Biology subjects

French, L.

Publications and source records attributed to French, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Monocyte Lineage Expansion Drives Transcriptomic Individuality in Genetically Identical Armadillo Quadruplets

Genetic diversity shapes phenotypes, yet even genetically identical individuals differ. In nine-banded armadillo (Dasypus novemcinctus) quadruplets, we previously showed that allele-specific expression (ASE) imbalances provide a stable molecular fingerprint of individuality. Here, we test whether such transcriptomic individuality reflects functional biological differences. We profiled bulk blood RNA from five cohorts of genetically identical quadruplets across three time points, and found persistent gene-expression signatures that predict individual identity. Focusing on a highly variable cohort, we then performed single-cell RNA-seq and ATAC-seq. In this litter, the most stably distinct individual showed an expanded monocyte-lineage compartment and gene-expression programs enriched for inflammatory and differentiation pathways. These cell-type and regulatory differences were stable over time and robust to experimental leprosy infection. Together, our results link transcriptomic individuality to lasting differences in immune-cell composition, illustrating how early stochastic events can produce persistent, biologically meaningful divergence among genetically identical individuals. TeaserGenetically identical armadillo quadruplets are identifiable by transcriptomic signatures shaped by cellular composition variation.

molecular biology↗

bioRxiv2025

Cross-species consensus atlas of the primate basal ganglia

The basal ganglia (BG) are conserved brain regions essential for motor control, learning, emotion, and cognition, and are implicated in neurological and psychiatric disease. Yet a unified cross-species taxonomy of BG cell types is lacking, limiting translation of BG circuit mechanisms, interpretation of human genetic risk, and development of cell type-targeted tools. We present a multiomic consensus atlas of 1.8 million nuclei from human, macaque, and marmoset spanning eight BG structures. Integrating cross-species gene expression, open chromatin, and spatial profiling enables definition of conserved and divergent cell types. Alignment to existing mouse and human atlases identifies 61 homologous cell types conserved over 80 million years. We identify a STRd D2 StrioMat Hybrid medium spiny neuron (MSN) type with molecular, electrophysiological, and morphological features that clarify hybrid MSN identities. Comparative cis-regulatory analysis reveals conserved sequence grammars that encode cell identity and inform viral targeting strategies, providing a foundational resource for BG evolution, function, and disease.

neuroscience↗

bioRxiv2025

Anillin-dependent actin assembly at PML NBs protects genome stability

Nuclear filamentous actin (F-actin) is emerging as a key regulator of genome stability1-6. During replication stress, transient bursts of nuclear actin assembly in S-phase promote fork remodelling and repair3,4, but how these bursts are initiated, regulated, and whether nuclear F-actin also act on DNA lesions inherited across cell cycles, remains unknown. Here, we show that replication stress induces nuclear actin assembly at liquid-liquid phase-separated (LLPS) promyelocytic leukaemia nuclear bodies (PML NBs), driven by the actin-binding protein Anillin. Although best known as a cytokinesis factor, Anillin localises to PML NBs in interphase, where it concentrates monomeric actin (G-actin) and establishes a favourable environment for spontaneous actin assembly. Filament growth within these condensates remodels PML NB morphology and composition, releasing sequestered AKT into the nucleoplasm. AKT is subsequently phosphorylated and activated, and this nuclear AKT activity is required to regulate 53BP1 nuclear bodies in G1. These protective LLPS compartments shield under-replicated DNA inherited from the stressed S-phase until the following S-phase. This prevents premature engagement by aberrant repair pathways that would otherwise generate toxic intermediates and culminate in mitotic failure. Together, these findings define a condensate-to-filament pathway in which nuclear F-actin dynamically reorganises phase-separated compartments to safeguard genome stability across cell cycles.

cell biology↗

bioRxiv2025

Accurate spatial localization of Allen Human Brain Atlas gene expression data for human neuroimaging

The Allen Human Brain Atlas has been a tremendously impactful resource in neuroimaging. The usefulness of this resource in neuroimaging arises from spatial coordinates of dissected tissue samples being provided in relation to a Montreal Neurological Institute (MNI)-space standard brain template, thereby allowing for the integration of gene expression and spatially standardized neuroimaging data. In fact, two previous sets of spatial coordinates exist, and surprisingly, the accuracy of these coordinates in placing dissected tissue samples in correct anatomical locations within MNI-space have not been examined. Here, we show that there are significant inaccuracies in the two previous sets of coordinates, and provide a refined set of coordinates as a resource to the neuroscience community. We show (through analyses of meta-analytic data and a re-analysis of real study data) that using previous inaccurate coordinates can result in dramatically different genes being identified, which could compromise further downstream analyses.

neuroscience↗

bioRxiv2025

Cluster replicability in single-cell and single-nucleus atlases of the mouse brain

Single-cell RNA sequencing has advanced our understanding of cellular heterogeneity. Ensuring the replicability of identified cell clusters across studies is essential for determining their biological robustness. We assess the replicability of cell clusters identified in two large mouse brain atlases, one generated using single-cell RNA sequencing and the other with single nuclei. Both profile over 4 million cells and group them into over 5000 clusters. Using transcriptome-wide neighbor voting, we identify 2009 reciprocally matched cluster pairs with consistent spatial localization and coordinated gene expression, which were also observed in datasets from multiple species. Reciprocal clusters are enriched in the cerebellum, where lower diversity aids replicability, while the hypothalamuss heterogeneity limits agreement. Distinguishing close clusters is much more challenging than differentiating a cluster from most others, especially when using marker genes. By incorporating replicability data, we provide a stronger foundation for investigating the newly identified clusters and their biological meaning.

neuroscience↗

bioRxiv2024

Cross-expression analysis reveals patterns of coordinated gene expression in spatial transcriptomics

Spatial transcriptomics promises to transform our understanding of tissue biology by molecularly profiling individual cells in situ. A fundamental question they allow us to ask is how nearby cells orchestrate their gene expression. Rather than focus on how these cells (samples) communicate with each other, we reframe the problem to investigate how genes (features) coordinate their expression between neighboring cells. To study these phenomena - called cross-expression - we compare all genes to find pairs that coordinate their expression between adjacent cells, thereby avoiding curating gene lists or annotating cell types. Our end-to-end method recovers ligand-receptor pairs as cross-expressing genes and finds gene combinations that mark anatomical regions, complementing marker gene-based region annotation. Leveraging the overlapping genes across different panels, we use multiple atlas-scale adult mouse brain datasets (~25 million cells, 695 samples, 8 technologies) to create an integrated, meta-analytic cross-expression network, whose communities are enriched in spatial processes such as synaptic signaling and G protein coupled receptor activity. Highlighting cross-expressions biological utility, our network shows that genes Drd1 and Gpr6, which are individually implicated in Parkinsons disease (PD) and are being pursued as therapeutic targets, are cross-expressed within the striatum, hinting at their joint role in PD pathophysiology. We provide an efficient R package (https://github.com/gillislab/CrossExpression/) to computationally analyze and visually explore cross-expression patterns, which allow us to better understand how genes coordinate their expression in space to perform tissue-level functions.

bioinformatics↗

bioRxiv2024

Homologous recombination promotes mitotic death to suppress the innate immune response

Double strand breaks (DSBs) can initiate mitotic catastrophe, a complex oncosuppressive phenomenon characterized by cell death during or after cell division. Through single-cell analysis of extended live imaging, we unveiled how cell cycle-regulated DSB repair guides disparate mitotic catastrophe outcomes. Our data reveal that toxic double Holliday junctions (dHjs) generated during homologous recombination (HR) promote non-immunogenic intrinsic apoptosis in the immediate mitosis after S or G2-phase DSB induction. Conversely, the combined activity of non-homologous end joining (NHEJ), microhomology mediated end joining (MMEJ), and single strand annealing (SSA) enable G1 phase cells to tolerate high DSB loads at the cost of aberrant cell division, innate immune response activation and delayed extrinsic lethality. Targeting NHEJ, MMEJ, or SSA promotes HR-dependent mitotic death, while suppressing mitotic death fosters a robust immunogenic response. Together the data indicate that a temporal repair hierarchy, coupled with cumulative DSB load, serves as a reliable predictor of mitotic catastrophe outcomes. In this pathway, HR suppress the innate immune response by promoting mitotic lethality.

cell biology↗

bioRxiv2022

Organization of thalamocortical structural covariance and a corresponding 3D atlas of the mouse thalamus

For information from sensory organs to be processed by the brain, it is usually passed to appropriate areas of the cerebral cortex. Almost all of this information passes through the thalamus, a relay structure that reciprocally connects to the vast majority of the cortex. The thalamus facilitates this information transfer through a set of thalamocortical connections that vary in cellular structure, molecular profiles, innervation patterns, and firing rates. Additionally, corticothalamic connections allow for intracortical information transfer through the thalamus. These efferent and afferent connections between the thalamus and cortex have been the focus of many studies, and the importance of cortical connectivity in defining thalamus anatomy is demonstrated by multiple studies that parcellate the thalamus based on cortical connectivity profiles. Here, we examine correlated morphological variation between the thalamus and cortex, or thalamocortical structural covariance. For each voxel in the thalamus as a seed, we construct a cortical structural covariance map that represents correlated cortical volume variation, and examine whether high structural covariance is observed in cortical areas that are functionally relevant to the seed. Then, using these cortical structural covariance maps as features, we subdivide the thalamus into six non-overlapping regions (clusters of voxels), and assess whether cortical structural covariance is associated with cortical connectivity that specifically originates from these regions. We show that cortical structural covariance is high in areas of the cortex that are functionally related to the seed voxel, cortical structural covariance varies along cortical depth, and sharp transitions in cortical structural covariance profiles are observed when varying seed locations in the thalamus. Subdividing the thalamus based on structural covariance, we additionally demonstrate that the six thalamic clusters of voxels stratify cortical structural covariance along the dorsal-ventral, medial-lateral, and anterior-posterior axes. These cluster-associated structural covariance patterns are prominently detected in cortical regions innervated by fibers projecting out of their related thalamic subdivisions. Together, these results advance our understanding of how the thalamus and the cortex couple in their volumes. Our results indicate that these volume correlations reflect functional organization and structural connectivity, and further provides a novel segmentation of the mouse thalamus that can be used to examine thalamic structural variation and thalamocortical structural covariation in disease models.

neuroscience↗

bioRxiv2021

LaminaRGeneVis: a tool to visualize gene expression across the laminar architecture of the human neocortex

Application of RNA sequencing has enabled the characterization of genome-wide gene expression in the human brain, including distinct layers of the neocortex. Neuroanatomically, the molecular patterns that underlie the laminar organization of the neocortex can help link structure to circuitry and function. To advance our understanding of cortical architecture, we created LaminaRGeneVis, a web application that displays across-layer cortical gene expression from multiple datasets. These datasets were collected using bulk, single-nucleus, and spatial RNA sequencing methodologies and these data were harmonized to facilitate comparisons between datasets. The online resource facilitates single- and multi-gene analyses by providing figures and statistics for user-friendly assessment of laminar gene expression patterns in the adult human neocortex. Availability and implementationLaminaRGeneVis is available at https://ethanhkim.shinyapps.io/laminargenevis. The source code and data is accessible at https://github.com/ethanhkim/laminargenevis.

neuroscience↗

bioRxiv2021

Evaluation of deep convolutional neural networks for in situ hybridization gene expression image representation

High resolution in situ hybridization (ISH) images of the brain capture spatial gene expression at cellular resolution. These spatial profiles are key to understanding brain organization at the molecular level. Previously, manual qualitative scoring and informatics pipelines have been applied to ISH images to determine expression intensity and pattern. To better capture the complex patterns of gene expression in the human cerebral cortex, we applied a machine learning approach. We propose gene re-identification as a contrastive learning task to compute representations of ISH images. We train our model on a ISH dataset of ~1,000 genes obtained from postmortem samples from 42 individuals. This model reaches a gene re-identification rate of 38.3%, a 13x improvement over random chance. We find that the learned embeddings predict expression intensity and pattern. To test generalization, we generated embeddings in a second dataset that assayed the expression of 78 genes in 53 individuals. In this set of images, 60.2% of genes are re-identified, suggesting the model is robust. Importantly, this dataset assayed expression in individuals diagnosed with schizophrenia. Gene and donor-specific embeddings from the model predict schizophrenia diagnosis at levels similar to that reached with demographic information. Mutations in the most discriminative gene, SCN4B, may help understand cardiovascular associations with schizophrenia and its treatment. We have publicly released our source code, embeddings, and models to spur further application to spatial transcriptomics. In summary, we propose and evaluate gene re-identification as a machine learning task to represent ISH gene expression images.

neuroscience↗

bioRxiv2020

A pH-eQTL interaction at the RIT2-SYT4 Parkinson's disease risk locus in the substantia nigra

Parkinsons disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinsons disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. To assess these pH associations in relation to PD risk, we examined the two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain (n=100). Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the GTEx dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 was not seen. This null finding may be due to the short postmortem intervals (PMI) of the GTEx tissue samples. In the BrainEAC data, we tested the effect of PMI and only observed the interactions in the longer PMI samples. These previously unknown associations suggest novel mechanistic roles for rs12456492, RIT2, and SYT4 in the regulation of pH in the substantia nigra.

neuroscience↗

bioRxiv2020

Susceptibility to gingipains and transcriptomic response to P. gingivalis highlights the ribosome, hypothalamus, and cholinergic neurons

Porphyromonas gingivalis, a keystone species in the development of periodontal disease, is a suspected cause of Alzheimers disease. This bacterium is reliant on gingipain proteases, which cleave host proteins after arginine and lysine residues. To characterize gingipain susceptibility, we performed enrichment analyses of arginine and lysine proportion proteome-wide. Proteins in the SRP-dependent cotranslational protein targeting to membrane pathway were enriched for these residues and previously associated with periodontal and Alzheimers disease. These ribosomal genes are up-regulated in prefrontal cortex samples with detected P. gingivalis sequences. Other differentially expressed genes have been previously associated with dementia (ITM2B, MAPI, ZNF267, and DHX37). For an anatomical perspective, we characterized the expression of the P. gingivalis associated genes in the mouse and human brain. This analysis highlighted the hypothalamus, cholinergic neurons, and the basal forebrain. Our results suggest markers of neural P. gingivalis infection and link the gingipain and cholinergic hypotheses of Alzheimers disease.

genomics↗

bioRxiv2020

Differential and spatial expression meta-analysis of genes identified in genome-wide association studies of depression

Major depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and affects individuals of all ages. It causes significant psychosocial impairments and is a major cause of disability. A recent consortium study identified 102 genetic variants and 269 genes associated with depression. To provide targets for future depression research, we prioritized these recently identified genes using expression data. We examined differential expression of these genes in three studies that profiled gene expression of MDD cases and controls across multiple brain regions. In addition, we integrated anatomical expression information to determine which brain regions and transcriptomic cell-types highly express the candidate genes. We highlight 11 of the 269 genes with the most consistent differential expression: MANEA, UBE2M, CKB, ITPR3, SPRY2, SAMD5, TMEM106B, ZC3H7B, LST1, ASXL3 and HSPA1A. The majority of these top genes were found to have sex-specific differential expression. We place greater emphasis on MANEA as it is the top gene in a more conservative analysis of the 269. Specifically, differential expression of MANEA was strongest in cerebral cortex regions and had opposing sex-specific effects. Anatomically, our results suggest the importance of the dorsal lateral geniculate nucleus, cholinergic, monoaminergic, and enteric neurons. These findings provide a guide for targeted experiments to advance our understanding of the genetic underpinnings of depression.

bioinformatics↗

bioRxiv2019

Transcriptomic analysis of brain hypometabolism links the cholinergic and gingipain hypotheses of Alzheimer's disease pathogenesis

Alzheimers disease (AD) starts decades before clinical symptoms appear. Low glucose utilization in regions of the cerebral cortex marks early AD and is clinically useful. To identify these regions, we conducted a voxel-wise meta-analysis of positron emission tomography studies that compared AD patients with healthy controls. This meta-analysis included 27 studies that assayed glucose utilization in 915 AD patients and 715 healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes with expression patterns associated with this hypometabolism pattern in the cerebral cortex. Of the six brains in the Atlas, one demonstrated a strong spatial association with the hypometabolism pattern. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when compared with the other five brains. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which primarily encode cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes progressively increases across AD-associated states of microglial activation. In addition, genes involved in cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, and vacuole sorting are associated with the hypometabolism map. These genes suggest disruption of the protein life cycle and neuroimmune activation. Taken together, our molecular characterization of cortical hypometabolism reveals a molecular link to AD associated hypometabolism that may be relevant to preclinical stages.

bioinformatics↗

bioRxiv2019

Cellular correlates of cortical thinning throughout the lifespan

Cortical thinning occurs throughout the entire life and extends to late-life neurodegeneration, yet the neurobiological substrates are poorly understood. Here, we used a virtual-histology technique and gene expression data from the Allen Human Brain Atlas to compare the regional profiles of longitudinal cortical thinning through life (4004 MRIs) with those of gene expression for several neuronal and non-neuronal cell types. The results were replicated in three independent longitudinal datasets. We found that inter-regional profiles of cortical thinning related to expression profiles for marker genes of CA1 pyramidal cells, astrocytes and microglia during development and in aging. During the two stages of life, the relationships went in opposite directions: greater gene expression related to less thinning in development and vice versa in aging. The association between cortical thinning and cell-specific gene expression was also present in mild cognitive impairment and Alzheimers Disease. These findings suggest a role of astrocytes and microglia in promoting and supporting neuronal growth and dendritic structures through life that affects cortical thickness during development, aging, and neurodegeneration. Overall, the findings contribute to our understanding of the neurobiology underlying variations in MRI-derived estimates of cortical thinning through life and late-life disease.

neuroscience↗

bioRxiv2018

White matter microstructure in women with acute and remitted anorexia nervosa: an exploratory neuroimaging study

Anorexia nervosa (AN) is a highly heritable psychiatric disorder characterized by starvation and emaciation and associated with changes in brain structure. The precise nature of these changes remains unclear, as does their developmental time course and capacity for reversal with weight restoration. In this exploratory neuroimaging study, we sought to characterize changes in white matter microstructure in women with acute and remitted AN. Diffusion-weighted MRI data was collected from underweight women with a current diagnosis of AN (acAN: n=23), weight-recovered women with a past diagnosis of AN (recAN: n=23), and age-matched healthy control women (HC: n=24). Image processing and analysis were performed with Tract-Based Spatial Statistics, part of FSL, and group differences in voxel-wise, brain-wide fractional anisotropy (FA) and mean diffusivity (MD), indices of white matter microstructure, were tested with nonparametric permutation and threshold free cluster enhancement. No significant main effect of group on FA was identified. A significant main effect of group on MD was observed in a large cluster covering 9.2% of white matter and including substantial portions of the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus, and post hoc analyses revealed similar effects of group on axial diffusivity (AD) and radial diffusivity (RD). Cluster-wise MD was significantly higher in acAN participants (+3.8%) and recAN participants (+2.9%) than healthy controls, and the same was true for cluster-wise AD and RD. Trait-based increases in diffusivity, consistent with atypical myelination and impaired axon integrity, suggest a link between altered white matter microstructure and vulnerability to AN, and evidence of reduced oligodendrocyte density in AN provides further support for this hypothesis. Potential mechanisms of action include atypical neurodevelopment and systemic inflammation.

neuroscience↗

bioRxiv2018

Molecular neuroanatomy of anorexia nervosa

Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using unbiased genome-wide methods, recent studies have associated a variety of genes with the disorder. We characterized these genes by projecting them into aggregated gene expression data from reference transcriptomic atlases of the prenatal and adult human brain. We found that genes from an induced stem cell study of anorexia nervosa are expressed at higher levels in the lateral parabrachial and the ventral tegmental areas. The adult expression enrichment of the lateral parabrachial is confirmed with genes from two independent genetic studies. In the fetal brain, enrichment of the ventral tegmental area is also observed for the six genes near the only common variant associated with the disorder (rs4622308). We also observed signals in the adult and fetal pontine raphe, but they were not observed when using the genes from the genetic studies. In addition to signals related to calcitonin gene-related peptide neurons and the tachykinin, we found more than the expected number of microglia marker genes within the gene sets. Using mouse transcriptomic data, we identified several anorexia nervosa associated genes that are differentially expressed during food deprivation. While these genes that respond to fasting are not enriched in the gene sets, we highlight RPS26 which is proximal to rs4622308. We did not observe expression enrichment in the cingulate cortex or hypothalamus suggesting other targets for deep brain stimulation should be considered for severe cases. This work improves our understanding of the neurobiological causes of anorexia nervosa by suggesting disturbances in subcortical appetitive circuits.

neuroscience↗

bioRxiv2018

BDNF controls neuropsychiatric manifestation via autophagic regulation of p62 and GABAA receptor trafficking

Reduced BDNF and GABAergic inhibition co-occur in neuropsychiatric diseases, including major depression. Genetic rodent studies show a causal link, suggesting the presence of biological pathways that mediate this co-occurrence. Here we show that mice with reduced Bdnf (Bdnf+/-) have upregulated expression of sequestosome-1/p62, an autophagy-associated stress response protein, and reduced surface presentation of 5 subunit-containing GABAA receptor (5-GABAAR) in prefrontal cortex (PFC) pyramidal neurons. Reducing p62 gene dosage restored 5-GABAAR surface expression and rescued the PFC-relevant behavioral deficits of Bdnf+/- mice, including cognitive inflexibility and sensorimotor gating deficits. Increasing p62 levels was sufficient to recreate the molecular and behavioral profiles of Bdnf+/- mice. Finally, human postmortem corticolimbic transcriptome analysis suggested reduced autophagic activity in depression. Collectively, the data reveal that autophagy regulation through control of p62 dosage may serve as a mechanism linking reduced BDNF signaling, GABAergic deficits, and psychopathology associated with PFC functional deficits across psychiatric disorders.\n\nHIGHLIGHTSBDNF constitutively promotes autophagy in cortical pyramidal neurons\n\nReduced BDNF causes elevated autophagy-regulator p62 expression, leading to lower surface 5-GABAAR presentation\n\nIncreasing p62 levels mimics cognition-related behavioral deficits in Bdnf+/- mice\n\nAltered postmortem corticolimbic gene expression suggests reduced autophagic activity in depression

neuroscience↗