were para- or polyphyletic. Multiple hybridization events likely occurred across the phylogeny at subgeneric levels, e.g., Subg. Rubus (blackberries) x Subg. Idaeobatus (raspberries) and Subg. Idaeobatus x Subg. Cylactis (Arctic berries) hybrids. The raspberry heritage within known cultivated blackberry hybrids was confirmed. The most recent common ancestor of the genus was most likely distributed in North America. Multiple distribution events occurred during the Miocene (about 20 Ma) from North America into Asia and Europe across the Bering land bridge and southward crossing the Panamanian Isthmus. Rubus species diversified greatly in Asia during the Miocene.\n\nConclusionsRubus taxonomy does not reflect phylogenetic relationships and subgeneric revision is warranted. Target capture sequencing confirmed that most subgenera are para- or polyphyletic. The most recent common ancestor migrated from North America towards Asia, Europe, and Central and South America early in the Miocene then diversified. Ancestors of the genus Rubus may have migrated to Oceania by long distance bird dispersal. This phylogeny presents a roadmap for further Rubus taxonomic and phylogenetic research.

evolutionary biology↗

bioRxiv2019

Completing Linnaeus’s Inventory of the Swedish Insect Fauna: Only 5000 Species Left

Despite more than 250 years of taxonomic research, we still have only a vague idea about the true size and composition of the faunas and floras of the planet. Many biodiversity inventories provide limited insight because they focus on a small taxonomic subsample or a tiny geographic area. Here, we report on the size and composition of the Swedish insect fauna, thought to represent roughly half of the diversity of multicellular life in one of the largest European countries. Our results are based on more than a decade of data from the Swedish Taxonomy Initiative and its massive inventory of the countrys insect fauna, the Swedish Malaise Trap Project The fauna is considered one of the best known in the world, but the initiative has nevertheless revealed a surprising amount of hidden diversity: more than 3,000 new species (301 new to science) have been documented so far. Here, we use three independent methods to analyze the true size and composition of the fauna at the family or subfamily level: (1) assessments by experts who have been working on the most poorly known groups in the fauna; (2) estimates based on the proportion of new species discovered in the Malaise trap inventory; and (3) extrapolations based on species abundance and incidence data from the inventory. For the last method, we develop a new estimator, the combined non-parametric estimator, which we show is less sensitive to poor coverage of the species pool than other popular estimators. The three methods converge on similar estimates of the size and composition of the fauna, suggesting that it comprises around 33,000 species. Of those, 8,600 (26%) were unknown at the start of the inventory and 5,000 (15%) still await discovery. We analyze the taxonomic and ecological composition of the estimated fauna, and show that most of the new species belong to Hymenoptera and Diptera groups that are decomposers or parasitoids. Thus, current knowledge of the Swedish insect fauna is strongly biased taxonomically and ecologically, and we show that similar but even stronger biases have distorted our understanding of the fauna in the past. We analyze latitudinal gradients in the size and composition of known European insect faunas and show that several of the patterns contradict the Swedish data, presumably due to similar knowledge biases. Addressing these biases is critical in understanding insect biomes and the ecosystem services they provide. Our results emphasize the need to broaden the taxonomic scope of current insect monitoring efforts, a task that is all the more urgent as recent studies indicate a possible worldwide decline in insect faunas.

ecology↗

bioRxiv2019

Revisiting the Origin of the Octoploid Strawberry

The cultivated strawberry, Fragaria xananassa, originated in France approximately 270 years ago via hybridization between two wild species introduced from North and South America. Both the cultivated strawberry and its parental species are octoploids with 2n=8x=56 chromosomes. In the recent publication of the genome of the cultivated strawberry, the authors present a novel phylogenetic hypothesis, proposing that each of the four subgenomes originated from a different 2n=2x=14 diploid progenitor. They further suggest that the hexaploid species Fragaria moschata was a direct ancestor of the strawberries. We reanalyzed the four octoploid subgenomes in a phylogenomic context, and found that only two extant diploids were progenitors, a result that is consistent with several previous studies. We also conducted a phylogenetic analysis of genetic linkage-mapped loci in the hexaploid F. moschata, and resolved its origin as independent of the octoploids. We identified assumptions in their tree-searching algorithm that prevented it from accepting extinct or unsampled progenitors, and we argue that this is a critical weakness of their approach. Correctly identifying their diploid progenitors is important for understanding and predicting the responses of polyploid plants to climate change and associated environmental stress.

plant biology↗

bioRxiv2018

Machine learning identifies the immunological signature of Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease, with a strongly debated pathophysiological origin. Both adaptive and innate immune processes have been proposed as primary drivers, which may account for the observed clinical heterogeneity, but few high-depth studies have been performed. Here we profiled the adaptive immune system of 85 JIA patients and 43 age-matched controls, identifying immunological changes unique to JIA and others common across a broad spectrum of childhood inflammatory diseases. The JIA immune signature was shared between clinically distinct subsets, but was accentuated in the systemic JIA patients and those patients with active disease. Despite the extensive overlap in the immunological spectrum exhibited by healthy children and JIA patients, machine learning analysis of the dataset proved capable of diagnosis of JIA patients with ~90% accuracy. These results pave the way for large-scale longitudinal studies of JIA, where machine learning could be used to predict immune signatures that correspond to treatment response group.

immunology↗

bioRxiv2018

Mice deficient in nucleoporin Nup210 develop peripheral T cell alterations

The nucleopore is an essential structure of the eukaryotic cell, regulating passage between the nucleus and cytoplasm. While individual functions of core nucleopore proteins have been identified, the role of other components, such as Nup210, are poorly defined. Here, through the use of an unbiased ENU mutagenesis screen for mutations effecting the peripheral T cell compartment, we identified a Nup210 mutation in a mouse strain with altered CD4 / CD8 T cell ratios. Through the generation of Nup210 knockout mice we identified Nup210 as having a T cell-intrinsic function in the peripheral homeostasis of T cells. Remarkably, despite the deep evolutionary conservation of this key nucleopore complex member, no other major phenotypes developed, with viable and healthy knockout mice. These results identify Nup210 as an important nucleopore complex component for peripheral T cells, and raise further questions of why this nucleopore component shows deep evolutionary conservation despite seemingly redundant functions in most cell types.

immunology↗

bioRxiv2018

Both functional trait divergence and trait plasticity confer polyploid advantage in changing environments

Polyploidy, or whole genome duplication, exists in all eukaryotes and is thought to drive ecological and evolutionary success especially in plants. The mechanisms of polyploid success in ecologically relevant contexts, however, remain largely unknown. Here we conducted an extensive test of functional trait divergence and trait plasticity in conferring polyploid fitness advantage in changing environments by growing clonal replicates of a worldwide genotype collection of six polyploid and five diploid wild strawberry (Fragaria) species in three climatically different common gardens. Among leaf functional traits, we detected divergence in means but not plasticities between polyploids and diploids, suggesting that increased genomic redundancy does not necessarily translate into broader phenotypic amplitude in polyploids. Across the heterogeneous garden environments, however, polyploids exhibited fitness advantage, which was conferred by both trait means and adaptive trait plasticities, supporting a jack-and-master hypothesis for polyploids. Our findings provide unparalleled insight into the prevalence and persistence of polyploidization.

ecology↗

bioRxiv2017

Repeated translocation of a gene cassette drives sex chromosome turnover in strawberries

Turnovers of sex-determining systems represent important diversifying forces across eukaryotes. Shifts in sex chromosomes, but conservation of the master sex-determining genes, characterize distantly-related animal lineages. Yet in plants, where separate sexes have evolved repeatedly and sex chromosomes are typically homomorphic, we do not know whether such translocations drive turnovers within closely related groups. This phenomenon can only be demonstrated by identifying sex-associated nucleotide sequences, still largely unknown in plants. The wild North American octoploid strawberries (Fragaria) exhibit separate sexes (dioecy) with homomorphic, female heterogametic (ZW) inheritance, yet sex maps to at least three different chromosomes. To characterize these turnovers, we sequenced the complete genomes of 60 plants of known sex from five Fragaria taxa. We identified 31-mers unique to females and assembled their reads into contigs. Remarkably, a short (13 kb) sequence is observed in nearly all females and never in male-fertile individuals, implicating it as the sex-determining region (SDR). This female-specific \"SDR cassette\" contains both a gene with a known role in fruit and pollen production and a novel retrogene absent on Z and autosomal chromosomes. Comparing SDR cassettes across taxa reveals a history of repeated translocation, which can be ordered temporally due to the capture of adjacent sequence with each successive move. The accumulation of these \"souvenirs\" suggests an adaptive basis for the expanding (up to at least 23 kb) hemizygous region. This is the first plant SDR known to be translocated, and it suggests a new mechanism (\"move-lock-grow\") for expansion and diversification of incipient sex chromosomes.\n\nSignificance StatementSex chromosomes frequently restructure themselves during organismal evolution, often becoming highly differentiated. This dynamic process is poorly understood for most taxa, especially during the early stages typical of many dioecious plants. In wild strawberries, a sex-determining region of DNA has repeatedly changed its genomic location, each time increasing the size of the hemizygous female-specific sequence. This observation shows for the first time that plant sex regions can \"jump\", and suggests that this phenomenon may be adaptive by gathering and locking new genes into linkage with sex. This conserved and presumed causal sequence with a variable genomic location presents a unique opportunity to understand how sex chromosomes first begin to differentiate.

evolutionary biology↗