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Filamentous fungi produce a diverse array of secondary metabolites (SMs) critical for defense, virulence, and communication. The metabolic pathways that produce SMs are found in contiguous gene clusters in fungal genomes, an atypical arrangement for metabolic pathways in other eukaryotes. Comparative studies of filamentous fungal species have shown that SM gene clusters are often either highly divergent or uniquely present in one or a handful of species, hampering efforts to determine the genetic basis and evolutionary drivers of SM gene cluster divergence. Here, we examined SM variation in 66 cosmopolitan strains of a single species, the opportunistic human pathogen Aspergillus fumigatus. Investigation of genome-wide within-species variation revealed 5 general types of variation in SM gene clusters: nonfunctional gene polymorphisms; gene gain and loss polymorphisms; whole cluster gain and loss polymorphisms; allelic polymorphisms, in which different alleles corresponded to distinct, nonhomologous clusters; and location polymorphisms, in which a cluster was found to differ in its genomic location across strains. These polymorphisms affect the function of representative A. fumigatus SM gene clusters, such as those involved in the production of gliotoxin, fumigaclavine, and helvolic acid as well as the function of clusters with undefined products. In addition to enabling the identification of polymorphisms, the detection of which requires extensive genome-wide synteny conservation (e.g., mobile gene clusters and nonhomologous cluster alleles), our approach also implicated multiple underlying genetic drivers, including point mutations, recombination, and genomic deletion and insertion events as well as horizontal gene transfer from distant fungi. Finally, most of the variants that we uncover within A. fumigatus have been previously hypothesized to contribute to SM gene cluster diversity across entire fungal classes and phyla. We suggest that the drivers of genetic diversity operating within a fungal species shown here are sufficient to explain SM cluster macroevolutionary patterns.
Due to their functional independence, proteins that comprise standalone metabolic units, which we name single-protein metabolic modules, may be particularly prone to gene duplication (GD) and horizontal gene transfer (HGT). Flavohemoglobins (flavoHbs) are prime examples of single-protein metabolic modules, detoxifying nitric oxide (NO), a ubiquitous toxin whose antimicrobial properties many life forms exploit, to nitrate, a common source of nitrogen for organisms. FlavoHbs appear widespread in bacteria and have been identified in a handful of microbial eukaryotes, but how the distribution of this ecologically and biomedically important protein family evolved remains unknown. Reconstruction of the evolutionary history of 3,318 flavoHb protein sequences covering the family's known diversity showed evidence of recurrent HGT at multiple evolutionary scales including intrabacterial HGT, as well as HGT from bacteria to eukaryotes. One of the most striking examples of HGT is the acquisition of a flavoHb by the dandruff- and eczema-causing fungus Malassezia from Corynebacterium Actinobacteria, a transfer that growth experiments show is capable of mediating NO resistance in fungi. Other flavoHbs arose via GD; for example, many filamentous fungi possess two flavoHbs that are differentially targeted to the cytosol and mitochondria, likely conferring protection against external and internal sources of NO, respectively. Because single-protein metabolic modules such as flavoHb function independently, readily undergo GD and HGT, and are frequently involved in organismal defense and competition, we suggest that they represent "plug-and-play" proteins for ecological arms races.
© The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Horizontal gene transfer (HGT) among bacteria, archaea, and viruses is widespread, but the extent of transfers from these lineages into eukaryotic organisms is contentious. Here we systematically identify hundreds of genes that were likely acquired horizontally from a variety of sources by the early-diverging fungal phyla Microsporidia and Cryptomycota. Interestingly, the Microsporidia have acquired via HGT several genes involved in nucleic acid synthesis and salvage, such as those encoding thymidine kinase (TK), cytidylate kinase, and purine nucleotide phosphorylase. We show that these HGT-derived nucleic acid synthesis genes tend to function at the interface between the metabolic networks of the host and pathogen. Thus, these genes likely play vital roles in diversifying the useable nucleic acid components available to the intracellular parasite, often through the direct capture of resources from the host. Using an in vivo viability assay, we also demonstrate that one of these genes, TK, encodes an enzyme that is capable of activating known prodrugs to their active form, which suggests a possible treatment route for microsporidiosis. We further argue that interfacial genes with well-understood activities, especially those horizontally transferred from bacteria or viruses, could provide medical treatments for microsporidian infections.
Ubiquitin activating enzyme E1 plays a pivotal role in ubiquitin based protein signaling through regulating the initiating step of the cascade. Previous studies demonstrated that E1 is inhibited by covalent modification of reactive cysteines contained within the ubiquitin-binding groove and by conditions that increase oxidative stress and deplete cellular antioxidants. In this study, we determined the relative contribution of covalent adduction and oxidative stress to E1 inhibition produced by ziram and sodium N,N-dimethyldithiocarbamate (DMDC) in HEK293 cells. Although no dithiocarbamate-derived E1 adducts were identified on E1 using shotgun LC/MS/MS for either ziram or DMDC, both dithiocarbamates significantly decreased E1 activity, with ziram demonstrating greater potency. Ziram increased intracellular levels of zinc and copper, DMDC increased intracellular levels of only copper, and both dithiocarbamates enhanced oxidative injury evidenced by elevated levels of protein carbonyls and expression of heme oxygenase-1. To assess the contribution of intracellular copper transport to E1 inhibition, coincubations were performed with the copper chelator triethylenetetramine hydrochloride (TET). TET significantly protected E1 activity for both of the dithiocarbamates and decreased the associated oxidative injury in HEK293 cells as well as prevented dithiocarbamate-mediated lipid peroxidation assayed using an ethyl aracidonate micelle system. Because TET did not completely ameliorate intracellular transport of copper or zinc for ziram, TET apparently maintained E1 activity through its ability to diminish dithiocarbamate-mediated oxidative stress. Experiments to determine the relative contribution of elevated intracellular zinc and copper were performed using a metal free incubation system and showed that increases in either metal were sufficient to inhibit E1. To evaluate the utility of the HEK293 in vitro system for screening environmental agents, a series of additional pesticides and metals was assayed, and eight agents that produced a significant decrease and five that produced a significant increase in activated E1 were identified. These studies suggest that E1 is a sensitive redox sensor that can be modulated by exposure to environmental agents and can regulate downstream cellular processes.
Reduced metabolic efficiency, toxic intermediate accumulation, and deficits of molecular building blocks, which all stem from disruptions of flux through metabolic pathways, reduce organismal fitness. Although these represent shared selection pressures across organisms, the genetic signatures of the responses to them may differ. In fungi, a frequently observed signature is the physical linkage of genes from the same metabolic pathway. In contrast, human metabolic genes are rarely tightly linked; rather, they tend to show tissue-specific coexpression. We hypothesized that the physical linkage of fungal metabolic genes and the tissue-specific coexpression of human metabolic genes are divergent yet analogous responses to the range of selective pressures imposed by disruptions of flux. To test this, we examined the degree to which the human homologs of physically linked metabolic genes in fungi (fungal linked homologs or FLOs) are coexpressed across six human tissues. We found that FLOs are significantly more correlated in their expression profiles across human tissues than other metabolic genes. We obtained similar results in analyses of the same six tissues from chimps, gorillas, orangutans, and macaques. We suggest that when selective pressures remain stable across large evolutionary distances, evidence of selection in a given evolutionary lineage can become a highly reliable predictor of the signature of selection in another, even though the specific adaptive response in each lineage is markedly different.
© The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: email@example.com.
For the past several decades, amphibian populations have been decreasing around the globe at an unprecedented rate. Batrachochytrium dendrobatidis (Bd), the fungal pathogen that causes chytridiomycosis in amphibians, is contributing to amphibian declines. Natural and anthropogenic environmental factors are hypothesized to contribute to these declines by reducing the immunocompetence of amphibian hosts, making them more susceptible to infection. Antimicrobial peptides (AMPs) produced in the granular glands of a frog's skin are thought to be a key defense against Bd infection. These peptides may be a critical immune defense during metamorphosis because many acquired immune functions are suppressed during this time. To test if stressors alter AMP production and survival of frogs exposed to Bd, we exposed wood frog (Lithobates sylvaticus) tadpoles to the presence or absence of dragonfly predator cues crossed with a single exposure to three nominal concentrations of the insecticide malathion (0, 10, or 100 parts per billion [ppb]). We then exposed a subset of post-metamorphic frogs to the presence or absence of Bd zoospores and measured frog survival. Although predator cues and malathion had no effect on survival or size at metamorphosis, predator cues increased the time to metamorphosis by 1.5 days and caused a trend of a 20% decrease in hydrophobic skin peptides. Despite this decrease in peptides determined shortly after metamorphosis, previous exposure to predator cues increased survival in both Bd-exposed and unexposed frogs several weeks after metamorphosis. These results suggest that exposing tadpoles to predator cues confers fitness benefits later in life.
Genomic analyses have proliferated without being tied to tangible phenotypes. For example, although coordination of both gene expression and genetic linkage have been offered as genetic mechanisms for the frequently observed clustering of genes participating in fungal metabolic pathways, elucidation of the phenotype(s) favored by selection, resulting in cluster formation and maintenance, has not been forthcoming. We noted that the cause of certain well-studied human metabolic disorders is the accumulation of toxic intermediate compounds (ICs), which occurs when the product of an enzyme is not used as a substrate by a downstream neighbor in the metabolic network. This raises the hypothesis that the phenotype favored by selection to drive gene clustering is the mitigation of IC toxicity. To test this, we examined 100 diverse fungal genomes for the simplest type of cluster, gene pairs that are both metabolic neighbors and chromosomal neighbors immediately adjacent to each other, which we refer to as "double neighbor gene pairs" (DNGPs). Examination of the toxicity of their corresponding ICs shows that, compared with chromosomally nonadjacent metabolic neighbors, DNGPs are enriched for ICs that have acutely toxic LD50 doses or reactive functional groups. Furthermore, DNGPs are significantly more likely to be divergently oriented on the chromosome; remarkably, ∼40% of these DNGPs have ICs known to be toxic. We submit that the structure of synteny in metabolic pathways of fungi is a signature of selection for protection against the accumulation of toxic metabolic intermediates.
Iron is an essential nutrient for both humans and pathogenic microbes. Because of its ability to exist in one of two oxidation states, iron is an ideal redox catalyst for diverse cellular processes including respiration and DNA replication. However, the redox potential of iron also contributes to its toxicity; thus, iron concentration and distribution must be carefully controlled. Given the absolute requirement for iron by virtually all human pathogens, an important facet of the innate immune system is to limit iron availability to invading microbes in a process termed nutritional immunity. Successful human pathogens must therefore possess mechanisms to circumvent nutritional immunity in order to cause disease. In this review, we discuss regulation of iron metabolism in the setting of infection and delineate strategies used by human pathogens to overcome iron-withholding defenses.
Copyright © 2013 Elsevier Inc. All rights reserved.
In fungi, nuclear pore complexes are free to move through the nuclear envelope; however, little is known about how movement is regulated. New evidence reveals roles for molecular motors and potential impacts on genomic organization.
Copyright © 2012 Elsevier Ltd. All rights reserved.