Biology subjects

Kane, M.

Publications and source records attributed to Kane, M..

14 recordsLinked to original sources

bioRxiv2026

Genomic signatures of selection and putative adaptive introgression during the African expansion of the house mouse

How species adapt to novel environments following biological invasion remains a central question in evolutionary biology. The recent human-mediated expansion of the western house mouse (Mus musculus domesticus) across Africa provides an opportunity to investigate the genomic basis of these rapid evolutionary responses. Using whole-genome data from 218 wild mice sampled across Europe and Africa, we combined complementary genome-wide differentiation, genotype-environment association, haplotype-based selection, and localized introgression analyses to investigate genomic signatures of selection and assess the contribution of interspecific gene flow from the native congener Mus spretus to these patterns. Genome-wide differentiation analyses identified candidate regions enriched for immune and epithelial-barrier functions, chemosensory perception, and neural or developmental pathways. Genotype-environment association analyses recovered fewer candidates linked mainly to precipitation, whereas haplotype-based scans highlighted recent selective signals involving sensory, immune, and neural functions. Across analyses, candidate regions were dominated by non-coding variation, supporting a predominantly regulatory and likely polygenic genomic architecture. Although excess allele sharing with M. spretus varied among populations, overlap between introgression and selection candidates was limited but greater than expected by chance. Several overlapping regions were also present in European populations, indicating that introgressed variants likely predated African colonization. Overall, our results suggest that the genomic signatures accompanying the African expansion of house mice were driven mainly by selection on M. m. domesticus variation, whereas introgressed M. spretus alleles contributed to a smaller subset of candidate loci and may have played a role in adaptation in African populations.

evolutionary biology↗

bioRxiv2026

Determinants in gammaretroviral Env dictate the production of neutralizing antibodies

Protective immune responses are shaped by the nature of the infectious pathogen. Some viral infections are self-limiting and stimulate lasting immunity, while others activate poor responses that fail to control the infection or prevent development of disease. Little is known concerning the specific viral determinants that control whether a given viral infection will result in protective immunity. Here, we demonstrate that strains of the gammaretrovirus, murine leukemia virus, differ in their ability to stimulate neutralizing antibody production via a noncanonical pathway. Additionally, we show that virus-specific production of neutralizing immune responses is unique to infection, suggesting that the activation of alternative antibody responses is triggered by the infectious process rather than the unique nature of specific viral antigens. Viral chimeras indicate that activation of neutralizing antiviral antibody production is determined by the receptor-binding domain, and that the surface subunit controls binding to and infection of various cell types. The ability of specific viral factors to determine the outcome of infection and the induction of distinctive immune responses between closely related retroviral strains provides an ideal model for the dissection of both host and viral determinants underlying the control of viral infection and the production of neutralizing antibodies. SUMMARYWe report here that retroviral envelope glycoprotein determines stimulation of GC B cell responses and the production of neutralizing antibodies in the absence of IFN{gamma}-signaling, thus defining the factors that stimulate non-canonical immune responses and further developing the knowledge required for vaccine development.

immunology↗

bioRxiv2026

SFPQ dysregulation promotes TDP-43 pathology through a pathogenic feedback loop

TDP-43 proteinopathies comprise a group of clinically distinct neurodegenerative disorders unified by common pathological changes in the RNA-binding protein TDP-43, including nuclear loss of function (LOF), cytoplasmic mislocalisation and aggregation. The presence of these hallmarks across diverse diseases, such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), alzheimers disease (AD) and Limbic-predominant Age-related TDP-43 Encephalopathy (LATE), suggests the involvement of convergent upstream regulatory mechanisms. This study identified SFPQ (Splicing Factor Proline and Glutamine Rich) as one such factor. The depletion of nuclear SFPQ, in addition to its cytoplasmic accumulation and aggregation has been described across ALS, AD and FTD patient studies and in multiple genetic models of these diseases. Evidence to date places SFPQ pathology downstream of TDP-43 dysfunction. This study provided further evidence that TDP-43 drives SFPQ pathology while revealing a reciprocal role for SFPQ in regulating TDP-43 homeostasis. Our data shoed that SFPQ LOF was associated with a shift in TDP-43 RNA isoform usage away from the canonical protein-coding transcript towards isoforms predicted to undergo nonsense-mediated decay (NMD). Consistent with this, TDP-43 protein expression was reduced across multiple model systems in which SFPQ expression was suppressed. Furthermore, cytoplasmic accumulation of SFPQ was found to promote the mislocalisation of TDP-43 and its sequestration within SFPQ-containing cytoplasmic condensates that exhibited progressively reduced molecular mobility over time. Collectively, these findings identify SFPQ as an active contributor to multiple facets of TDP-43 pathology, support a bidirectional relationship between the two proteins, and suggest the existence of a feed-forward, self-amplifying mechanism that may contribute to disease progression in TDP-43 proteinopathies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/740184v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@12855eorg.highwire.dtl.DTLVardef@1f1e068org.highwire.dtl.DTLVardef@c3fb00org.highwire.dtl.DTLVardef@93f0ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

TLR7-independent control of retroviral infection

Development of effective immune responses against any pathogen requires efficient activation of the innate immune system followed by induction of an appropriate adaptive immune response using specific signaling pathways tailored to each infection. The sole innate immune receptor implicated in the induction of adaptive immunity to retroviral infection is Toll like receptor 7 (TLR7). We have found that germinal center responses, neutralizing antibody production, and clearance of murine leukemia virus (MLV) infection in BALB.J and C57BL/6N (B6N) mice occurs in the absence of TLR7 signaling. This suggests that a previously unknown alternative sensing pathway exists for the activation of protective immune responses upon retroviral infection. Genetic crosses indicate that the ability to control retroviral infection in the absence of TLR7 signaling is determined by the same recessive mechanism in both B6N and BALB.J mice, suggesting that TLR7-independent responses do not result from a gain-of-function of an alternative pattern recognition receptor. Additionally, we observed that TLR7-deficient BALB.J mice produce neutralizing antibodies against mouse mammary tumor virus (MMTV) infection, indicating that this alternative sensing pathway is active against retroviruses of multiple genera. Finally, we determined that the alternative sensing pathway is also independent of both MyD88 and STING signaling. The ability of mice of two genetic backgrounds to control retroviral infection in the absence of TLR7 signaling provides a valuable tool for the identification of a novel mechanism of retrovirus control. The dissection of this pathway has the potential to alter our understanding of the requirements for the stimulation of antigen-specific neutralizing immunity. Significance StatementInnate immune sensors are required for induction of pathogen-specific immune responses, and the development of novel vaccines requires an understanding of the basic mechanisms by which the immune system detects and responds to pathogens. While multiple innate immune receptors have been implicated in the sensing of retroviral infection, only Toll-like receptor 7 (TLR7) has been found to upregulate adaptive immune responses. Here, we demonstrate that an additional TLR7-independent mechanism for the activation of antiretroviral antibody responses is present in inbred mice from two genetic backgrounds. This finding has implications for the selection of mouse models for the study of antiviral immune responses and has the potential to alter our understanding of the requirements for the stimulation of antigen-specific neutralizing immunity.

microbiology↗

bioRxiv2025

Human TDP-43 overexpression in zebrafish motor neurons triggers MND-like phenotypes through gain-of-function mechanism

Dysregulation of the TAR DNA-binding protein 43 (TDP-43), including intraneuronal cytoplasmic mislocalisation and aggregation is a feature of multiple neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), limbic-predominant age-related TDP-43 encephalopathy (LATE) and alzheimers disease (AD). Unravelling the causes and functional consequences of TDP-43 dysregulation is paramount to understanding disease mechanisms as well as identifying effective therapeutic targets. Here we present a comprehensive in vivo characterisation of three stable transgenic zebrafish models that express human TDP-43 variants in motor neurons. We demonstrate that overexpression of predominantly nuclear wildtype TDP-43, cytoplasm-targeted TDP-43, and an ALS-linked variant (G294V) each induce toxic gain-of-function effects, leading to impaired motor function, motor neuron loss, and muscle atrophy. Importantly, these models reveal distinct phenotypes, with the ALS-linked mutant exhibiting axonal transport deficits and neuromuscular junction disruption, while cytoplasmic mislocalised TDP-43 heightened susceptibility to oxidative stress. Two FDA-approved drugs used to treat ALS, edaravone and riluzole, were examined in these models and revealed that edaravone, but not riluzole, was effective in rescuing motor deficits associated with cytoplasmic TDP-43 expression and, to a lesser extent, mutant TDP-43G294V. Collectively, these findings reveal distinct pathological consequences of TDP-43 dysregulation, providing neuron-centric mechanistic insights, and establish the humanised TDP-43 zebrafish as an efficient system for preclinical therapeutic testing. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/663393v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@18c4a50org.highwire.dtl.DTLVardef@162df7forg.highwire.dtl.DTLVardef@3f2848org.highwire.dtl.DTLVardef@6d9439_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Interplay between the cyclophilin homology domain of RANBP2 and MX2 regulates HIV-1 capsid dependencies on nucleoporins

Interlinked interactions between the viral capsid (CA), nucleoporins (Nups), the antiviral protein myxovirus resistance 2 (MX2/MXB) influence HIV-1 nuclear entry and the outcome of infection. Although RANBP2/NUP358 has been repeatedly identified as a critical player in HIV-1 nuclear import and MX2 activity, the mechanism by which RANBP2 facilitates HIV-1 infection is not well understood. To explore the interactions between MX2, the viral CA, and RANBP2, we utilized CRISPR-Cas9 to generate cell lines expressing RANBP2 from its endogenous locus but lacking the C-terminal cyclophilin (Cyp) homology domain, and found that both HIV-1 and HIV-2 infection were reduced significantly in RANBP2{Delta}Cyp cells. Importantly, although MX2 still localized to the nuclear pore complex in RANBP2{Delta}Cyp cells, antiviral activity against HIV-1 was decreased. By generating cells expressing specific point mutations in the RANBP2-Cyp domain we determined that the effect of the RANBP2-Cyp domain on MX2 anti-HIV-1 activity is due to direct interactions between RANBP2 and CA. We further determined that CypA and RANBP2-Cyp have similar effects on HIV-1 integration targeting. Finally, we found that the Nup requirements for HIV infection and MX2 activity were altered in cells lacking the RANBP2-Cyp domain. These findings demonstrate that the RANBP2-Cyp domain affects viral infection and MX2 sensitivity by altering CA-specific interactions with cellular factors that affect nuclear import and integration targeting. Significance StatementHIV-1 entry into the nucleus is an essential step in viral replication that involves complex interactions between the viral capsid and multiple cellular proteins, including nucleoporins such as RANBP2. Nups also mediate the function of the antiviral protein MX2, however determining the precise role of Nups in HIV infection has proved challenging due to the complex nature of the nuclear pore and significant pleiotropic effects elicited by Nup depletion. We have used precise gene editing to assess the role of the Cyp domain of RANBP2 in HIV-1 infection and MX2 activity. We find that this domain affects viral infection, nucleoporin requirements, MX2 sensitivity, and integration targeting in a CA-specific manner, providing detailed insights into how RANBP2 contributes to HIV-1 infection.

microbiology↗

bioRxiv2024

Spatiotemporal binding of cyclophilin A and CPSF6 to capsid regulates HIV-1 nuclear entry and integration

Human immunodeficiency virus type 1 (HIV-1) capsid, which is the target of the antiviral lenacapavir, protects the viral genome and binds multiple host proteins to influence intracellular trafficking, nuclear import, and integration. Previously, we showed that capsid binding to cleavage and polyadenylation specificity factor 6 (CPSF6) in the cytoplasm is competitively inhibited by cyclophilin A (CypA) binding and regulates capsid trafficking, nuclear import, and infection. Here we determined that a capsid mutant with increased CypA binding affinity had significantly reduced nuclear entry and mislocalized integration. However, disruption of CypA binding to the mutant capsid restored nuclear entry, integration, and infection in a CPSF6-dependent manner. Furthermore, relocalization of CypA expression from the cell cytoplasm to the nucleus failed to restore mutant HIV-1 infection. Our results clarify that sequential binding of CypA and CPSF6 to HIV-1 capsid is required for optimal nuclear entry and integration targeting, informing antiretroviral therapies that contain lenacapavir.

microbiology↗

bioRxiv2023

Virus specificity and nucleoporin requirements for MX2 activity are affected by GTPase function and capsid-CypA interactions

Human myxovirus resistance 2 (MX2/MXB) is an interferon-induced GTPase that inhibits human immunodeficiency virus-1 (HIV-1) infection by preventing nuclear import of the viral preintegration complex. The HIV-1 capsid (CA) is the major viral determinant for sensitivity to MX2, and complex interactions between MX2, CA, nucleoporins (Nups), cyclophilin A (CypA), and other cellular proteins influence the outcome of viral infection. To explore the interactions between MX2, the viral CA, and CypA, we utilized a CRISPR-Cas9/AAV approach to generate CypA knock-out cell lines as well as cells that express CypA from its endogenous locus, but with specific point mutations that would abrogate CA binding but should not affect enzymatic activity or cellular function. We found that infection of CypA knock-out and point mutant cell lines with wild-type HIV-1 and CA mutants recapitulated the phenotypes observed upon cyclosporine A (CsA) addition, indicating that effects of CsA treatment are the direct result of blocking CA-CypA interactions and are therefore independent from potential interactions between CypA and MX2 or other cellular proteins. Notably, abrogation of GTP hydrolysis by MX2 conferred enhanced antiviral activity when CA-CypA interactions were abolished, and this effect was not mediated by the CA-binding residues in the GTPase domain, or by phosphorylation of MX2 at position T151. We additionally found that elimination of GTPase activity also altered the Nup requirements for MX2 activity. Our data demonstrate that the antiviral activity of MX2 is affected by CypA-CA interactions in a virus-specific and GTPase activity-dependent manner. These findings further highlight the importance of the GTPase domain of MX2 in regulation of substrate specificity and interaction with nucleocytoplasmic trafficking pathways. Author SummaryHIV-1 entry into the nucleus is an essential step in viral replication that involves complex interactions between the viral capsid and multiple cellular proteins, including the proline isomerase cyclophilin A. Nuclear entry of HIV-1 and other primate lentiviruses is inhibited by the antiviral protein MX2. Here, we show that direct interactions between capsid and cyclophilin A affect the antiviral activity and specificity of MX2, and that these interactions are altered when the enzymatic activity of MX2 is eliminated. We demonstrate that abolishing enzymatic activity of MX2 also alters the requirements for nuclear pore complex components for viral restriction. Our study provides new insights into how the enzymatic function of MX2 affects inhibition of lentiviral nuclear import.

microbiology↗

bioRxiv2022

Genetic differences between 129S substrains affect antiretroviral immune responses

Inbred mouse lines vary in their ability to mount protective antiretroviral immune responses, and even closely related strains can exhibit opposing phenotypes upon retroviral infection. Here, we found that 129S mice inherit a previously unknown mechanism for the production of anti-murine leukemia virus (MLV) antibodies and control of infection. The resistant phenotype is controlled by two dominant loci that are independent from known MLV-resistance genes. We also show that production of anti-MLV antibodies in 129S7, but not 129S1 mice is independent of interferon gamma (IFN{gamma}) signaling. Thus, our data indicate that 129S mice inherit an unknown mechanism for control of MLV infection and demonstrate that there is genetic variability in 129S substrains that affects their ability to mount antiviral immune responses. ImportanceUnderstanding the genetic basis for production of protective antiviral immune responses is crucial for the development of novel vaccines and adjuvants. Additionally, characterizing the genetic and phenotypic variability in inbred mice has implications for the selection of strains for targeted mutagenesis, choice of controls, and for broader understanding of the requirements for protective immunity.

microbiology↗

bioRxiv2020

Genome-wide maps of enhancer regulation connect risk variants to disease genes

Genome-wide association studies have now identified tens of thousands of noncoding loci associated with human diseases and complex traits, each of which could reveal insights into biological mechanisms of disease. Many of the underlying causal variants are thought to affect enhancers, but we have lacked genome-wide maps of enhancer-gene regulation to interpret such variants. We previously developed the Activity-by-Contact (ABC) Model to predict enhancer-gene connections and demonstrated that it can accurately predict the results of CRISPR perturbations across several cell types. Here, we apply this ABC Model to create enhancer-gene maps in 131 cell types and tissues, and use these maps to interpret the functions of fine-mapped GWAS variants. For inflammatory bowel disease (IBD), causal variants are >20-fold enriched in enhancers in particular cell types, and ABC outperforms other regulatory methods at connecting noncoding variants to target genes. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes via variants in enhancers that act in different cell types. Guided by these variant-to-function maps, we show that an enhancer containing an IBD risk variant regulates the expression of PPIF to tune mitochondrial membrane potential. Together, our study reveals insights into principles of genome regulation, illuminates mechanisms that influence IBD, and demonstrates a generalizable strategy to connect common disease risk variants to their molecular and cellular functions.

genetics↗

bioRxiv2020

Characterizing Sleep-Wake Circadian Rhythm Consolidation in Early Childhood and Its Association with Motor Development Using Actigraphy

BackgroundWearable devices have been widely used in clinical studies to study daily activity patterns, but the analysis remains the major obstacle for researchers. Study ObjectiveThis study proposed a novel method to characterize sleep-activity rhythms using actigraphy and further used it to describe early childhood daily rhythm formation and examine its association with physical development. MethodsWe developed a machine learning-based Penalized Multi-band Learning (PML) algorithm to sequentially infer dominant periodicities based on Fast Fourier Transform (FFT) and further characterize daily rhythms. We implemented and applied the algorithm to Actiwatch data collected from a 262 healthy infant cohort at 6-, 12-, 18-, and 24-month old, with 159, 101, 111, and 141 subjects participating at each time point respectively. Autocorrelation analysis and Fishers test for harmonic analysis with Bonferroni correction were applied to compare with PML. The association between activity rhythm features and early childhood motor development, assessed by Peabody Developmental Motor Scales-Second Edition (PDMS-2), was studied through linear regression. ResultsPML results showed that 1-day periodicity is most dominant at 6 and 12 months, whereas 1-day, 1/3-day, and 1/2-day periodicities are most dominant at 18 and 24 months. These periodicities are all significant in Fishers test, with 1/4-day periodicity also significant at 12 months. Autocorrelation effectively detected 1-day periodicity but not others. At 6 months, PDMS-2 is associated with assessment seasons. At 12 months, PDMS-2 is associated with seasons and FFT signals at 1/3-day periodicity (P<.001) and 1/2-day periodicity (P=.04). In particular, subcategories of stationary, locomotion, and gross motor are associated with FFT signals at 1/3-day periodicity (P<.001). ConclusionsThe proposed PML algorithm can effectively conduct circadian rhythm analysis using time-series wearable device data. Application of the method effectively characterized sleep-wake rhythm development and identified the association between daily rhythm formation and motor development during early childhood.

neuroscience↗

bioRxiv2019

Impact of historical and current features of the cityscape on the genetic structure of the house mouse (Mus musculus domesticus) in Dakar (Senegal, West Africa)

AO_SCPLOWBSTRACTC_SCPLOWPopulation genetic approaches may be used to investigate dispersal patterns of species living in highly urbanized environment in order to improve management strategies for biodiversity conservation or pest control. However, in such environment, population genetic structure may reflect both current features of the cityscape and urbanization history. This can be especially relevant when focusing on exotic commensal rodents that have been introduced in numerous primary colonial European settlements. Accounting for spatial and temporal cityscape heterogeneity to determine how past and recent demographic events may interplay to shape current population genetic structure of synanthropic rodents may provide useful insights to manage their populations. In this study, we addressed these issues by focusing on the house mouse, Mus musculus domesticus, in Dakar, Senegal, where the species may have been introduced as soon as Europeans settled in the middle of the nineteenth century. We examined genetic variation at one mitochondrial locus and 15 nuclear microsatellite markers from individuals sampled in 14 sampling sites representing different stages of urbanization history and different socio-economic environments in Dakar. We used various approaches, including model-based genetic clustering and model-free smoothing of pairwise genetic estimates. We further linked observed spatial genetic patterns to historical and current features of Dakar cityscape using random forest and Bayesian conditional autoregressive models. Results are consistent with an introduction of the house mouse at colonial time and the current genetic structure exhibits a gradient-like pattern reflecting the historical process of spatially continuous expansion of the city from the first European settlement. The genetic patterns further suggest that population dynamics of the house mouse is also driven by the spatial heterogeneity of the current cityscape, including socio-economics features, that translate in habitat quality. Our results highlight the potential importance of accounting for past demographic events to understand spatial genetic patterns of nonnative invasive commensal rodents in highly urbanized environment.

ecology↗

bioRxiv2019

Activity-by-Contact model of enhancer specificity from thousands of CRISPR perturbations

Mammalian genomes harbor millions of noncoding elements called enhancers that quantitatively regulate gene expression, but it remains unclear which enhancers regulate which genes. Here we describe an experimental approach, based on CRISPR interference, RNA FISH, and flow cytometry (CRISPRi-FlowFISH), to perturb enhancers in the genome, and apply it to test >3,000 potential regulatory enhancer-gene connections across multiple genomic loci. A simple equation based on a mechanistic model for enhancer function performed remarkably well at predicting the complex patterns of regulatory connections we observe in our CRISPR dataset. This Activity-by-Contact (ABC) model involves multiplying measures of enhancer activity and enhancer-promoter 3D contacts, and can predict enhancer-gene connections in a given cell type based on chromatin state maps. Together, CRISPRi-FlowFISH and the ABC model provide a systematic approach to map and predict which enhancers regulate which genes, and will help to interpret the functions of the thousands of disease risk variants in the noncoding genome.

genetics↗

bioRxiv2017

Biological invasions in rodent communities: from ecological interactions to zoonotic bacterial infection issues

Several hypotheses (such as enemy release, novel weapon, spillback and dilution/density effect) suggest changes in host-parasite ecological interactions during biological invasion events. Such changes can impact both invasion process outcome and the dynamics of exotic and/or endemic zoonotic diseases. To evaluate these predictions, we investigated the ongoing invasions of the house mouse Mus musculus domesticus, and the black rat, Rattus rattus, in Senegal (West Africa). We focused on zoonotic bacterial communities depicted using 16S rRNA amplicon sequencing approach in both invasive and native rodents sampled along two well-defined invasion routes. Overall, this study provided new ecological evidence connecting parasitism and rodent invasion process, with diverse potential roles of zoonotic bacteria in the invasion success. Our results also highlighted the main factors that lie behind bacterial community structure in commensal rodents. Further experimental studies as well as comparative spatio-temporal surveys are necessary to decipher the actual role of zoonotic bacteria in these invasions. Our data also gave new support for the difficulty to predict the direction in which the relationship between biodiversity changes and disease risk could go. These results should be used as a basis for public health prevention services to design reservoir monitoring strategies based on multiple pathogen surveillance.

ecology↗