Host specialization in the fungal plant pathogen Zymoseptoria tritici

The three closely related plant pathogenic species Zymoseptoria tritici (synonym: Mycosphaerella graminicola), Z. pseudotritici and Z. ardabiliae are hemi-biotrophic, ascomycete fungi with different host ranges. Z. tritici emerged at the onset of agriculture and is specialized to its host Triticum aestivum (bread wheat). In contrast Z. pseudotritici and Z. ardabiliae infect different wild grass species at the center of origin and diversification of the Zymoseptoria grass pathogens and are unable to infect wheat. Accelerated evolution of single genes is a key feature of pathogen adaptation following a host shift. Genes under positive selection exhibit an elevated ratio of non-synonymous (replacement) mutations to synonymous (silent) mutations. A ratio above 1 is indicative of positive selection and these positively selected genes can be identified by comparative genome analyses of closely related species that infect different hosts. From a comparative genome study of Zymoseptoria species the four positively selected genes Zt80707, Zt89160, Zt103264, and Zt110804 were chosen without a priori information about gene function or structure. In this study it was shown that the four selected genes are up-regulated in planta. The genes are not involved in axenic growth of Z. tritici as shown by an in vitro assay, supporting a pathogenicity related role of the four gene products. The virulence of Z. tritici on wheat was significantly reduced for the two deletion mutants (Zt80707 and Zt103264) and both showed an impaired development of the asexual fruiting bodies (pycnidia) on wheat. The deletion of Zt89160 caused a hypervirulent reaction in wheat while the fourth mutant (Zt110804) showed no detectable change in virulence-phenotype. The protein Zt80707 was moreover shown to be exclusively secreted in Z. tritici indicating that positive selection in this protein most likely relates to a novel extracellular function. Adaptation to the host plant wheat was shown for the proteins Zt80707 and Zt89160 as both deletion phenotypes could not or only partially be restored when the genes in Z. tritici were replaced with their orthologs of Z. pseudotritici. The presented results demonstrate that evolutionary predictions provide a strong tool for the identification of genes involved in host adaptation and pathogen development. In addition it was shown that adaptive evolution during host specialization also strongly affects non-secreted proteins without effector function (Zt89160, Zt103264, and Zt110804)

LEGIDA gezählt

Zahlen sind oft ein Politikum. Dabei hinterfragt zumeist niemand die Richtigkeit dieser Zahlen, obwohl sie in vielen Fällen die Grundlage von politischen Entscheidungen sind. Das Vertrauen der Öffentlichkeit in staatliche Institutionen und Behörden verhindert möglicherweise jegliche Erwägungen, dass es sich um unsichere »Pi mal Daumen«-Schätzungen handeln könnte.  In diesem Artikel werden wir anhand der Legida-Demonstrationen in Leipzig zeigen, dass offizielle Zahlen durchaus falsch sein können und stets hinterfragt werden sollten. Gemeinsam mit Studierenden der Universität Leipzig erhoben wir mit Hilfe dreier unabhängiger Methoden die Teilnehmerzahl der zweiten Legida-Demonstration. Wir legen im Detail dar, welche Methoden wir verwendeten und wie die von uns veröffentlichte Schätzung von 4.000–5.000 Teilnehmern zustande kam. Ebenso erläutern wir mögliche Fehler der einzelnen Methoden und weitere Probleme die zu verzerrten Ergebnissen führen können. Numbers are often political. Yet in very few cases they are being scrutinized even so they depict the foundation of political decisions and in many cases. The public trust in institutions and the administration may preclude any considerations that they are potentially unconfident rule of the thumb estimates.  The article highlights the case of the Legida-demonstrations in Leipzig and shows, that official statistics can be wrong and should always be questioned. In cooperation with students of the University of Leipzig we collected the number of participants of the second Legida-demonstration using three independent methodological approaches. We show in detail which methods we used and how they resulted in our published estimation of 4.000 to 5.000 participants. Furthermore we explain potential errors and problems of the individual methods that can result in biased outcomes. &nbsp

Expression Profiling of the Wheat Pathogen Zymoseptoria tritici Reveals Genomic Patterns of Transcription and Host-Specific Regulatory Programs

Host specialization by pathogens requires a repertoire of virulence factors as well as fine-tuned regulation of gene expression. The fungal wheat pathogen Zymoseptoria tritici (synonym Mycosphaerella graminicola) is a powerful model system for the discovery of genetic elements that underlie virulence and host specialization. We transcriptionally profiled the early stages of Z. tritici infection of a compatible host (wheat) and a noncompatible host (Brachypodium distachyon). The results revealed infection regulatory programs common to both hosts and genes with striking wheat-specific expression, with many of the latter showing sequence signatures of positive selection along the Z. tritici lineage. Genes specifically regulated during infection of wheat populated two large clusters of coregulated genes that may represent candidate pathogenicity islands. On evolutionarily labile, repeat-rich accessory chromosomes (ACs), we identified hundreds of highly expressed genes with signatures of evolutionary constraint and putative biological function. Phylogenetic analyses suggested that gene duplication events on these ACs were rare and largely preceded the diversification of Zymoseptoria species. Together, our data highlight the likely relevance for fungal growth and virulence of hundreds of Z. tritici genes, deepening the annotation and functional inference of the genes of this model pathogen

Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and meta-analysis

: EPHPP quality rating scores (DOCX 38 kb

World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions

BACKGROUND: To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions. METHODS: In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40-80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance. FINDINGS: Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0·685 (95% CI 0·629-0·741) to 0·833 (0·783-0·882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40-64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt. INTERPRETATION: We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. FUNDING: World Health Organization, British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence, UK Medical Research Council, and National Institute for Health Research

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Host specialization in the fungal plant pathogen Zymoseptoria tritici

The three closely related plant pathogenic species Zymoseptoria tritici (synonym: Mycosphaerella graminicola), Z. pseudotritici and Z. ardabiliae are hemi-biotrophic, ascomycete fungi with different host ranges. Z. tritici emerged at the onset of agriculture and is specialized to its host Triticum aestivum (bread wheat). In contrast Z. pseudotritici and Z. ardabiliae infect different wild grass species at the center of origin and diversification of the Zymoseptoria grass pathogens and are unable to infect wheat. Accelerated evolution of single genes is a key feature of pathogen adaptation following a host shift. Genes under positive selection exhibit an elevated ratio of non-synonymous (replacement) mutations to synonymous (silent) mutations. A ratio above 1 is indicative of positive selection and these positively selected genes can be identified by comparative genome analyses of closely related species that infect different hosts. From a comparative genome study of Zymoseptoria species the four positively selected genes Zt80707, Zt89160, Zt103264, and Zt110804 were chosen without a priori information about gene function or structure. In this study it was shown that the four selected genes are up-regulated in planta. The genes are not involved in axenic growth of Z. tritici as shown by an in vitro assay, supporting a pathogenicity related role of the four gene products. The virulence of Z. tritici on wheat was significantly reduced for the two deletion mutants ( Zt80707 and Zt103264) and both showed an impaired development of the asexual fruiting bodies (pycnidia) on wheat. The deletion of Zt89160 caused a hypervirulent reaction in wheat while the fourth mutant ( Zt110804) showed no detectable change in virulence-phenotype. The protein Zt80707 was moreover shown to be exclusively secreted in Z. tritici indicating that positive selection in this protein most likely relates to a novel extracellular function. Adaptation to the host plant wheat was shown for the proteins Zt80707 and Zt89160 as both deletion phenotypes could not or only partially be restored when the genes in Z. tritici were replaced with their orthologs of Z. pseudotritici. The presented results demonstrate that evolutionary predictions provide a strong tool for the identification of genes involved in host adaptation and pathogen development. In addition it was shown that adaptive evolution during host specialization also strongly affects non-secreted proteins without effector function (Zt89160, Zt103264, and Zt110804)