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Winter, D.

Publications and source records attributed to Winter, D..

18 recordsLinked to original sources

Lysosomal proteome and lipidome analyses of intestinal cells reveal the crucial role of bis(monoacylglycero)phosphate for autophagosome-lysosome fusion

The transport of about 70 enzymes to lysosomes depends on mannose 6-phosphate signals formed by GNPTAB. Editing of Gnptab in an intestinal mouse cell line revealed the loss of multiple lysosomal enzymes associated with the accumulation of sphingomyelins, ceramides, and cholesterol, and reduced levels of bis(monoacylglycero)phosphate (BMP) in lysosomal proteomes and lipidomes. By cross-correlation we identified two subsets of lysosomal lipid-modifying enzymes linked with mixed unsaturated or di-monosaturated BMP. Autophagy-related proteins functioning in early stages of autophagosome formation associated with neutral ceramides, whereas proteins involved in autophagosome-lysosome fusion correlated with negatively charged BMPs. Therefore, the high cholesterol and low BMP level of lysosomes might be causal for impaired autophagic flux in GNPTAB deficient cells. We propose a functional axis of three lysosomal proteins as potential target to improve the autophagic flux in cells with dysfunctional lysosomes and in a newly established intestinal organoid model suitable as novel experimental tool.

cell biology↗

Development and evaluation of a core genome multi-locus sequence typing scheme for the Enterobacter cloacae complex

The Enterobacter cloacae species complex (ECC) comprises a group of closely related, opportunistic Gram negative bacteria of major public health concern due to their frequent involvement in healthcare-associated infections and their capacity to acquire and disseminate multidrug resistance, including carbapenemases. Because members of this complex are often difficult to distinguish phenotypically and their taxonomic status is subject to debate, there is a need for a standardized, species-complex wide typing scheme based on whole genome sequencing (WGS) that can be applied to any species within the complex. In this study we have developed and evaluated a core genome multi-locus sequence typing (cgMLST) scheme suitable for species within the ECC. Using 3442 publicly available genomes from 27 ECC species or subspecies we developed a scheme with 1812 loci, comprising loci present in 99% of all genomes. Among the 3442 isolates in our study, 99.9% had 95% or more of the cgMLST targets, indicating that the schema is well-defined and representative for the breadth of ECC species in our study. On two independent evaluation datasets, the scheme reliably resolved epidemiologically linked isolates with 0-3 allelic differences and returned the same outbreak clusters defined previously by higher resolution core genome SNP (cgSNP) analysis. Hierarchical clustering analysis at different levels of resolution showed that the cgMLST profiles could potentially be used to differentiate between species and sub-lineages in the complex. The cgMLST schema will improve the ability of public health laboratories to perform WGS-based surveillance of ECC species.

bioinformatics↗

Miniaturized Lysosome Enrichment through Selective Plasma Membrane Destabilization

Organelle enrichment presents a prerequisite for the unbiased biochemical analysis of cellular subcellular compartments. The performance of this step is decisive for the experiments success, and despite the high sensitivity of downstream analytical strategies, such as enzymatic assays, western blotting, or mass spectrometry (MS)-based OMICs approaches, typically tens of millions of cells are required, standing in stark contrast. Here, we demonstrate that selective rupture of the plasma membrane constitutes a limiting factor for the reduction of cell numbers and present an approach to overcome this limitation through detergent-based plasma membrane destabilization, followed by mechanical homogenization. By combination of this strategy with two common methods for lysosome enrichment, namely superparamagnetic iron oxide nanoparticles (SPIONs) and immunoprecipitation via 3xHA-tagged TMEM192 (TMEM IP), we scale down lysosome enrichment to only half a million cells and demonstrate that reduced input cell numbers yield superior results with respect to sample purity and organelle proteome characterization. HighlightsO_LIRelease of intact lysosomes negatively correlates with cell concentration. C_LIO_LICombination of detergent-based plasma membrane destabilization and mechanical homogenization increases lysosomal intactness from low cell numbers. C_LIO_LIEnrichment columns require a minimum sample input. C_LIO_LIImmunoprecipitation of intact lysosomes enables enrichment from lower cell numbers. C_LIO_LIProteomics of low input lysosome enriched fractions identifies superior performance. C_LI MotivationModern mass spectrometry (MS)-based proteomics strategies facilitate the detection and quantification of peptides and proteins with unprecedented sensitivity, enabling the analysis of low input samples down to single-cells. However, subcellular fractionation experiments typically require tens of millions of cells to achieve sufficient yield and purity, presenting a strong contrast. This restricts the application of organelle profiling to cell lines that can be grown in sufficient amounts, excluding many physiologically relevant species which are only available in small quantities. To be able to miniaturize subcellular fractionation experiments, it is of crucial importance to overcome this limitation and to miniaturize sample preparation strategies.

cell biology↗

ER-Lysosome Cholesterol Exchange Regulates Lysosomal Motility Through mTOR-Dependent LAMTOR1 Phosphorylation

The subcellular distribution of lysosomes, the main degradative organelles of mammalian cells, responds to metabolic cues in a highly dynamic way. While lysosomal positioning due to amino acid levels is well-characterized, cholesterol-dependent regulation of lysosomal motility is incompletely understood. We explored impaired lysosomal cholesterol export using a mass spectrometry-based multi-OMICs approach, identifying widespread reallocation of resources and signaling pathway modulation. We identified increased phosphorylation at LAMTOR1 serine 56 in response to cholesterol level perturbations. We demonstrate that this phosphorylation site is sufficient to disrupt Rag GTPases/SLC38A9 binding to the Ragulator complex, inhibiting canonical mTORC1 and facilitating binding of BORC, therefore promoting lysosomal retrograde movement. LAMTOR1 S56 phosphorylation responds exclusively to depletion of lysosomal limiting membrane cholesterol, is facilitated by mTOR, and presents a negative feedback loop for amino acid independent displacement of Ragulator bound Rag GTPases, limiting canonical mTORC1 activity. Mass spectrometry data are available via ProteomeXchange with identifier PXD073489. HighlightsO_LIPerturbation of lysosomal cholesterol homeostasis results in adaptation of cellular protein and lipid biosynthesis C_LIO_LILAMTOR1 is phosphorylated at serine 56 via mTORC1 C_LIO_LILAMTOR1 S56 phosphorylation is lysosomal membrane cholesterol dependent C_LIO_LILAMTOR1 S56 phosphorylation disrupts binding of Rag GTPases to the Ragulator complex C_LIO_LILAMTOR1 S56 phosphorylation promotes binding of Ragulator to BORC, facilitating lysosomal retrograde transport C_LI

molecular biology↗

Co-infections and cryptic pathogens uncovered by metatranscriptomics in New Zealands severe acute respiratory infections

Severe acute respiratory infections (SARI) are a leading cause of hospitalisation and mortality globally. Many SARI cases remain undiagnosed because kit-based PCR diagnostic panels are typically limited to one or a small number of known pathogens and may fail to identify low-abundance infections or novel, poorly characterised organisms. Here, we used metatranscriptomic sequencing to profile the total infectome of 300 PCR-negative SARI nasopharyngeal samples collected through sentinel hospital-based surveillance in New Zealand between 2014-2021. Our analysis revealed actively transcribing potential pathogens in 43% of SARI cases, comprising 10 RNA viruses, three DNA viruses, nine bacterial species and four fungal species. Notably, co-infections occurred in 26% of cases, revealing polymicrobial infections missed by routine diagnostics. Human rhinoviruses were the most frequently identified, despite not being detected by PCR, and multiple common-cold coronaviruses, human parechovirus A1 and parainfluenza virus type 4, were identified, although these were not included in the PCR screening panel. We also detected a range of bacterial and fungal species and uncovered highly expressed virulence and antimicrobial resistance genes. Infectome composition and diversity were shaped by key demographic and epidemiological factors, with strongest effects observed for age and year of sample collection, indicating that host characteristics and temporal dynamics influence both microbial richness and community structure. These findings highlight the limitations of current diagnostic strategies and the value of metatranscriptomics for comprehensive microbial identification. Integrating such genomic approaches into both clinical and public health frameworks could improve diagnostic accuracy, enabling more sensitive detection and characterisation of potential pathogens while also strengthening surveillance and outbreak response.

genomics↗

TWEAK is increased in ulcerative colitis and contributes to fibroblast-mediated monocyte activation via heterologous non-canonical NF-kB/STAT3 signalling

Background and AimsInteractions between fibroblasts and monocytes have emerged as a contributing factor in IBD pathogenesis and therapy resistance, owing to the ability of both cell types to participate in tissue inflammation and repair. We have previously shown that the TNF superfamily factor TWEAK (TNFSF12) can induce a UC-like inflammatory profile in colonic fibroblasts in vitro, in turn promoting monocyte adhesion and activation. However, the mechanisms underlying fibroblast-monocyte communication and its dysregulation in colitis are incompletely understood. MethodsHere we use co-culture models, human biopsies from ulcerative colitis (UC) patients and healthy donors, and public single-cell transcriptomics to characterise the mechanisms underlying fibroblast-mediated monocyte activation. ResultsWe show that TWEAK-treated inflammatory fibroblasts induce a transcriptional programme that resembles early monocyte/macrophage intermediates in UC and is enriched for genes associated with resistance to anti-TNF (TREM1, OSM, IL1B) and susceptibility to IBD (NOD2, ATG16L1). We find that conditioned media from TWEAK-treated fibroblast causes a sustained activation of STAT3 phosphorylation in monocytes, and that inhibition of the NF-{kappa}B Inducing Kinase (NIK) impairs the ability of inflammatory fibroblasts to activate STAT3 phosphorylation in monocytes, resulting in reduced expression of inflammatory mediators. Using tissues from UC patients, we show that the expansion of CD90+/PDPN+ inflammatory fibroblasts in UC correlates with the accumulation of TWEAK+ myeloid cells in the colonic mucosa, and that these fibroblasts co-localise with infiltrating monocytes in sites of active inflammation. ConclusionTogether, our findings suggest that the TWEAK/NF-{kappa}B/STAT3 axis represents an attractive target to tune inflammatory stroma/monocyte crosstalk.

immunology↗

Evaluating sampling strategies for the detection of avian influenza viruses in the environment

Highly pathogenic avian influenza (HPAI) viruses threaten humans, livestock and wildlife, highlighting the urgent need for early warning surveillance. Environmental RNA (eRNA) monitoring provides a safer, cost-effective and non-invasive alternative to direct pathogen testing, yet the effectiveness of different sample types for avian influenza viruses (AIVs) is unclear. We evaluated four eRNA-based sampling methods in urban waterfowl ponds over approximately one year. All methods combined with RT-qPCR and metagenomic sequencing detected AIV, but detections were asynchronous, likely reflecting low viral concentrations or detection limits. These results highlight both the promise and the current limitations of eRNA-based AIV surveillance. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/677014v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@e8e189org.highwire.dtl.DTLVardef@12f17fforg.highwire.dtl.DTLVardef@d09f5forg.highwire.dtl.DTLVardef@8f55fd_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

Absolute Quantification of Lysosomal Proteins by Multiple Reaction Monitoring Mass Spectrometry and QconCAT Protein Standards

ABSTRACTLysosomes are membrane-enclosed organelles that play a crucial role in the degradation of intra- and extracellular substrates and the regulation of metabolic signaling. These functions are carried out by a variety of proteins, of which > 150 are currently known to be located in the lysosomal lumen or to be embedded in its membrane. These proteins are typically low abundant, necessitating organelle enrichment experiments to enable their investigation by unbiased mass spectrometry-based proteomics analyses. Enrichment strategies have been applied in a plethora of studies to gain a deeper understanding of lysosomal composition and relative changes of lysosomal proteome abundance in a variety of pathological conditions. Such experiments are restricted, however, to selected cell lines and tissues and do not allow a direct analysis of the lysosomal proteome from whole cell or tissue lysates. Furthermore, they do not provide absolute quantities. We developed a multiple reaction monitoring mass spectrometry-based assay for the highly sensitive and reproducible absolute quantification of 143 mouse lysosomal proteins from any type of sample following the QconCAT strategy. We applied our approach to the investigation of mouse embryonic fibroblast whole cell lysates and lysosome-enriched fractions, providing absolute copy numbers per cell/lysosome for lysosomal hydrolases and membrane proteins. These data reveal a dynamic range of more than three orders of magnitude in protein expression and strong differences in the subcellular distribution of individual lysosomal proteins. Furthermore, we applied our strategy to the investigation of four primary cell types (macrophages, lung fibroblasts, osteoblasts, and osteoclasts), demonstrating pathway-specific heterogeneity of individual lysosomal protein classes and indicating protein-specific post-transcriptional regulation of expression levels.

molecular biology↗

Avian influenza virus surveillance across New Zealand and its subantarctic islands detects H1N9 in migratory shorebirds, but not 2.3.4.4b HPAI H5N1

Highly pathogenic avian influenza (HPAI) virus has never been detected in New Zealand. The potential impact of this virus on New Zealands wild birds would be catastrophic. To expand our knowledge of avian influenza viruses across New Zealand, we sampled wild aquatic birds from New Zealand, its outer islands and its subantarctic territories. Metatranscriptomic analysis of 700 individuals spanning 33 species revealed no detection of HPAI during the annual 2023-2024 migration. A single detection of H1N9 in red knots (Calidris canutus) was noted. This study provides a baseline for expanding avian influenza virus monitoring in New Zealand.

microbiology↗

Suprabasal cells retaining stem cell identity programs drive basal cell hyperplasia in eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an esophageal immune-mediated disease characterized by eosinophilic inflammation and epithelial remodeling, including basal cell hyperplasia (BCH) and loss of differentiation. Although BCH correlates with disease severity and with persistent symptoms in patients in histological remission, the molecular processes driving BCH remain poorly defined. Here, we demonstrate that despite the presence of BCH in all EoE patients examined, no increase in basal cell proportion was observed by scRNA-seq. Instead, EoE patients exhibited a reduced pool of KRT15+ COL17A1+ quiescent cells, a modest increase in KI67+ dividing epibasal cells, a substantial increase in KRT13+ IVL+ suprabasal cells, and a loss of differentiated identity in superficial cells. Suprabasal and superficial cell populations demonstrated increased quiescent cell identity scoring in EoE with the enrichment of signaling pathways regulating pluripotency of stem cells. However, this was not paired with increased proliferation. Enrichment and trajectory analyses identified SOX2 and KLF5 as potential drivers of the increased quiescent identity and epithelial remodeling observed in EoE. Notably, these findings were not observed in GERD. Thus, our study demonstrates that BCH in EoE results from an expansion of non-proliferative cells that retain stem-like transcriptional programs while remaining committed to early differentiation.

molecular biology↗

Proteomic Investigation of Neural Stem Cell to Oligodendrocyte Precursor Cell Differentiation Reveals Phosphorylation-Dependent Dclk1 Processing

Oligodendrocytes are generated via a two-step mechanism from pluripotent neural stem cells (NSCs): after differentiation of NSCs to oligodendrocyte precursor/NG2 cells (OPCs), they further develop into mature oligodendrocytes. The first step of this differentiation process is only incompletely understood. In this study, we utilized the neurosphere assay to investigate NSC to OPC differentiation in a time course-dependent manner by mass spectrometry-based (phospho-) proteomics. We identify double cortin like kinase 1 (Dclk1) as one of the most prominently regulated proteins in both datasets, and show that it undergoes a gradual transition between its short/long isoform during NSC to OPC differentiation. This is regulated by phosphorylation of its SP-rich region, resulting in inhibition of proteolytic Dclk1 long cleavage, and therefore Dclk1 short generation. Through interactome analyses of different Dclk1 isoforms by proximity biotinylation, we characterize their individual putative interaction partners and substrates.

cell biology↗

Species-wide genomics of kakapo provides transformational tools to accelerate recovery

The k[a]k[a]p[o] is a critically endangered, intensively managed, long-lived nocturnal parrot endemic to Aotearoa New Zealand. We generated and analyzed whole-genome sequence data for nearly all individuals living in early 2018 (169 individuals) to generate a high-quality species-wide genetic variant callset. We leverage extensive long-term metadata to quantify genome-wide diversity of the species over time and present new approaches using probabilistic programming, combined with a phenotype dataset spanning five decades, to disentangle phenotypic variance into environmental and genetic effects while quantifying uncertainty in small populations. We find associations for growth, disease susceptibility, clutch size, and egg fertility within genic regions previously shown to influence these traits in other species. Finally, we generate breeding values to predict phenotype and illustrate that active management over the past 45 years has maintained both genome-wide diversity and diversity in breeding values, and hence, evolutionary potential. We provide new pathways for informing future conservation management decisions for k[a]k[a]p[o], including prioritizing individuals for translocation and monitoring individuals with poor growth or high disease risk. Overall, by explicitly addressing the challenge of small sample size, we provide a template for the inclusion of genomic data that will be transformational for species recovery efforts around the globe.

genomics↗

Cross-linking of the Endolysosomal System Reveals Flotillin Structures and Putative Cargo

Lysosomes are well-established as the main cellular organelles for the degradation of macromolecules and emerging as regulatory centers of metabolism. They are of crucial importance for cellular homeostasis, which is exemplified by a plethora of disorders related to alterations in lysosomal function. In this context, protein complexes play a decisive role, regulating not only metabolic lysosomal processes, but also lysosome biogenesis, transport, and interaction with other organelles. Using cross-linking mass spectrometry, we analyzed lysosomes and early endosomes. Based on the identification of 5,376 cross-links, we investigated protein-protein interactions and structures of lysosome- and endosome-related proteins. In particular, we present evidence for a tetrameric assembly of the lysosomal hydrolase PPT1 and heterodimeric/- multimeric structures of FLOT1/FLOT2 at lysosomes and early endosomes. For FLOT1-/FLOT2- positive early endosomes, we identified >300 proteins presenting putative cargo, and confirm the latrophilin family of adhesion G protein-coupled receptors as substrates for flotillin-dependent endocytosis.

biochemistry↗

Multi cell line analysis of lysosomal proteomes reveals unique features and novel lysosomal proteins

Lysosomes play a key role in the regulation of cellular metabolism and are increasingly recognized as highly active and diverse organelles which are involved in a large variety of processes. Their essential role is exemplified by the detrimental consequences of lysosomal malfunction, which can result in lysosomal storage disorders, neurodegenerative diseases, and cancer. Using lysosome enrichment and mass spectrometry, we investigated the lysosomal proteomes of six common cell lines. We provide first evidence for cell-type specific differences of lysosomes on a large scale, showing highly variable levels of distinct lysosomal proteins within one cell type, while others are highly conserved among cell lines. Using stable isotope labelling and bimodal distribution analysis, we identify high confidence lysosomal proteins for each cell line. Multi cell line correlation of these data reveals potential novel lysosomal proteins, and we confirm lysosomal localization for five candidates. All data are available via ProteomeXchange with identifier PXD020600.

molecular biology↗

Characterising the methylome of Legionellalongbeachae serogroup 1 clinical isolates and assessing geo-temporal genetic diversity

Legionella longbeachae is an environmental bacterium that is commonly found in soil and composted plant material. In New Zealand (NZ) it is the most clinically significant Legionella species causing around two-thirds of all notified cases of Legionnaires disease. Here we report the sequencing and analysis of the geo-temporal genetic diversity of 54 L. longbeachae serogroup 1 (sg1) clinical isolates that were derived from cases from around NZ over a 22-year period, including one complete genome and its associated methylome. Our complete genome consisted of a 4.1 Mb chromosome and a 108 kb plasmid. The genome was highly methylated with two known epigenetic modifications, m4C and m6A, occurring in particular sequence motifs within the genome. Phylogenetic analysis demonstrated the 54 sg1 isolates belonged to two main clades that last shared a common ancestor between 108 BCE and 1608 CE. These isolates also showed diversity at the genome-structural level, with large-scale arrangements occurring in some regions of the chromosome and evidence of extensive chromosomal and plasmid recombination. This includes the presence of plasmids derived from recombination and horizontal gene transfer between various Legionella species, indicating there has been both intra-species and inter-species gene flow. However, because similar plasmids were found among isolates within each clade, plasmid recombination events may pre-empt the emergence of new L. longbeachae strains. Our high-quality reference genome and extensive genetic diversity data will serve as a platform for future work linking genetic, epigenetic and functional diversity in this globally important emerging environmental pathogen. Author SummaryLegionnaires disease is a serious, sometimes fatal pneumonia caused by bacteria of the genus Legionella. In New Zealand, the species that causes the majority of disease is Legionella longbeachae. Although the analyses of pathogenic bacterial genomes is an important tool for unravelling evolutionary relationships and identifying genes and pathways that are associated with their disease-causing ability, until recently genomic data for L. longbeachae has been sparse. Here, we conducted a large-scale genomic analysis of 54 L. longbeachae isolates that had been obtained from people hospitalised with Legionnaires disease between 1993 and 2015 from 8 regions around New Zealand. Based on our genome analysis the isolates could be divided into two main groups that persisted over time and last shared a common ancestor up to 1700 years ago. Analysis of the bacterial chromosome revealed areas of high modification through the addition of methyl groups and these were associated with particular DNA sequence motifs. We also found there have been large-scale rearrangements in some regions of the chromosome, producing variability between the different L. longbeacahe strains, as well as evidence of gene-flow between the various Legionella species via the exchange of plasmid DNA.

microbiology↗

Host infection by the grass-symbiotic fungus Epichloë festucaerequires catalytically active H3K9 and H3K36 methyl transferases

Recent studies have identified key genes in Epichloe festucae that control the symbiotic interaction of this filamentous fungus with its grass host. Here we report on the identification of specific fungal genes that determine its ability to infect and colonize the host. Deletion of setB, which encodes a homolog of the H3K36 histone methyltransferase Set2/KMT3, specifically reduced histone H3K36 trimethylation and led to severe defects in colony growth and hyphal development. The E. festucae {Delta}clrD mutant, which lacks the gene encoding the homolog of the H3K9 methyltransferase KMT1, displays similar developmental defects. Both mutants are completely defective in their ability to infect the host grass, and mutational studies of key residues in the catalytic SET domains from these proteins show that these phenotypes are dependent on the methyltransferase activities of SetB and ClrD. A comparison of the differences in the host transcriptome between seedlings inoculated with wild-type versus mutants suggests that the inability of these mutants to infect the host was not due to an aberrant host defense response. Co-inoculation of either {Delta}setB or {Delta}clrD with the wild-type strain enables these mutants to colonize the host. However, successful colonization by the mutants resulted in death or stunting of the host plant. Transcriptome analysis at the early infection stage identified four fungal candidate genes, three of which encode small-secreted proteins, that are differentially regulated in these mutants compared to wild-type. Deletion of crbA, which encodes a putative carbohydrate binding protein, resulted in significantly reduced host infection rates by E. festucae. Author SummaryThe filamentous fungus Epichloe festucae is an endophyte that forms highly regulated symbiotic interactions with the perennial ryegrass. Proper maintenance of such interactions is known to involve several signalling pathways, but much less is understood about the infection capability of this fungus in the host. In this study, we uncovered two epigenetic marks and their respective histone methyltransferases that are required for E. festucae to infect perennial ryegrass. Null mutants of the histone H3 lysine 9 and lysine 36 methyltransferases are completely defective in colonizing the host intercellular space, and these defects are dependent on the methyltransferase activities of these enzymes. Importantly, we observed no evidence for increased host defense response to these mutants that can account for their non-infection. Rather, these infection defects can be rescued by the wild-type strain in co-inoculation experiments, suggesting that failure of the mutants to infect is due to altered expression of genes encoding infection factors that are under the control of the above epigenetic marks that can be supplied by the wild-type strain. Among genes differentially expressed in the mutants at the early infection stage is a putative small-secreted protein with a carbohydrate binding function, which deletion in E. festucae severely reduced infection efficiency.

genetics↗

Analysis of Epichloë festucae small secreted proteins in the interaction with Lolium perenne

Epichloe festucae is an endophyte of the agriculturally important perennial ryegrass. This species systemically colonises the aerial tissues of this host where its growth is tightly regulated thereby maintaining a mutualistic symbiotic interaction. Recent studies have suggested that small secreted proteins, termed effectors, play a vital role in the suppression of host defence responses. To date only a few effectors with important roles in mutualistic interactions have been described. Here we make use of the fully assembled E. festucae genome and EffectorP to generate a suite of 141 effector candidates. These were analysed with respect to their genome location and expression profiles in planta and in several symbiosis-defective mutants. We found an association between effector candidates and a class of transposable elements known as MITEs, but no correlation with other dynamic features of the E. festucae genome, such as transposable element-rich regions. Three effector candidates and a small GPI-anchored protein were chosen for functional analysis based on their high expression in planta compared to in culture and their differential regulation in symbiosis defective E. festucae mutants. All three candidate effector proteins were shown to possess a functional signal peptide and two could be detected in the extracellular medium by western blotting. Localization of the effector candidates in planta suggests that they are not translocated into the plant cell, but rather, are localized in the apoplastic space or are attached to the cell wall. Deletion and overexpression of the effector candidates, as well as the putative GPI-anchored protein, did not affect the plant growth phenotype or restrict growth of E. festucae mutants in planta. These results indicate that these proteins are either not required for the interaction at the observed life stages or that there is redundancy between effectors expressed by E. festucae.

genetics↗

accuMUlate: A mutation caller designed for mutation accumulation experiments

MotivationMutation accumulation (MA) is the most widely used method for directly studying the effects of mutation. Modern sequencing technologies have led to an increased interest in MA experiments. By sequencing whole genomes from MA lines, researchers can directly study the rate and molecular spectra of spontaneous mutations and use these results to understand how mutation contributes to biological processes. At present there is no software designed specifically for identifying mutations from MA lines. Studies that combine MA with whole genome sequencing use custom bioinformatic pipelines that implement heuristic rules to identify putative mutations.\n\nResultsHere we describe O_SCPLOWACCUC_SCPLOWMUO_SCPLOWLATEC_SCPLOW, a program that is designed to detect mutations from MA experiments. O_SCPLOWACCUC_SCPLOWMUO_SCPLOWLATEC_SCPLOW implements a probabilistic model that reflects the design of a typical MA experiments while being flexible enough to accommodate properties unique to any particular experiment. For each putative mutation identified from this model O_SCPLOWACCUC_SCPLOWMUO_SCPLOWLATEC_SCPLOW calculates a set of summary statistics that can be used to filter sites that may be false positives. A companion tool, O_SCPLOWDENOMINATEC_SCPLOW, can be used to apply filtering rules based on these statistics to simulated mutations and thus identify the number of callable sites per sample.\n\nAvailabilitySource code and releases available from https://github.com/dwinter/accuMUlate.

bioinformatics↗