Biology subjects

Thompson, R.

Publications and source records attributed to Thompson, R..

At least 19 recordsLinked to original sources

bioRxiv2026

SCN1A haploinsufficiency disrupts neural progenitor networks and accelerates neurogenesis in human Dravet syndrome forebrain assembloids

Dravet syndrome is a severe childhood neurological disorder caused mostly due to mutations in the sodium channel gene SCN1A. Although the disorder is widely attributed to dysfunction of inhibitory neurons, growing evidence suggests that disease mechanisms may begin much earlier during brain development. To investigate the developmental consequences of SCN1A haploinsufficiency, we generated patient-derived dorsal-ventral forebrain assembloids that model key features of human corticogenesis. We found that SCN1A was expressed in ventricular zone neural progenitors and that its reduced expression was associated with impaired growth, disrupted ventricular zone organization, and progressive depletion of progenitor populations. We further demonstrated reduced progenitor proliferation and self-renewal, accelerated cell-cycle exit, and premature neuronal differentiation, leading to increased production of excitatory neurons and enhanced network excitability. Single cell transcriptomic analyses revealed reduced cycling radial glial cells, accelerated progenitor maturation, and dysregulation of gap junction and calcium signaling pathways. Following these findings, we examined progenitor calcium activity and found that SCN1A haploinsufficiency disrupted coordinated functional network organization, resulting in reduced recurrent connectivity and fragmentation of functional cellular assemblies. These abnormalities occurred despite preserved intrinsic electrophysiological properties of individual progenitors, indicating a defect in population-level coordination rather than single cell electrophysiology. Together, our findings identify disrupted progenitor communication as an early developmental consequence of SCN1A haploinsufficiency and suggest that abnormalities within neural progenitor populations contribute to altered corticogenesis, excitatory neurogenesis, and circuit hyperexcitability in Dravet syndrome. This work expands current disease models beyond interneuron dysfunction and highlights the developing ventricular zone as a potential therapeutic target.

neuroscience↗

bioRxiv2026

Surrogate variables and the risk of overfitting in neuropsychiatric gene expression analyses

The reproducibility crisis in biomedical research calls for re-evaluation of how common analytic approaches affect results. One such approach, surrogate variable analysis (SVA), is widely used to adjust for unmeasured drivers of variation in transcriptomic differential expression analyses. We systematically quantified the impact of SVA using synthetic data with known ground truth and fourteen brain RNA-seq and microarray datasets spanning Alzheimer's disease, autism spectrum disorder, bipolar disorder, schizophrenia, and Parkinson's disease. In synthetic data, SVA usage frequently led to high false positive rates. This issue was not revealed by standard diagnostics nor resolved by strategies such as maximizing cross-dataset signal correlation. In real data, using SVA reduced cross-cohort reproducibility of differential expression signatures regardless of the number of surrogate variables included. These findings show that SVA risks inducing overfitting at realistic signal levels, advocating for a cautious, case-by-case application, with a preference for modeling known covariates.

bioinformatics↗

bioRxiv2026

Distinct extracellular matrix states uncouple collagen accumulation from pathological fibrosis in Duchenne muscular dystrophy

Fibrosis severity is routinely inferred from collagen abundance, although whether collagen quantity determines pathological fibrosis remains unclear. In Duchenne muscular dystrophy (DMD), chronic muscle injury and inflammation drive extracellular matrix accumulation, making these processes difficult to disentangle. We exploit sarcospan overexpression in mdx mice, a model of DMD (mdxTG), which improves membrane integrity and muscle function despite persistent matrix remodeling. mdxTG muscle accumulates more collagen than mdx yet lacks its dense macrophage-rich scars. Matrisome proteomics and spatial transcriptomics reveal compositionally and spatially distinct matrix states, while decellularized mdxTG matrix protects myotubes from membrane damage relative to mdx matrix. Despite these differences, both dystrophic matrices remain stiff and induce nuclear YAP in fibro-adipogenic progenitors. Verteporfin suppresses collagen production and reduces fibrosis in vivo, while nuclear YAP is increased in FAPs from patients with DMD. Thus, collagen abundance alone does not define pathological fibrosis; matrix organization, biological activity, and mechanosignaling distinguish functionally distinct fibrotic states.

physiology↗

bioRxiv2026

Single-cell RNA sequencing of peripheral blood cells identifies transcriptomic signatures in Parkinson's disease

Parkinsons disease (PD) is a progressive age-related neurodegenerative disorder characterized by both motor and non-motor symptoms. The poorly understood prodromal period, decades-long progression, and disease-phenotype heterogeneity continue to impede the development of preventive and curative therapies. A growing appreciation of immune system changes during the progression of PD suggests that evaluating peripheral immune cells may help identify signatures relevant to disease etiology. We employed single-cell RNA sequencing to profile the transcriptomes of peripheral blood mononuclear cells (PBMCs) from a cohort of 12 patients with PD and 12 healthy controls, equally distributed by sex. Analysis identified gene expression signatures specific to immune cell lineages in PD when compared with healthy controls. Analysis of the dataset indicated that aspects of the PD-related changes were associated with sex, including metabolic and inflammatory changes. Further analysis of myeloid and T cell subsets identified additional pathways and gene expression profiles associated with PD. Trajectory analysis of the myeloid and T cell datasets indicated significant changes in the distribution of cells across states of gene expression in PD compared with controls. This work provides new evidence of peripheral immune cell changes in PD utilizing high-resolution transcriptomics in a cohort powered to analyze sex as a variable. HighlightsTranscriptomic dataset in a cohort powered to analyze immune phenotype in Parkinsons disease Parkinsons disease-specific gene expression signatures in peripheral immune cell lineages Identification of sex differences in the immune cell transcriptome in Parkinsons disease Trajectory analysis identifies changes in immune cell phenotypic distribution in Parkinsons monocytes

immunology↗

bioRxiv2025

Organelle distribution and protein translation defects in radial glia cells with mutations in Eml1

Cerebral cortical development is a finely regulated process, depending on key neuronal progenitors, giving rise to post-mitotic neurons that migrate to superficial regions in the developing brain. Disruptions can give rise to severe cortical malformations that are associated with intellectual disability and intractable epilepsy. Mutations in EML1/Eml1, coding for a microtubule (MT)-associated protein, lead to subcortical heterotopia (SH) in both humans and mice. In developing mutant mouse brains, ectopic apical radial glia (aRG) progenitors were found outside the normal proliferative ventricular zone (VZ). The normal role of Eml1 in these cells remains to be precisely determined. Using proteomics and imaging approaches, we compared brain tissue from control and mutant mice and identified microtubule and organelle dysregulation. Eml1 influences the trafficking of organelles to different compartments of aRG, where they may be involved in local functions. Thus, we find that mitochondrial and polysome distribution are altered in mutant conditions. Indeed, Eml1 interacts with translational machinery, and an overall downregulation of translation is observed when analysing the translatome of Eml1 mutant aRG. Paradoxically, an upregulation of translation-related mRNAs is also observed. These new data uncover an unprecedented function of Eml1, as well as associating novel subcellular patho-mechanisms with severe heterotopia formation.

neuroscience↗

bioRxiv2025

Local translation controls early reactive changes in perisynaptic astrocyte processes at pre-symptomatic stages of Alzheimer s disease

Early synaptic dysfunction is a hallmark of Alzheimers disease (AD), yet the astrocytic mechanisms underlying these alterations remain poorly defined. Here, we identify astrocyte perisynaptic processes (PAPs) as subcellular hotspots of early translational dysregulation in AD. Soluble A{beta}-2 rapidly enhanced global and local protein synthesis in primary astrocytes. In 5.5-month-old APP/PS1-dE9 (APP) mice, translating ribosome affinity purification (TRAP) revealed widespread remodeling of the PAP translatome, while whole-astrocyte translation remained largely unchanged. Dysregulated mRNAs were linked to neuroinflammation, synaptic remodeling, and endoplasmic reticulum stress, and alterations emerged prior to amyloid plaque deposition. Among them, Serpina3n exhibited increased mRNA abundance in PAPs, uncovering spatially restricted translational control. Mechanistically, early Serpina3n upregulation was partially driven by JAK-STAT3 signaling, with preferential effects in astrocyte processes. These findings reveal that local translation in astrocyte PAPs is an early and compartment-specific mechanism that may contribute to synaptic dysfunction and disease initiation in AD.

neuroscience↗

bioRxiv2025

Interleukin-6 is critical in the development of gcn2-mutation associated pulmonary vascular disease in mice

Biallelic mutations in eukaryotic translation initiation factor 2 kinase 4, EIF2AK4 (which encodes general control nonderepressible 2, GCN2) underpin heritable forms of pulmonary veno-occlusive disease (PVOD), a rare and fatal form of pulmonary hypertension. The mechanisms linking these are mostly uncharacterised. We demonstrate for the first time that homozygous loss of gcn2 is sufficient to cause mild pulmonary hypertension in mice. Single-cell transcriptomics of mouse lungs identified adventitial fibroblasts as having the greatest GCN2-dependent transcriptional differences, implicating them as key players in this model of PVOD. The most significantly upregulated pathways in gcn2-/- adventitial fibroblasts were inflammatory. Therefore, we went on to demonstrate a pro-inflammatory phenotype in gcn2-/- mouse embryonic fibroblasts and gcn2-/- mice. In a novel murine model of pulmonary hypertension induced by exposure to mitomycin C, deletion of interleukin-6 rescued the pulmonary vascular phenotype. When chronically exposed to lipopolysaccharide, the pulmonary hypertensive phenotype of gcn2-/- mice is exaggerated. Genetic ablation of interleukin-6 completely rescues both the baseline and LPS-exaggerated pulmonary hypertensive phenotype. Targeting Il6-dependent pathways may be useful in treating this deadly disease.

pathology↗

bioRxiv2025

Retroelement co-option disrupts the cancer transcriptional programme

BackgroundTranscriptional activation of otherwise repressed endogenous retroelements (RTEs) is a hallmark of cancer, shaping tumour progression and immunogenicity by multifaceted, yet incompletely understood mechanisms. MethodsWe used an extended pan-cancer transcriptome assembly to identify potential effects of RTEs on the genes near or within which they have integrated. These were subsequently verified in test cases by further analysis of transcriptional profiles in cancer patient data, and by in vitro studies involving restoration of gene activity, and proliferation and migration assays in cancer cell lines. ResultsWe report that cancer-specific transcriptional activation of RTEs causes frequent reduction or loss of gene function. Exonisation and alternative splicing of RTEs creates non-functional RNA and protein isoforms and derepressed RTE promoter activity initiates antisense transcription, both at the expense of the canonical isoforms. Contrary to theoretical expectation, transcriptionally activated RTEs affect genes with established tumour-promoting function, including the common essential RNGTT and the lung cancer-promoting CHRNA5 genes. Furthermore, the disruptive effect of RTE activation on adjacent tumour-promoting genes is associated with slower disease progression in clinical data, whereas experimental restoration of gene activity enhances tumour cell in vitro growth and invasiveness ConclusionsThese findings underscore the gene-disruptive potential of seemingly innocuous germline RTE integrations, unleashed only by their transcriptional utilisation in cancer. They further suggest that such metastable RTE integrations are co-opted as sensors of the epigenetic and transcriptional changes occurring during cellular transformation and as executors that disrupt the function of tumour-promoting genes.

genomics↗

bioRxiv2024

New tools to monitor Pseudomonas aeruginosa infection and biofilms in vivo in C. elegans.

Antimicrobial resistance is a growing health problem. Pseudomonas aeruginosa is a pathogen of major concern because of its multidrug resistance and global threat, especially in health-care settings. The pathogenesis and drug resistance of P. aeruginosa depends on its ability to form biofilms, making infections chronic and untreatable as the biofilm protects against antibiotics and host immunity. A major barrier to developing new antimicrobials is the lack of in vivo biofilm models. Standard microbiological testing is usually performed in vitro using planktonic bacteria, without representation of biofilms, reducing translatability. Here we develop tools to study both infection and biofilm formation by P. aeruginosa in vivo to accelerate development of strategies targeting infection and pathogenic biofilms. Using the nematode Caenorhabditis elegans and P. aeruginosa reporters combined with in vivo imaging we show that fluorescent P. aeruginosa reporters that form biofilms in vitro can be used to visualise tissue infection. Using automated tracking of C. elegans movement, we find that that the timing of this infection corresponds with a decline in health endpoints. In a mutant strain of P. aeruginosa lacking RhlR, a transcription factor that controls quorum sensing and biofilm formation, we find reduced capacity of P. aeruginosa to form biofilms, invade host tissues and negatively impact healthspan and survival. Our findings suggest that RhlR could be a new antimicrobial target to reduce P. aeruginosa biofilms and virulence in vivo and C. elegans could be used to more effectively screen for new drugs to combat antimicrobial resistance.

microbiology↗

bioRxiv2024

Protein Editing using a Concerted Transposition Reaction

Protein engineering through the chemical or enzymatic ligation of polypeptide fragments has proven enormously powerful for studying countless biochemical processes in vitro. In general, this strategy necessitates a protein folding step following ligation of the unstructured fragments, a requirement that constrains the types of systems amenable to the approach. Here, we report an in vitro strategy that allows internal regions of target proteins to be replaced in a single operation. Conceptually, our system is analogous to a DNA transposition reaction, but employs orthogonal pairs of split inteins to swap out a designated region of a host protein with an exogenous molecular cassette. We show using isotopic labeling experiments that this protein transposition reaction is concerted when the kinetics for the embedded intein pairs are suitably matched. Critically, this feature allows for efficient manipulation of protein primary structure in the context of a native fold. The utility of this method is illustrated using several protein systems including the multi-subunit chromatin remodeling complex, ACF, where we also show protein transposition can occur in situ within the cell nucleus. By carrying out a molecular cut and paste on a protein or protein complex under native folding conditions, our approach dramatically expands the scope of protein semisynthesis.

biochemistry↗

bioRxiv2024

IL-8 Instructs Macrophage Identity in Lateral Ventricle Contacting Glioblastoma

Adult IDH-wildtype glioblastoma (GBM) is a highly aggressive brain tumor with no established immunotherapy or targeted therapy. Recently, CD32+ HLA-DRhi macrophages were shown to have displaced resident microglia in GBM tumors that contact the lateral ventricle stem cell niche. Since these lateral ventricle contacting GBM tumors have especially poor outcomes, identifying the origin and role of these CD32+ macrophages is likely critical to developing successful GBM immunotherapies. Here, we identify these CD32+ cells as M_IL-8 macrophages and establish that IL-8 is sufficient and necessary for tumor cells to instruct healthy macrophages into CD32+ M_IL-8 M2 macrophages. In ex vivo experiments with conditioned medium from primary human tumor cells, inhibitory antibodies to IL-8 blocked the generation of CD32+ M_IL-8 cells. Finally, using a set of 73 GBM tumors, IL-8 protein is shown to be present in GBM tumor cells in vivo and especially common in tumors contacting the lateral ventricle. These results provide a mechanistic origin for CD32+ macrophages that predominate in the microenvironment of the most aggressive GBM tumors. IL-8 and CD32+ macrophages should now be explored as targets in combination with GBM immunotherapies, especially for patients whose tumors present with radiographic contact with the ventricular-subventricular zone stem cell niche. - IL-8 is expressed by GBM cells and enriched in lateral ventricle-contacting tumors - M_IL-8 macrophages are CD32+ HLA-DR++ CD163+ CD206+ CD86- PD-L1- - M_IL-8 macrophages instructed with IL-8 or GBM conditioned medium match human glioblastoma associated macrophages - IL-8 is necessary for GBM tumor cells to generate M_IL-8 macrophages

cancer biology↗

bioRxiv2024

Resilience to Early Life Adversity Effects on Stress Reactivity by Postnatal Knockdown of 5-HT1A Autoreceptors

Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that protect from the enduring effects of ELA are poorly understood. Serotonin 1A (5HT1A) autoreceptors in the raphe nuclei regulate adult stress vulnerability, but whether 5HT1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10 and tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In females, ELA decreased raphe 5HT neuron activity in adulthood and increased passive coping with the acute swim stress, corticosterone levels, neuronal activity, and corticotropin-releasing factor (CRF) levels in the paraventricular nucleus (PVN) of the hypothalamus. ELA also reduced neurogenesis in the ventral dentate gyrus (vDG) of the hippocampus, an important mediator of individual differences in stress susceptibility, and increased microglia activation in the PVN and vDG. These effects of ELA were specific to females and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal knockdown of 5HT1A autoreceptors prevented these effects of ELA on 5HT neuron activity, stress reactivity, neurogenesis, and neuroinflammation in adult female mice. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in the serotonin system, stress reactivity, and vDG function, and identify 5HT1A autoreceptors as potential targets to prevent these enduring effects of ELA.

neuroscience↗

bioRxiv2023

A novel framework to build saliva-based DNA methylation biomarkers: quantifying systemic chronic inflammation as a case study

Accessible and non-invasive biomarkers that measure human ageing processes and the risk of developing age-related disease are paramount in preventative healthcare. In this study, we describe a novel framework to train saliva-based DNA methylation (DNAm) biomarkers that are reproducible and biologically interpretable. By leveraging a reliability dataset with replicates across tissues, we demonstrate that it is possible to transfer knowledge from blood DNAm data to saliva DNAm data using DNAm proxies of blood proteins (EpiScores). We then apply these methods to create a new saliva-based epigenetic clock (InflammAge) that quantifies systemic chronic inflammation (SCI) in humans. Using a large blood DNAm human cohort with linked electronic health records and over 18,000 individuals (Generation Scotland), we demonstrate that InflammAge significantly associates with all-cause mortality, disease outcomes, lifestyle factors and immunosenescence; in many cases outperforming the widely used SCI biomarker C-reactive protein (CRP). We propose that our biomarker discovery framework and InflammAge will be useful to improve our understanding of the molecular mechanisms underpinning human ageing and to assess the impact of gero-protective interventions.

bioinformatics↗

bioRxiv2023

The nucleotide binding domain of NRC-dependent disease resistance proteins is sufficient to activate downstream helper NLR oligomerization and immune signaling

Nucleotide-binding domain and leucine-rich repeat (NLR) proteins with pathogen sensor activities have evolved to initiate immune signaling by activating helper NLRs. However, the mechanisms underpinning helper NLR activation by sensor NLRs remain poorly understood. Although coiled-coil (CC) type sensor NLRs such as the Potato virus X disease resistance protein Rx have been shown to activate the oligomerization of their downstream helpers NRC2 and NRC4, the domains involved in sensor-helper signaling are not known. Here, we show that the nucleotide binding (NB) domain within the NB-ARC of the Potato virus X disease resistance protein Rx is necessary and sufficient for oligomerization and immune signaling of downstream helper NLRs. In addition, the NB domains of the disease resistance proteins Gpa2 (cyst nematode resistance), Rpi-amr1, Rpi-amr3 (oomycete resistance) and Sw-5b (virus resistance) are also sufficient to activate their respective downstream NRC helpers. Moreover, the NB domain of Rx and its helper NRC2 form a minimal functional unit that can be transferred from solanaceous plants (lamiids) to the Campanulid species lettuce (Lactuca sativa). Our results challenge the prevailing paradigm that NLR proteins exclusively signal via their N-terminal domains and reveal a signaling activity for the NB domain of NRC-dependent sensor NLRs. We propose a model in which helper NLRs monitor the status of the NB domain of their upstream sensors.

plant biology↗

bioRxiv2023

NRF2 activation in the heart induces glucose metabolic reprogramming and mediates cardioprotection via upregulation of the pentose phosphate pathway.

RationaleThe transcription factor NRF2 is well recognized as a master regulator of antioxidant responses and cytoprotective genes. Previous studies showed that NRF2 protects mouse hearts during chronic hemodynamic overload at least in part by reducing oxidative stress. Evidence from other tissues suggests that NRF2 may modulate glucose intermediary metabolism but whether NRF2 has such effects in the heart is unclear. ObjectiveTo investigate the role of NRF2 in regulating glucose intermediary metabolism and cardiac function during disease stress. Methods and ResultsCardiomyocyte-specific Keap1 knockout (csKeap1KO) mice, deficient in the endogenous inhibitor of NRF2, were used as a novel model of constitutively active NRF2 signaling. Targeted metabolomics and isotopomer analysis were employed in studies with 13C6-glucose in csKeap1KO and wild-type (WT) mice. Pharmacological and genetic approaches were utilized in neonatal rat ventricular cardiomyocytes (NRVM) to explore molecular mechanisms. We found that cardiac-specific activation of NRF2 upregulated key enzymes of the Pentose Phosphate Pathway (PPP), redirected glucose metabolism towards the PPP and protected the heart against pressure overload-induced cardiac dysfunction. In vitro, knockdown of Keap1 upregulated PPP enzymes and reduced cell death in NRVM subjected to chronic neurohumoral stimulation. These pro-survival effects were abolished by pharmacological inhibition of the PPP or silencing of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of NRF2 in NRVM increased stress-induced DNA damage which was rescued by supplementing the cells with either NADPH or nucleosides, the two main products of the PPP. Activation of NRF2 also protected the heart against myocardial infarction-induced DNA damage, dysfunction, and adverse remodeling. ConclusionsThese results indicate that NRF2 regulates cardiac metabolic reprogramming by stimulating the diversion of glucose into the PPP, thereby providing cardiac protection during stress by generating NADPH and providing nucleotides to prevent stress-induced DNA damage.

physiology↗

bioRxiv2023

The amino acid composition of a protein influences its expression

The quantity of each protein in a cell only is only partially correlated with its gene transcription rate. Independent influences on protein synthesis levels include mRNA sequence motifs, amino acyl-tRNA synthesis levels, elongation factor action, and protein susceptibility to degradation. Here we report two novel forms of interaction between the amino acid composition of a protein and its expression level. In animals, the differing origins of amino acids define a nutritional classification system and indicate their potential for scarcity - essential amino acids (EAA) are solely obtained from dietary supply, non-essential amino acids (NEAA) from biosynthetic supply, and conditionally essential amino acids (CEAA) from both. Accessing public proteomic datasets, we demonstrate that CEAA sequence composition is inversely correlated with expression - a rule of supply that is further magnified by rapid cellular proliferation. Similarly, proteins with the most extreme compositions of EAA are reduced in abundance. Homeostatic responses to malnutrition may result from the reductions in expression of extreme composition proteins participating in biological systems such as taste and food-seeking behaviour, oxidative phosphorylation, and chemokine function. The rule can also influence general human phenotypes and disease susceptibility: stature proteins are enriched in CEAAs, and a curated dataset of over 700 cancer proteins is significantly under-represented in EAAs. A second rule, whereby individual amino acids influence protein expression is also described. This rule is shared across all kingdoms of life and rooted in the immutable structural and encoding parameters of each amino acid. Species-specific environmental survival pathways are shown to be enriched in proteins with amino acid compositions favouring higher expression according to this rule. These two rules of protein expression regulation promise new insights into systems biology, evolutionary studies, experimental research design, and public health intervention.

biochemistry↗

bioRxiv2023

Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes

Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network analysis of protein-protein interactions, pathways and metabolomics. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. We explore this in more detail for one of the proteins not previously associated with the NMJ, USH2A. Loss of the zebrafish USH2A ortholog revealed some effects on early movement and gross NMJ morphology. This work showcases how coupling multilayer network analysis with personalized -omics information provides molecular explanations to the varying severity of rare diseases; paving the way for sorting out similar cases in other rare diseases.

bioinformatics↗

bioRxiv2022

Contact-number-driven virus evolution: a multi-level modeling framework for the evolution of acute or persistent RNA virus infection

Viruses evolve in infected host populations, and host population dynamics affect viral evolution. RNA viruses with a short duration of infection and a high peak viral load, such as and SARS-CoV-2, are maintained in human populations. By contrast, RNA viruses characterized by a long infection duration and a low peak viral load (e.g., borna disease virus) can be maintained in nonhuman populations, and why the persistent viruses evolved has been rarely explored. Here, using a multi-level modeling approach including both individual-level virus infection dynamics and population-scale transmission, we consider virus evolution based on the host environment, specifically, the effect of the contact history of infected hosts. We found that, with a highly dense contact history, viruses with a high virus production rate but low accuracy are likely to be optimal, resulting in a short infectious period with a high peak viral load. In contrast, with a low-density contact history, viral evolution is toward low virus production but high accuracy, resulting in long infection durations with low peak viral load. Our study sheds light on the origin of persistent viruses and why acute viral infections but not persistent virus infection tends to prevail in human society.

evolutionary biology↗