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Abstract BackgroundCOVID-19 booster vaccinations mitigate transmission and reduce the morbidity and mortality associated with infection. However, the optimal date for booster administration remains uncertain. Geographic variation in infection rates throughout the year makes it challenging to intuit the best yearly booster administration date to effectively prevent infection, and also challenging to provide best guidance on how to alter booster administration in response to a breakthrough infection. MethodsWe leveraged longitudinal antibody and reinfection probabilities with spatiotemporal projections of COVID-19 incidence to develop a geographically informed approach to optimizing the timing of booster vaccination. We assessed the delay in booster vaccination that is warranted following breakthrough infections whenever they occur during the year, enabling a personalized assessment of optimal timing that acknowledges and respects diversity of COVID-19 immune status, addressing a substantial barrier to uptake. ResultsYearly booster vaccination on any date is beneficial to prevention of infection. However, each location exhibits as much as a 3–4-fold range in degree of protection by date of uptake. Optimal COVID-19 booster vaccination dates are location-specific, typically in early autumn in the Northern Hemisphere. Infection late in the interval between boosts substantially alters the optimal boosting date. ConclusionsConsiderable benefit accrues from aptly timing COVID-19 booster vaccination campaigns, which can be tailored to specific locations. Individuals can acquire the greatest benefit from booster vaccination by timing it optimally, including delaying in cases of infection late in the interval between boosts. These results provide location-specific guidance for public health policy, healthcare provider recommendations, and individual decision-making. 

In opportunistic human pathogenic fungi, changes in gene expression play a crucial role in the progression of growth stages from early spore germination through host infection. Comparative transcriptomics between diverse fungal pathogens and non-pathogens provided insights into regulatory mechanisms behind the initiation of infectious processes. We examined the gene expression patterns of 3,845 single-copy orthologous genes (SCOGs) across five phylogenetically distinct species, including the opportunistic human pathogens Fusarium oxysporum, Aspergillus fumigatus, and A. nidulans, and nonpathogenic species Neurospora crassa and Trichoderma asperelloides, at four sequential stages of spore germination. Ancestral status of gene expression was inferred for nodes along the phylogeny. By comparing expression patterns of the SCOGs with their most recent common ancestor (MRCA), we identified genes that exhibit divergent levels of expression during spore germination when comparing fungal pathogens to non-pathogens. We focused on genes related to the MAPK pathway, nitrogen metabolism, asexual development, G-protein signaling, and conidial-wall integrity. Notably, orthologs of the transcription activator abaA, a known central regulator of conidiation, exhibited significant divergence in gene expression in F. oxysporum. This dramatic expression change in abaA was accompanied by structural modifications of phialides in F. oxysporum, and revealed how these changes impact development of offspring, formation of aerial hyphae, spore production, and pathogenicity. Our research provides insights into ecological adaptations observed during the divergence of these species, specifically highlighting how divergence in gene expression during spore germination contributes to their ability to thrive in distinct environments. 

Abstract Protein sequence evolution in the presence of epistasis makes many previously acceptable amino acid residues at a site unfavorable over time. This phenomenon of entrenchment has also been observed with neutral substitutions using Potts Hamiltonian models. Here, we show that simulations using these models often evolve non-neutral proteins. We introduce a Neutral-with-Epistasis (N×E) model that incorporates purifying selection to conserve fitness, a requirement of neutral evolution. N×E protein evolution revealed a surprising lack of entrenchment, with site-specific amino-acid preferences remaining remarkably conserved, in biologically realistic time frames despite extensive residue coupling. Moreover, we found that the overdispersion of the molecular clock is caused by rate variation across sites introduced by epistasis in individual lineages, rather than by historical contingency. Therefore, substitutional entrenchment and rate contingency may indicate that adaptive and other non-neutral evolutionary processes were at play during protein evolution. 

Background Removal of zero-COVID restrictions in China led to a surge in COVID-19 cases. In response, countries imposed restrictions on Chinese travelers. However, border policies imposed may not have been informed by accurate data and may not have provided substantial benefits. Methods We analyzed quarantines sufficient to prevent additional in-country transmission for February 13–19, 2023 based on World Health Organization (WHO) and self-reported infections to estimate prevalence. Results We have shown that self-reported prevalence data indicated more stringent border restrictions compared to WHO-published prevalence statistics. No travel restrictions were required for Singapore, South Korea, and Japan so that infections would not be greater than with complete border closure. However, a 1-, 2-, and 3-day quarantine were indicated for England, Germany, and Scotland respectively. A 10-, 13-, and 14-day quarantine were required for Italy, France, and the Philippines, respectively, to prevent an increase in within-country infections due to travel. Vietnam and Thailand required a complete border shutdown. Conclusion Our results demonstrated the necessity for accurate and timely reporting of pandemic statistics to prevent an increase in viral spread. Through the minimum quarantine analysis, countries can use science to determine policy, minimize international friction, and improve the cost-efficiency of interventions. 

Lineage-specific genes (LSGs) have long been postulated to play roles in the establishment of genetic barriers to intercrossing and speciation. In the genome ofNeurospora crassa, most of the 670NeurosporaLSGs that are aggregated adjacent to the telomeres are clustered with 61% of the HET-domain genes, some of which regulate self-recognition and define vegetative incompatibility groups. In contrast, the LSG-encoding proteins possess few to no domains that would help to identify potential functional roles. Possible functional roles of LSGs were further assessed by performing transcriptomic profiling in genetic mutants and in response to environmental alterations, as well as examining gene knockouts for phenotypes. Among the 342 LSGs that are dynamically expressed during both asexual and sexual phases, 64% were detectable on unusual carbon sources such as furfural, a wildfire-produced chemical that is a strong inducer of sexual development, and the structurally-related furan 5-hydroxymethyl furfural (HMF). Expression of a significant portion of the LSGs was sensitive to light and temperature, factors that also regulate the switch from asexual to sexual reproduction. Furthermore, expression of the LSGs was significantly affected in the knockouts ofadv-1andpp-1that regulate hyphal communication, and expression of more than one quarter of the LSGs was affected by perturbation of the mating locus. These observations encouraged further investigation of the roles of clustered lineage-specific and HET-domain genes in ecology and reproduction regulation inNeurospora, especially the regulation of the switch from the asexual growth to sexual reproduction, in response to dramatic environmental conditions changes. 

Fusarium graminearumandMagnaporthe oryzaeare two of the most important pathogens of cereal grains worldwide. Despite years of research, strong host resistance has not been identified forF. graminearum, so other methods of control are essential. 

Advances in genomics and transcriptomics accompanying the rapid accumulation of omics data have provided new tools that have transformed and expanded the traditional concepts of model fungi. Evolutionary genomics and transcriptomics have flourished with the use of classical and newer fungal models that facilitate the study of diverse topics encompassing fungal biology and development. Technological advances have also created the opportunity to obtain and mine large datasets. One such continuously growing dataset is that of the Sordariomycetes, which exhibit a richness of species, ecological diversity, economic importance, and a profound research history on amenable models. Currently, 3,574 species of this class have been sequenced, comprising nearly one-third of the available ascomycete genomes. Among these genomes, multiple representatives of the model genera Fusarium , Neurospora , and Trichoderma are present. In this review, we examine recently published studies and data on the Sordariomycetes that have contributed novel insights to the field of fungal evolution via integrative analyses of the genetic, pathogenic, and other biological characteristics of the fungi. Some of these studies applied ancestral state analysis of gene expression among divergent lineages to infer regulatory network models, identify key genetic elements in fungal sexual development, and investigate the regulation of conidial germination and secondary metabolism. Such multispecies investigations address challenges in the study of fungal evolutionary genomics derived from studies that are often based on limited model genomes and that primarily focus on the aspects of biology driven by knowledge drawn from a few model species. Rapidly accumulating information and expanding capabilities for systems biological analysis of Big Data are setting the stage for the expansion of the concept of model systems from unitary taxonomic species/genera to inclusive clusters of well-studied models that can facilitate both the in-depth study of specific lineages and also investigation of trait diversity across lineages. The Sordariomycetes class, in particular, offers abundant omics data and a large and active global research community. As such, the Sordariomycetes can form a core omics clade, providing a blueprint for the expansion of our knowledge of evolution at the genomic scale in the exciting era of Big Data and artificial intelligence, and serving as a reference for the future analysis of different taxonomic levels within the fungal kingdom. 

ABSTRACT Secondary metabolite clusters (SMCs) encode the machinery for fungal toxin production. However, understanding their function and analyzing their products requires investigation of the developmental and environmental conditions in which they are expressed. Gene expression is often restricted to specific and unexamined stages of the life cycle. Therefore, we applied comparative genomics analyses to identify SMCs in Neurospora crassa and analyzed extensive transcriptomic data spanning nine independent experiments from diverse developmental and environmental conditions to reveal their life cycle-specific gene expression patterns. We reported 20 SMCs comprising 177 genes—a manageable set for investigation of the roles of SMCs across the life cycle of the fungal model N. crassa —as well as gene sets coordinately expressed in 18 predicted SMCs during asexual and sexual growth under three nutritional and two temperature conditions. Divergent activity of SMCs between asexual and sexual development was reported. Of 126 SMC genes that we examined for knockout phenotypes, al-2 and al-3 exhibited phenotypes in asexual growth and conidiation, whereas os-5 , poi-2 , and pmd-1 exhibited phenotypes in sexual development. SMCs with annotated function in mating and crossing were actively regulated during the switch between asexual and sexual growth. Our discoveries call for attention to roles that SMCs may play in the regulatory switches controlling mode of development, as well as the ecological associations of those developmental stages that may influence expression of SMCs. IMPORTANCE Secondary metabolites (SMs) are low-molecular-weight compounds that often mediate interactions between fungi and their environments. Fungi enriched with SMs are of significant research interest to agriculture and medicine, especially from the aspects of pathogen ecology and environmental epidemiology. However, SM clusters (SMCs) that have been predicted by comparative genomics alone have typically been poorly defined and insufficiently functionally annotated. Therefore, we have investigated coordinate expression in SMCs in the model system N. crassa , and our results suggest that SMCs respond to environmental signals and to stress that are associated with development. This study examined SMC regulation at the level of RNA to integrate observations and knowledge of these genes in various growth and development conditions, supporting combining comparative genomics and inclusive transcriptomics to improve computational annotation of SMCs. Our findings call for detailed study of the function of SMCs during the asexual-sexual switch, a key, often-overlooked developmental stage. 

The nature of saprophytic and mycoparasitic hyphal growth of Trichoderma spp. has been studied extensively, yet its initiation via conidial germination in this genus is less well understood. Using near-synchronous germinating cultures of Trichoderma asperelloides, we followed the morphological progression from dormant conidia to initial polar growth to germling formation and to evidence for first branching. We found that the stage-specific transcriptional profile of T. asperelloides is one of the most dynamic described to date: transcript abundance of over 5000 genes—comprising approximately half of the annotated genome—was unremittingly reduced in the transition from dormancy to polar growth. Conversely, after the onset of germination, the transcript abundance of approximately a quarter of the genome was unremittingly elevated during the transition from elongation to initial branching. These changes are a testimony to the substantial developmental events that accompany germination. Bayesian network analysis identified several chitinase- and glucanase-encoding genes as active transcriptional hubs during germination. Furthermore, the expression of specific members of the chitin synthase and glucan elongase families was significantly increased during germination in the presence of Rhizoctonia solani—a known host of the mycoparasite—indicating that host recognition can occur during the early stages of mycoparasite development. 

ABSTRACT Gene expression divergence through evolutionary processes is thought to be important for achieving programmed development in multicellular organisms. To test this premise in filamentous fungi, we investigated transcriptional profiles of 3,942 single-copy orthologous genes (SCOGs) in five related sordariomycete species that have morphologically diverged in the formation of their flask-shaped perithecia. We compared expression of the SCOGs to inferred gene expression levels of the most recent common ancestor of the five species, ranking genes from their largest increases to smallest increases in expression during perithecial development in each of the five species. We found that a large proportion of the genes that exhibited evolved increases in gene expression were important for normal perithecial development in Fusarium graminearum . Many of these genes were previously uncharacterized, encoding hypothetical proteins without any known functional protein domains. Interestingly, the developmental stages during which aberrant knockout phenotypes appeared largely coincided with the elevated expression of the deleted genes. In addition, we identified novel genes that affected normal perithecial development in Magnaporthe oryzae and Neurospora crassa , which were functionally and transcriptionally diverged from the orthologous counterparts in F. graminearum . Furthermore, comparative analysis of developmental transcriptomes and phylostratigraphic analysis suggested that genes encoding hypothetical proteins are generally young and transcriptionally divergent between related species. This study provides tangible evidence of shifts in gene expression that led to acquisition of novel function of orthologous genes in each lineage and demonstrates that several genes with hypothetical function are crucial for shaping multicellular fruiting bodies. IMPORTANCE The fungal class Sordariomycetes includes numerous important plant and animal pathogens. It also provides model systems for studying fungal fruiting body development, as its members develop fruiting bodies with a few well-characterized tissue types on common growth media and have rich genomic resources that enable comparative and functional analyses. To understand transcriptional divergence of key developmental genes between five related sordariomycete fungi, we performed targeted knockouts of genes inferred to have evolved significant upward shifts in expression. We found that many previously uncharacterized genes play indispensable roles at different stages of fruiting body development, which have undergone transcriptional activation in specific lineages. These novel genes are predicted to be phylogenetically young and tend to be involved in lineage- or species-specific function. Transcriptional activation of genes with unknown function seems to be more frequent than ever thought, which may be crucial for rapid adaption to changing environments for successful sexual reproduction.