Biology subjects

Asgari, D.

Publications and source records attributed to Asgari, D..

7 recordsLinked to original sources

bioRxiv2026

Pleiotropy constrains the evolution of immune system plasticity while promoting domain modularity

Pleiotropic genes control multiple traits. This can result in evolutionary antagonism because adaptation that favors one trait can interfere with the function of another. While pleiotropic genes show statistical signatures of evolutionary constraint, many of them contain multiple domains that may evolve under different selective pressures. This could either strengthen or alleviate gene-level constraint. Here, we study pleiotropy within the immune system of six Drosophila species to disentangle gene and domain-level evolution. We hypothesized that the multifunctional nature of pleiotropic genes may promote within-gene variation in evolutionary rates of their domains compared to non-pleiotropic genes. Consistently, we found a greater within-gene variation in evolutionary rate among domains of pleiotropic genes than other gene classes, despite relatively low between-gene variation in evolutionary rates among pleiotropic genes. Non-pleiotropic genes, on the other hand, show a more heterogeneous selective pressure at the gene level. Regardless of pleiotropy status, domains within antiviral proteins show elevated evolutionary rates, while signaling protein domains show elevated ratios of radical to conservative amino acid substitutions, which likely have a significant effect on protein structure and function. Finally, an examination of plasticity in infection-induced gene expression responses across species revealed that non-pleiotropic genes with elevated evolutionary rates were also more likely to demonstrate variation in plasticity, but this relationship did not extend to pleiotropic genes. Overall, our results identify differences in evolutionary patterns across various biological levels (i.e., gene, domain, protein, and expression), showing that domain-specific evolution can potentially alleviate gene-level constraints.

evolutionary biology↗

bioRxiv2024

How the Structure of Signaling Regulation Evolves: Insights from an Evolutionary Model

To remain responsive to environmental changes, signaling pathways attenuate their activity with negative feedback loops (NFLs), where proteins produced upon stimulation downregulate the response. NFLs function both upstream of signaling to reduce input and downstream to reduce output. Unlike upstream NFLs, downstream NFLs directly regulate gene expression without the involvement of intermediate proteins. Thus, we hypothesized that downstream NFLs evolve under more stringent selection than upstream NFLs. Indeed, genes encoding downstream NFLs exhibit a slower evolutionary rate than upstream genes. Such differences in selective pressures could result in the robust evolution of downstream NFLs while making the evolution of upstream NFLs more sensitive to changes in signaling proteins and stimuli. Here, we test these assumptions within the context of immune signaling. Our minimal model of immune signaling predicts robust evolution of downstream NFLs to changes in model parameters. This is consistent with their critical role in regulating signaling and the conservative rate of evolution. Furthermore, we show that the number of signaling steps needed to activate a downstream NFL is influenced by the cost of signaling. Our model predicts that upstream NFLs are more likely to evolve under a shorter half-life of signaling proteins, absence of host-pathogen co-evolution, and a high infection rate. Although it has been proposed that NFLs evolve to reduce the cost of signaling, we show that a high cost does not necessarily predict the evolution of upstream NFLs. The insights from our model have broad implications for understanding the evolution of regulatory mechanisms across signaling pathways.

evolutionary biology↗

bioRxiv2024

Resources modulate developmental shifts but not infection tolerance upon coinfection in an insect system

Energetic resources fuel immune responses and parasite growth within organisms, but it is unclear whether energy allocation is sufficient to explain changes in infection outcomes under the threat of multiple parasites. We manipulated diet in flour beetles (Tribolium confusum) infected with two natural parasites to investigate the role of resources in shifting metabolic and immune responses after single and co-infection. Our results suggest that gregarine parasites alter the within-host energetic environment, and by extension juvenile development time, in a diet- dependent manner. Gregarines do not affect host resistance to acute bacterial infection but do stimulate the expression of an alternative set of immune genes and promote damage to the gut, ultimately contributing to reduced survival regardless of diet. Thus, energy allocation is not sufficient to explain the immunological contribution to coinfection outcomes, emphasizing the importance of mechanistic insight for predicting the impact of coinfection across levels of biological organization.

ecology↗

bioRxiv2024

Positioning of negative feedback loops within immune signaling pathways influences host fitness through noise in AMP expression

Signaling pathways depend on negative and positive feedback loops (NFLs and PFLs) to regulate internal noise. Across diverse organisms, signaling is regulated by NFLs that function at different cellular locations. These range from NFLs functioning upstream near signal-receiving receptors to those downstream within the nucleus. While previous studies have examined the relationship between NFLs, internal noise in signaling pathways, and network topology, none have directly addressed how the cellular location of NFLs impacts noise regulation. This is significant given the almost ubiquitous presence of multi-level regulation systems within signaling pathways. Here, we use stochastic models inspired by Imd and Toll signaling to address this gap within the context of immune signaling. We use both mechanistic and evolutionary models to demonstrate how noise is regulated by NFLs and how this, in turn, affects the hosts ability to fight off infection while minimizing immunopathologic effects of excessive immune gene expression. We found that downstream NFLs reduce noise in antimicrobial peptides (AMP) expression for some parameter values. On the other hand, upstream NFLs amplify the noise, but the presence of a strong PFL can reduce this noise. Our evolutionary simulations suggest that the mechanisms through which the downstream NFL operates within the cell can affect the evolution of the upstream NFLs. The results of our study provide insight into why distinct signaling pathways are regulated by varying numbers of NFLs, which operate in different cellular locations and employ diverse mechanisms to control gene expression. Author SummarySignaling pathways are noisy biological circuits. This noise is caused by random fluctuations in the number of proteins that function within these pathways. To properly respond to external stimuli, the ratio of noise to information needs to be minimized. To regulate noise, biological pathways produce proteins that either reduce (negative feedback) or amplify (positive feedback) signaling following stimulation. Negative feedback loops can shut down signaling by interfering with the first steps of signaling, which entail the detection of stimuli. Conversely, signaling might be left intact, and instead, negative feedback loops might interfere with the last step, which is the production of output. These regulatory differences can affect noise within signaling pathways. Here, we examined this using stochastic (inherently random) models to simulate immune signaling in response to pathogens. We found that negative feedback loops that function at later stages of signaling can decrease noise in the output, while negative feedback loops that act at earlier stages amplify the noise, but this noise can be reduced by the presence of a strong positive feedback loop.

evolutionary biology↗

bioRxiv2022

Uncertainty favors an induced immune response to infection

Organisms use constitutive or induced defenses against pathogens, parasites, and herbivores. Constitutive defenses are constantly on, whereas induced defenses are activated upon exposure to an enemy. Constitutive and induced defenses each have costs and benefits, which can affect the type of defense that evolves in response to pathogens. Previous models that compared the two lacked mechanistic details about host defense, did not consider pathogen proliferation rates, or lacked both features. To address this gap, we developed a detailed mechanistic model of the well-characterized Drosophila melanogaster immune signaling network. We evaluated the factors favoring the evolution of constitutive and induced defenses by comparing the fitness of each strategy under stochastic fly-bacteria interactions. We show that an induced defense is favored when bacteria are at low density, heterogeneously distributed, or have fluctuating distributions in ways that depend on the bacterial proliferation rate. Our model also predicts that the specific negative regulators that optimize the induced response depend on the bacterial proliferation rate. We therefore conclude that an induced immune defense is favored in environments where bacterial encounters are uncertain--because of heterogeneity in spatial or temporal distributions--but that benefit depends on the mechanism of induction and pathogen properties.

evolutionary biology↗

bioRxiv2021

Induction and inhibition of Drosophila X chromosome gene expression are both impeded by the dosage compensation complex

Sex chromosomes frequently differ from the autosomes in the frequencies of genes with sexually dimorphic or tissue-specific expression. Multiple hypotheses have been put forth to explain the unique gene content of the X chromosome, including selection against male-beneficial X-linked alleles, expression limits imposed by the haploid dosage of the X in males, and interference by the dosage compensation complex (DCC) on expression in males. Here, we investigate these hypotheses by examining differential gene expression in Drosophila melanogaster following several treatments that have widespread transcriptomic effects: bacterial infection, viral infection, and abiotic stress. We found that genes that are induced (up-regulated) by these biotic and abiotic treatments are frequently under-represented on the X chromosome, but so are those that are repressed (down-regulated) following treatment. We further show that whether a gene is bound by the DCC in males can largely explain the paucity of both up- and down-regulated genes on the X chromosome. Specifically, genes that are bound by the DCC, or close to a DCC high-affinity site, are unlikely to be up- or down-regulated after treatment. This relationship, however, could partially be explained by a correlation between differential expression and breadth of expression across tissues. Nonetheless, our results suggest that DCC binding, or the associated chromatin modifications, inhibit both up- and down-regulation of X chromosome gene expression within specific contexts. We propose multiple possible mechanisms of action for the effect, including a role of Males absent on the first (Mof), a component of the DCC, as a dampener of gene expression variance in both males and females. This effect could explain why the Drosophila X chromosome is depauperate in genes with tissue-specific or induced expression, while the mammalian X has an excess of genes with tissue-specific expression.

genomics↗

bioRxiv2021

Gene expression in Lucilia sericata (Diptera: Calliphoridae) larvae exposed to Pseudomonas aeruginosa and Acinetobacter baumanii identifies shared and microbe-specific induction of immune genes

Antibiotic resistance is a continuing challenge in medicine. There are various strategies for expanding antibiotic therapeutic repertoires, including the use of blow flies. Their larvae exhibit strong antibiotic and antibiofilm properties that alter microbiome communities. One species, Lucilia sericata, is used to treat problematic wounds due to its debridement capabilities and its excretions and secretions that kill some pathogenic bacteria. There is much to be learned about how L. sericata interacts with microbiomes at the molecular level. To address this deficiency, gene expression was assessed after feeding exposure (1 hour or 4 hours) to two clinically problematic pathogens: Pseudomonas aeruginosa and Acinetobacter baumanii. The results identified immunity related genes that were differentially expressed when exposed to these pathogens, as well as non-immune genes possibly involved in gut responses to bacterial infection. There was a greater response to P. aeruginosa that increased over time, while few genes responded to A. baumanii exposure and expression was not time-dependent. The response to feeding on pathogens indicates a few common responses and features distinct to each pathogen, which is useful in improving wound debridement therapy and helps develop biomimetic alternatives.

immunology↗