Biology subjects

Kane, A.

Publications and source records attributed to Kane, A..

14 recordsLinked to original sources

bioRxiv2026

Single-cell lung eQTL dataset of Asian never-smokers highlights the roles of alveolar cells in lung cancer etiology

Single-cell expression quantitative trait loci (sc-eQTL) analyses are powerful in identifying context-specific susceptibility genes from genome-wide association studies (GWAS) loci. However, few studies have comprehensively investigated cells of lung cancer origin in non-European populations. Here, we built a lung sc-eQTL dataset from 129 Korean women never-smokers with epithelial cell enrichment. eQTL mapping identified 2,229 genes with an eQTL in 33 cell types, including East Asian-specific findings when compared to predominantly European datasets. Integration with single-cell chromatin accessibility data demonstrated an enrichment of cell-type specific eQTLs in cell-type matched candidate enhancers, while shared eQTLs were more frequently found near promoters. Colocalization and transcriptome-wide association study unveiled 36 susceptibility genes from 22 cell types in 22 lung cancer loci, including 10 loci not achieving genome-wide significance in prior GWAS. Around 47% of these genes were from cells of the alveoli, underscoring their importance, especially in lung adenocarcinoma (LUAD) susceptibility. Focusing on the trajectory of alveolar epithelial cell regeneration, we detected 785 cell-state-interacting QTLs, which overlapped with 28% (10) of the identified susceptibility genes. Finally, we experimentally validated East Asian-and alveolar type 2 cell-specific eQTL of TCF7L2 underlying East Asian LUAD locus, 10q25.2. Consistent with its role as a Wnt/{beta}-catenin effector, TCF7L2 displayed significant effect on lung adenocarcinoma cell growth. Our data highlighted context-specific susceptibility genes, especially from alveolar cells of lung, contributing to lung cancer etiology.

genetics↗

bioRxiv2025

Uncovering hidden behaviours: a GPS-Accelerometry approach to behaviour classification in storm-petrels

Biologging has transformed ecological research, yet studying the at-sea behaviour of small seabirds remains challenging due to trade-offs between device size and data resolution. Miniature GPS devices (<1 g) have been deployed on storm-petrels but their coarse temporal resolution limits behavioural classification, particularly resting. Accelerometers offer detailed behavioural data but lack spatial context, and some species are too small to simultaneously carry both devices. We deployed GPS devices on breeding European storm-petrels, including a subset recently developed with integrated accelerometers. Using accelerometer-informed rest periods, we developed a semi-supervised three-state Hidden Markov Model to classify transiting, foraging, and resting across all GPS tracks, even those without accelerometer data. Detection of resting behaviour by the semi-supervised model improved substantially compared to an unsupervised GPS-only model which only identified 17% of true resting events. Resulting time-activity budgets closely matched accelerometer-only studies, validating behaviour classifications, while also providing spatial context. Foraging peaked in the early hours of the night, whereas resting was most frequent in the afternoon. This is the first application of a combined GPS-accelerometer approach to a small storm-petrel species. Our method improves behavioural classification in small seabirds, providing new insights into the spatial and temporal dynamics of their at-sea behaviour.

ecology↗

bioRxiv2025

Associations Between Frailty and Cognitive Outcomes Across the Lifespan of Mice

Advancements in monitoring biological and brain aging with precise measures of health and longevity have the potential to accelerate research on pharmacological, genetic, and aging-related interventions. Over the past decade, frailty index has been used as an assessment tool for rodents, evaluating more than 30 non-invasive parameters that are strongly associated with chronological age, correlated with mortality, and sensitive to lifespan-altering interventions. However, whether aging phenotypes captured by the frailty index reflect brain aging remains unclear. In this study, we examined the relationship between frailty index and cognitive ability in young (3-4 months), middle-aged (12 months), and old (24 months) male and female C57BL/6J mice using a battery of behavioral and locomotor assays to determine whether frailty index scores can predict performance in tasks evaluating behavioral and cognitive function. Among the behavioral assays tested, frailty index scores had good correlation with the percentage of time spent in the center of the open-field apparatus, the duration spent in the open arms of the elevated plus maze, and the time spent in the target hole of the Barnes maze. These findings indicate that the frailty index not only reflects general physiological aging but may also serve as a reliable predictor of age-related cognitive decline in mice, providing a valuable tool for studies of interventions targeting brain aging.

neuroscience↗

bioRxiv2024

Analog epigenetic cell memory by graded DNA methylation

Chemical modifications to histones and DNA play a crucial role in the regulation of transcription and in the maintenance of chromatin states that are not permissive to gene expression [1-3]. However, the landscape of gene expression states that these modifications stably maintain remains uncharted. Here, we show that gene expression can be memorized at a wide range of levels thus implementing analog epigenetic memory. Mechanistically, we find that DNA methylation serves a primary role in maintaining memory across cell divisions while histone modifications only follow DNA methylation to regulate gene expression. Employing targeted epigenetic editing and time-course analysis, we analyzed the temporal stability of gene expression and DNA methylation post removal of epigenetic effectors. We found that the grade of DNA methylation in the genes promoter, defined as the mean fraction of methylated CpGs, remains stable over time and inversely correlates with gene expression level. By contrast, Histone 3 lysine 9 trimethylation (H3K9me3) could not persist after removal of its writer in the absence of DNA methylation. These experimental findings, combined with our chromatin modification model, indicate that the absence of positive feedback mechanisms around DNA methylation - unlike those found in histone modifications - enable the temporal stability of the DNA methylation grade, which leads to analog memory. These results expand current knowledge on how epigenetic memory is achieved in natural systems. Moreover, we anticipate that analog memory through graded DNA methylation will enable to program mammalian cells with fine-grained information storage. This capability will significantly enhance the sophistication of engineered cell functionality in applications including tissue engineering, organoids, and cell therapies.

bioengineering↗

bioRxiv2023

Attenuation of the CpG Island Methylator Phenotype and lack of WNT signaling activation restrains Kras mutant intestinal neoplasia

BackgroundSerrated neoplasia accounts for [~]25% of colorectal cancer. These cancers arise from serrated precursor lesions. Hyperplastic polyps initiated by either BRAF or KRAS mutation activating MAPK signalling are common, but premalignant sessile serrated lesions with KRAS mutation are rare. Here, we model Kras and Braf mutant neoplasia in vivo to compare histological, gene expression and DNA methylation manifestations associated with activation of these oncogenes. MethodsWe employ cre-recombinase dependent BrafV637 and KrasG12D murine models, and cross animals with those bearing the Villin-CreERT2 transgene to direct temporospatial activation of these oncogenes to the murine intestine. We examine histology, and genome-scale DNA methylation and gene expression via reduced representation bisulphite sequencing and RNA-Seq, respectively. We performed differential gene expression, methylation and pathways analysis to identify oncogene specific alterations. ResultsProlonged exposure to oncogenic Braf is associated with a time-dependent accumulation of murine serrated precursors (P=3x10-10) and advanced murine serrated lesions and invasive cancer (8x10- 8). Kras mutant animals acquire fewer precursor lesions (P=0.06) and have a significantly lower probability of developing advanced serrated lesions (P=0.004). Braf and Kras mutant animals develop pronounced hyperplasia, however the severity is significantly less in Kras mutant animals. Kras mutant advanced serrated lesions rarely develop aberrant WNT signaling activation (1/23). Gene expression profiling showed divergent transcriptomic profiles between Braf and Kras mutant intestines, with the former overexpressing genes associated with immune and inflammatory signaling. Deconvolution analysis revealed a comparably higher macrophage infiltrate (P=0.025) and upregulation of M1 macrophage gene sets in the Braf mutant intestine (P=0.0008), contributing to chronic inflammatory signalling. Both Kras and Braf mutations lead to accumulation of substantial temporal DNA methylation alterations, however a subset of CpG sites (1,306) show an attenuated rate of DNA methylation accumulation in the Kras mutant intestine compared with Braf mutant animals. ConclusionsIn this study, we show that Kras mutation can induce serrated intestinal neoplasia, however the latency period and penetrance is significantly lower when compared with Braf mutation. Aberrant WNT signalling is common in lesions arising in the context of Braf mutation, but rare in Kras mutant neoplasms. We show marked transcriptomic disparities between these models, with a tendency for the Braf mutant intestine to upregulate immunological processes. Our DNA methylation analysis reveals an attenuated CIMP-like phenotype that is specific to the Kras mutant intestine, consistent with our previous works in humans. These data have significant implications for our understanding of how MAPK-induced neoplasia develops within the intestine. SynopsisBRAF and KRAS mutant hyperplastic polyps have disparate malignant potential and the reason for this is unclear given both oncogenes activate MAPK signalling. We show that the DNA methylation alterations that follow Kras mutation are attenuated and that hyperactivation of WNT signaling is rare, providing a molecular mechanism that restrains malignant transformation.

cancer biology↗

bioRxiv2023

Context-aware single-cell multiome approach identified cell-type specific lung cancer susceptibility genes

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Accessible chromatin peak detection identified cell-type-specific candidate cis-regulatory elements (cCREs) from each lung cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor abundance and footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare proliferating epithelial cell types, such as AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs, including those in TERT. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including those not detected in tissue- or cell-line-based approaches. cCRE-gene linkage uncovered that adjacent genes expressed in different cell types are correlated with distinct subsets of coinherited CCVs, including JAML and MPZL3 at the 11q23.3 locus. Our data revealed the cell types and contexts where the lung cancer susceptibility genes are functional.

genomics↗

bioRxiv2023

Soft selection affects introgression dynamics and the viability of populations experiencing intrusion of maladapted individuals

The deliberate release of captive-bred individuals, the accidental escape of domesticated strains, or the invasion of closely related conspecifics into wild populations can all lead to introgressive hybridisation, which poses a challenge for conservation and wildlife management. Rates of introgression and the magnitude of associated demographic impacts vary widely across ecological contexts. However, the reasons for this variation remain poorly understood. One rarely considered phenomenon in this context is soft selection, wherein relative trait values determine success in intraspecific competition for a limiting resource. Here we develop an eco-genetic model explicitly focussed on understanding the influence soft selection has on the eco-evolutionary dynamics of wild populations experiencing intrusion from foreign/domesticated individuals. While based on a generalised salmonine lifecycle, the model is applicable to any taxon that experiences incursion from locally maladapted genotypes, in addition to phenotype-dependent competition for a limiting resource (e.g., breeding sites, feeding territories). The effects of both acute and chronic intrusion depended strongly on the relative competitiveness of intruders versus locals. When intruders were competitively inferior, soft selection limited their reproductive success (ability to compete for limited spawning sites), which prevented strong introgression or population declines from occurring. In contrast, when intruders were competitively superior, this amplified introgression and led to increased maladaptation of the admixed population. This had negative consequences for population size and population viability. The results were sensitive to the intrusion level, the magnitude of reproductive excess, trait heritability, and the extent to which intruders were maladapted relative to locals. Our findings draw attention to under- appreciated interactions between soft selection and maladaptive hybridisation, which may be critical to determining the impact captive breeding programmes and domesticated escapees can have on otherwise self-sustaining wild populations.

evolutionary biology↗

bioRxiv2022

Patching Science - amending the literature through version control

The ideal of self-correction in science is not well served by the current culture and system surrounding amendments to published literature. Here we report on a survey (N = 132) that highlights academics dissatisfaction with the status quo and their support for an alternative approach. We then describe our view of how amendments could and should work by drawing on the idea of an author-led version control system. Here authors would include a link in their published manuscripts to an updatable website (e.g. a GitHub repository or similar) that could be disseminated in the event of any amendment. Such a system is already in place for computer code and, as such, requires nothing but buy-in from the scientific community - a community that is already evolving towards various open science frameworks. This would remove a number of frictions that discourage amendments thus leading to an improved scientific literature and a healthier academic climate.

scientific communication and education↗

bioRxiv2022

Comparative analysis of the Illumina Mouse Methylation BeadChip and Reduced Representation Bisulphite Sequencing for routine DNA methylation analysis of murine samples

BackgroundResearching the murine epigenome in disease models has been hampered by the lack of an appropriate and cost-effective DNA methylation array. Until recently, investigators have been limited to the relatively expensive and analysis intensive bisulphite sequencing methods. Here, we performed a comprehensive, comparative analysis between the new Mouse Methylation BeadChip (MMB) and reduced representation bisulphite sequencing (RRBS) in two murine models of colorectal carcinogenesis, providing insight into the utility to each platforms in a real world environment. ResultsWe captured 1.47x106 CpGs by RRBS and 2.64x105 CpGs by MMB, mapping to 13,778 and 13,365 CpG islands, respectively. RRBS captured significantly more CpGs per island (median 41 for RRBS versus 2 for MMB). We found that 64.4% of intra-island CpG methylation variability can be captured by measuring approximately one quarter of CpG island (CGI) CpGs. MMB was more precise in measuring DNA methylation, especially at sites that had low RRBS coverage. This impacted differential methylation analysis, with more statistically significantly differentially methylated CpG sites identified by MMB in all experimental conditions, however the difference was minute when appropriate thresholding for the magnitude of methylation change (0.2 beta value difference) was applied, providing confidence that both techniques can identify similar differential DNA methylation. Gene ontology enrichment analysis of differentially hypermethylated gene promoters identified similar biological processes and pathways by both RRBS and MMB across two murine model systems. ConclusionMMB is an effective tool for profiling the murine methylome that performs comparably to RRBS, identifying similar differentially methylated pathways. Although MMB captures a similar proportion of CpG islands, it does so with fewer CpGs per island. We show that subsampling informative CpGs from CpG islands is an appropriate strategy to capture whole island variation. Choice of technology is experiment dependent and will be predicated on the underlying biology being probed.

genomics↗

bioRxiv2022

Measurements of damage and repair in aging mice and humans reveals that robustness and resilience decrease with age, operate over broad timescales, and are affected differently by interventions

As an organism ages, its health-state is determined by a balance between the processes of damage and repair. Measuring these processes requires longitudinal data. We extract damage and repair rates from repeated observations of health deficits in mice and humans to explore the contribution of robustness and resilience, which respectively decrease damage rates and increase repair rates, to aging health. We find a conserved decline with age in robustness and resilience in mice and humans, implying that both contribute to worsening health in aging. A decline in robustness, however, has a greater effect than a decline in resilience on accelerating damage accumulation with age, and a greater association with reduced survival. We also find that deficits are damaged and repaired over a wide range of timescales ranging from the shortest measurement scales towards organismal lifetime timescales. We explore the effect of systemic interventions that have been shown to improve health, including the angiotensin-converting enzyme inhibitor enalapril and voluntary exercise for mice, and household wealth for humans. We find that these interventions affect both damage and repair rates - but in different proportions for different interventions. These findings have implications for how health in aging, and interventions targeting health, are conceptualized and assessed.

systems biology↗

bioRxiv2020

Mechanosensation Mediates Long-Range Spatial Decision-Making in an Aneural Organism

The unicellular protist Physarum polycephalum is an important emerging model for understanding how aneural organisms process information toward adaptive behavior. Here, we reveal that Physarum can use mechanosensation to reliably make decisions about distant objects its environment, preferentially growing in the direction of heavier, substrate-deforming but chemically-inert masses. This long-range mass-sensing is abolished by gentle rhythmic mechanical disruption, changing substrate stiffness, or addition of a mechanosensitive transient receptor potential channel inhibitor. Computational modeling revealed that Physarum may perform this calculation by sensing the fraction of its growth perimeter that is distorted above a threshold strain - a fundamentally novel method of mechanosensation. Together, these data identify a surprising behavioral preference relying on biomechanical features and not nutritional content, and characterize a new example of an aneural organism that exploits physics to make decisions about growth and form. HighlightsO_LIThe aneural Physarum makes behavioral decisions by control of its morphology C_LIO_LIIt has a preference for larger masses, which it can detect at long range C_LIO_LIThis effect is mediated by mechanosensing, not requiring chemical attractants C_LIO_LIMachine learning reveals that it surveys environment and makes decision in < 4 hours C_LIO_LIA biophysical model reveals how its pulsations enable long-distance mapping of environmental features C_LI

animal behavior and cognition↗

bioRxiv2020

APC Mutation marks an aggressive subtype of BRAF mutant colorectal cancers that are associated with early-onset and dismal prognosis

Background & AimsWNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers. MethodsWe performed exome-sequencing on 24 BRAF mutant colorectal cancers and analysed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apcmin/+ and BrafV637/Villin-CreERT2/+ mouse, respectively. ResultsRNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (P< 2x10-5), advanced stage (P<0.01), and poor survival (P=0.026). Apcmin/+/BrafV637 animals had more numerous and larger SI and colonic lesions (P<0.0001 and P<0.05, respectively), and a markedly reduced survival (Median survival: 3.2 months, P=8.8x10-21) compared to animals with Apc or Braf mutation alone. ConclusionsThe WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome. SynopsisWe have comprehensively evaluated the somatic mutation landscape of WNT signaling regulators in serrated colorectal cancers. We identified a mosaic of mutations that may be responsible for elevating WNT signaling in this context. Approximately 20% of serrated colorectal cancers harbor truncating APC mutation, and these cancers confer extremely poor prognoses.

cancer biology↗

bioRxiv2019

Influence of plant genotype and soil on the wheat rhizosphere microbiome: identification of a core microbiome across eight African and European soils

Here, we assessed the relative influence of wheat genotype, agricultural practices (conventional vs organic) and soil type on the rhizosphere microbiome. We characterized the prokaryotic (archaea, bacteria) and eukaryotic (fungi, protists) communities in soils from four different countries (Cameroon, France, Italy, Senegal) and determined if a rhizosphere core microbiome existed across these different countries. The wheat genotype had a limited effect on the rhizosphere microbiome (2% of variance) as the majority of the microbial taxa were consistently associated to multiple wheat genotypes grown in the same soil. Large differences in taxa richness and in community structure were observed between the eight soils studied (57% variance) and the two agricultural practices (10% variance). Despite these differences between soils, we observed that 179 taxa (2 archaea, 104 bacteria, 41 fungi, 32 protists) were consistently detected in the rhizosphere, constituting a core microbiome. In addition to being prevalent, these core taxa were highly abundant and collectively represented 50% of the reads in our dataset. Based on these results, we identify a list of key taxa as future targets of culturomics, metagenomics and wheat synthetic microbiomes. Additionally, we show that protists are an integral part of the wheat holobiont that is currently overlooked. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/777383v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@dd56a6org.highwire.dtl.DTLVardef@163b5f7org.highwire.dtl.DTLVardef@13f6bd7org.highwire.dtl.DTLVardef@c10d9d_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2019

Development of a model estimating root length density from root impacts on a soil profile in pearl millet (Pennisetum glaucum (L.) R. Br). Application to measure root system response to water stress in field conditions

Pearl millet, unlike other cereals, is able to withstand dry and hot conditions and plays an important role for food security in arid and semi-arid areas of Africa and India. However, low soil fertility and drought constrain pearl millet yield. One of the main targets to address these constraints through agricultural practices or breeding is root system architecture. In this study, in order to easily phenotype the root system in field conditions, we developed a model to predict root length density (RLD) of pearl millet plants from root intersection densities (RID) counted on a trench profile in field conditions. We identified root orientation as an important parameter to improve the relationship between RID and RLD. Root orientation was notably found to differ between thick roots (more anisotropic with depth) and fine roots (isotropic at all depths). We used our model to study pearl millet root system response to drought and showed that pearl millet reorients its root growth toward deeper soil layers that retain more water in these conditions. Overall, this model opens ways for the characterization of the impact of environmental factors and management practices on pearl millet root system development.

plant biology↗