Biology subjects

McCarroll, S. A.

Publications and source records attributed to McCarroll, S. A..

At least 19 recordsLinked to original sources

bioRxiv2026

A multi-omic atlas in the African turquoise killifish reveals increased glucocorticoid signaling as a hallmark of brain aging

Aging is the leading risk factor for cognitive impairment and neurodegeneration, yet molecular changes that unfold in the brain over time, and how they drive this vulnerability, remain unclear. The naturally short-lived African turquoise killifish (Nothobranchius furzeri) offers a powerful model to understand brain aging on an accelerated timescale and test the impact of potential interventions. Here, we present a multi-omic atlas of brain aging of female and male African turquoise killifish from 2 independent genetic strains of different captive lifespans, encompassing single-nuclei RNA-seq, single nuclei ATAC-seq, and bulk ATAC-seq to capture transcriptional and regulatory changes. Interestingly, our atlas indicates that aging leads to a significant expansion of microglia numbers, regardless of sex or strain, which we independently validate using in-situ hybridization. In addition, we identify robust and conserved gene regulation changes, that are consistent with activation of glucocorticoid signalling as a hallmark (and potential driver) of vertebrate brain aging. Furthermore, pharmacological inhibition of glucocorticoid receptor activity starting at middle-age led to significant rescue of key molecular and cellular aging phenotypes. Thus, our study provides a powerful resource and framework to leverage the African turquoise killifish and rapidly uncover actionable pathways driving brain aging.

neuroscience↗

bioRxiv2026

Inter-individual variation of cellular and gene-expression properties of the human striatum

The human brain varies from person to person in ways that shape behaviors and vulnerabilities, yet the cellular and molecular bases for inter-individual variation are largely unknown. Here we describe an analysis of cellular and gene-expression variation in four key structures of the striatum complex - the caudate, putamen, nucleus accumbens, and internal capsule - as well as the prefrontal cortex, from single-nucleus RNA-seq analysis of 3.9 million nuclei from 178 adult brain donors. We found that people with more astrocytes in any one brain region tended to have this property in all brain regions sampled; the same was true of striatal interneurons, microglia, and oligodendrocyte precursor cells (OPCs). OPCs showed attrition with age, declining in numbers by approximately 40% between age 30 and age 80 in both gray matter and white matter regions. We identified thousands of age-associated (but few sex-associated) variations in gene expression; the vast majority of these effects of age were cell-type-specific. Aging most strongly affected gene expression in projection neurons - especially striatal medium spiny neurons (MSNs/SPNs) - and had a much smaller effect on gene expression in interneurons. Individuals ages could be predicted to within about five years based on RNA-expression patterns from any of the striatal cell types. Common genetic variants detectably affected the expression levels of some ten thousand genes; the great majority of these effects were cell-type-specific. These data will provide a foundation for exploring natural inter-individual variation, aging, and tissue-based studies of human brain vulnerabilities.

neuroscience↗

bioRxiv2026

Mesoscale molecular architecture of the human striatum across cell types and lifespan

The human striatum is a central hub for a diverse array of motor, cognitive, and affective behaviors, yet it lacks obvious cytoarchitectural boundaries that define functional territories. Here, we uncover a robust and molecularly defined mesoscale architecture in the human striatum. Using Slide-tags, a scalable single-nucleus spatial transcriptomics technology, we profiled 1.1 million cells across the full span of the anterior striatum of 19 postmortem donors, spatially mapping all striatal populations. Our data uncover a natural subdivision of the striatum into six zones, each defined by molecularly distinct populations of medium spiny neurons, and featuring spatially coordinated neuron-astrocyte signaling. Relative to MSNs in ventral zones, MSNs in dorsal zones exhibit higher expression of genes for synaptic remodeling and plasticity via ephrin and TGF-beta, while the ventral zone is defined by greater expression of semaphorin, protein chaperone, and hedgehog signaling pathways. By imputing zonal identities onto a larger single-nucleus RNA-seq cohort of 131 donors, we find that the dorsal zones exhibit greater age-related transcriptional changes, and that overall, the gene-expression differences that define spatial zonation patterns are attenuated with advancing age. This atlas provides a mesoscale molecular definition of human striatal anatomy, linking cell type identity to functional specialization and aging susceptibility.

neuroscience↗

bioRxiv2026

A supervised ontology-aware cell annotation method forsingle-cell transcriptomic data

Many single-cell RNA-seq annotation methods ignore the hierarchical nature of cell type classification. We present a probability propagation strategy that enforces ontological consistency and improves performance when applied to existing models without retraining. Combined with a lightweight logistic regression model trained on 42 million human cells, this yields SOCAM, a fast and interpretable classifier. We also introduce a hop-based F1 score for ontology-aware evaluation. Code and models are available open source.

bioinformatics↗

bioRxiv2025

A shared DNA-repeat toxicity threshold, reached somatically at cell-type-specific rates, unites cortical and striatal neurodegeneration in Huntingtons disease

Huntingtons disease (HD) affects two major brain areas - the striatum and cerebral cortex - in ways that differ in timing, severity, and gene-expression changes. For these reasons, and because many cortical neurons project axons to the affected striatal neurons, striatal and cortical atrophy have long been proposed to have distinct mechanisms, with one potentially a secondary consequence of the other. In the striatum, we recently found that neurons degenerate asynchronously as their own huntingtin (HTT) gene CAG-repeat tracts, typically inherited at 40-50 CAGs, expand somatically beyond 150 CAGs. To ask whether a similar or different dynamic affects the cerebral cortex, we analyzed HTT CAG repeats and genome-wide RNA expression together in more than 130,000 nuclei from 12 cortical areas of brain donors with HD. The resulting data revealed that cortical and striatal neurodegeneration in fact result from analogous sequences of cell-autonomous events, each instructed by somatic expansion of a neurons own HTT CAG repeat. Analyses revealed that somatic expansion beyond a high toxicity threshold (of about 150 CAGs) is necessary and sufficient to initiate pathological changes; that this pathogenicity length threshold is shared by striatal and cortical projection neurons of all types; and that cortical area, cortical layer, and axonal projections play only incidental roles, as proxies for the true driver: profound (up to 50-fold) variation among types and subtypes of pyramidal neurons in the likelihood of reaching the 150-CAG toxicity threshold in a human lifetime. These results also suggest that containing somatic DNA-repeat expansion below this high toxicity threshold would protect both brain areas in HD.

genetics↗

bioRxiv2025

Gene editing in "cell villages" enables exploring disease-relevant mutations in many genetic backgrounds

Understanding how individual genetic backgrounds shape the effects of disease-associated mutations is central to elucidating the biology of complex psychiatric disorders. We developed a scalable village editing strategy that enables simultaneous genome editing across multiple induced pluripotent stem cell (iPSC) lines, allowing systematic assessment of how polygenic context modulates the impact of specific mutations. Using pooled CRISPR editing in 15 iPSC lines spanning a range of schizophrenia (SCZ) polygenic risk scores, we generated homozygous and heterozygous knockouts in two known SCZ-associated genes: LRP1, involved in cholesterol import, and NRXN1, a presynaptic adhesion molecule. By mixing all lines prior to editing and de-multiplexing them afterward, we efficiently produced multi-donor knockout neurons at scale. Transcriptomic profiling revealed that LRP1 and NRXN1 loss produce both shared and donor-specific effects on neuronal gene expression, with variable perturbation of neurotransmitter transport and cholesterol biosynthesis pathways across genetic backgrounds. These results demonstrate that village editing enables systematic dissection of gene-background interactions in human neurons, offering a powerful framework for studying the polygenic architecture of psychiatric disease.

cell biology↗

bioRxiv2025

Genes and environment profoundly affect the human virome

Many viruses have adapted to persist in infected humans for life1,2. Variable host control of their ongoing abundance ("load") can lead to clearance or disease3-5. We analyzed the viral DNA load of 31 common viruses in human blood and saliva using whole-genome sequencing data from UK Biobank (n=490,401), All of Us (n=414,817), and SPARK (n=12,519). Viral DNA load varied markedly with age, time of day, and season; most viruses were also present at greater abundance in men than in women. Human genetic variation at dozens of loci associated with DNA load of seven viruses: Epstein-Barr virus (EBV, 45 loci), human herpesvirus 7 (HHV-7, 37 loci), HHV-6B, Merkel cell polyomavirus, and three anelloviruses. Variation at the major histocompatibility complex (MHC) locus generated the strongest associations (p = 5.8x10-9 to 2.5x10-1459), which were specific to each virus. The HLA-B*08:01 allele also exhibited a host-virus genetic interaction with EBV subtype (p = 7.4x10-70). Other human genetic effects implicated genes encoding proteins that process peptides for antigen presentation, such as ERAP1 (HHV-7, p = 2.7x10-78) and ERAP2 (EBV, p = 4.6x10-111). Mendelian randomization analyses supported a strong causal effect of EBV DNA load on increased risk of Hodgkin lymphoma (p = 1.8x10-3) but not multiple sclerosis (p = 0.52). This suggests that higher chronic EBV load increases lymphoma risk, whereas associations of EBV infection with autoimmune conditions reflect host immune responses to particular viral epitopes.

genetics↗

bioRxiv2025

Genetics-to-structure multiscale analysis identifies disrupted calcium homeostasis as a mechanism of psychiatric disease

Neuropsychiatric disorders are highly heritable, but the molecular mechanisms linking risk variants to disease remain unclear1. Linking genetics to biological mechanisms requires integrating evidence across scales, from sequence variation to gene regulation to protein function. Here we integrate genetic, transcriptomic, and structural evidence to identify dysregulation of neuronal Ca2+ dynamics as a contributing mechanism. We analyzed single-nucleus neuronal RNA-seq data together with genome-wide association study (GWAS) heritability in a new way to identify gene expression programs enriched for psychiatric risk; genes encoding Ca2+ flux pathway genes were implicated by this analysis, a result that was then confirmed by concentrations of rare coding variants in these same genes in persons with psychiatric disorders. A critical gene in this biology, ATP2B2, encodes a Ca2+-extruding ATPase pump2 linked to neuropsychiatric disorders primarily through missense variants. To recognize specific molecular functions affected by these missense variants, we developed a 3D-neighborhood-based method that maps missense variants onto AlphaFold3-predicted protein structures and tests clustering of protein-altering variants in three-dimensional space. This approach revealed clustering of these missense changes in the Ca2+ pore and ATP:Mg2+ coordination site of ATP2B2. To validate the structural predictions arising from the genetic analysis, we determined the structure of human Ca2+-bound ATP2B2 at 2.64 [A] resolution by cryogenic electron microscopy. The structure replicated the 3D mutational hotspots identified by the genetic analysis, supporting the observation that neuropsychiatric variants cluster near specific catalytic sites of ATP2B2. In vitro experiments revealed that missense variants prioritized by the structural clustering analysis impaired ATP2B2-mediated Ca2+ extrusion in cellular and biochemical assays. Together, these findings suggest that precise regulation of Ca2+ dynamics is a contributing mechanism in neuropsychiatric disorders and establish a structure-based framework for predicting the mechanistic impact of missense variants.

genetics↗

bioRxiv2025

Human genetic variation shapes the response of neurons to interferons

Inflammation is increasingly recognized as important to neuropathology, including more classic neuroimmune disease as well as neurodegenerative and neuropsychiatric disorders. Interferons (IFN) are important mediators of central nervous system inflammation. Individuals appear to vary in susceptibility to neuroinflammatory pathology, suggesting that identifying human genetic modifiers of the neuronal IFN response might provide insight into disease pathophysiology. To identify potential modifiers, we stimulated neuronal "cellular villages" of iPSC-derived neurons from over one hundred donors with IFN-alpha (IFNa) or IFN-gamma (IFNg). We then correlated allele states of common variable SNPs to gene expression to identify hundreds of expression quantitative trait loci (eQTLs), many of which emerged specifically upon IFN treatment. We characterized the distinct but overlapping neuronal transcriptional responses to IFNa and IFNg, and identified specific response QTLs. Functional annotation of STAT1 binding to the genome in response to IFN stimulus identified STAT1 binding sites as enriched for response-regulating human genetic variation and also enabled identification of loci with IFN-dependent allele-specific binding of STAT1. These results demonstrate how human genetic variation can influence IFN-dependent mechanisms in neurons in disease-relevant ways.

molecular biology↗

bioRxiv2025

Astrocytic-supplied cholesterol drives synaptic gene expression programs in developing neurons and downstream astrocytic transcriptional programs

Astrocytes participate in neuronal synaptic programs that are enriched for genetic associations in schizophrenia and autism spectrum disorders (ASD). To better understand how these co-regulated cellular programs are induced during early neuronal development, we studied astrocytes and iPSC-derived neurons in co-cultures and mono-cultures at 16 time points spanning 0.5 hours to 8 days. We found that upregulation in astrocytes of genes involved in cholesterol biosynthesis preceded the activation of synaptic gene programs in neurons and upregulation of the astrocytic Nrxn1. Neuronal knockdown of key cholesterol receptors led to downregulation of neuronal synaptic genes and induced a robust transcriptional response in the astrocytes, including further upregulation of Nrxn1. This suggests that astrocyte-supplied cholesterol drives these neuronal changes and that bi-directional signalling is occuring. The genes upregulated in neurons were enriched for deleterious variants in schizophrenia and neurodevelopmental disorders, suggesting that their pathogenic effect may be, in part, mediated by reduced buffering capacity for changes in the astrocyte cholesterol supply to neurons. These findings highlight the critical role of astrocyte-neuron interactions in psychiatric and neurodevelopmental disorders, particularly in relation to lipid metabolism and synaptic plasticity.

molecular biology↗

bioRxiv2024

Insights into the causes and consequences of DNA repeat expansions from 700,000 biobank participants

Expansions and contractions of tandem DNA repeats are a source of genetic variation in human populations and in human tissues: some expanded repeats cause inherited disorders, and some are also somatically unstable. We analyzed DNA sequence data, derived from the blood cells of >700,000 participants in UK Biobank and the All of Us Research Program, and developed new computational approaches to recognize, measure and learn from DNA-repeat instability at 15 highly polymorphic CAG-repeat loci. We found that expansion and contraction rates varied widely across these 15 loci, even for alleles of the same length; repeats at different loci also exhibited widely variable relative propensities to mutate in the germline versus the blood. The high somatic instability of TCF4 repeats enabled a genome-wide association analysis that identified seven loci at which inherited variants modulate TCF4 repeat instability in blood cells. Three of the implicated loci contained genes (MSH3, FAN1, and PMS2) that also modulate Huntingtons disease age-at-onset as well as somatic instability of the HTT repeat in blood; however, the specific genetic variants and their effects (instability-increasing or-decreasing) appeared to be tissue-specific and repeat-specific, suggesting that somatic mutation in different tissues--or of different repeats in the same tissue--proceeds independently and under the control of substantially different genetic variation. Additional modifier loci included DNA damage response genes ATAD5 and GADD45A. Analyzing DNA repeat expansions together with clinical data showed that inherited repeats in the 5 UTR of the glutaminase (GLS) gene are associated with stage 5 chronic kidney disease (OR=14.0 [5.7-34.3]) and liver diseases (OR=3.0 [1.5-5.9]). These and other results point to the dynamics of DNA repeats in human populations and across the human lifespan.

genetics↗

bioRxiv2024

Transcriptome-wide characterization of genetic perturbations

Single cell CRISPR screens such as Perturb-seq enable transcriptomic profiling of genetic perturbations at scale. However, the data produced by these screens are often noisy due to cost and technical constraints, limiting power to detect true effects with conventional differential expression analyses. Here, we introduce TRanscriptome-wide Analysis of Differential Expression (TRADE), a statistical framework which estimates the transcriptome-wide distribution of true differential expression effects from noisy gene-level measurements. Within TRADE, we derive multiple novel, interpretable statistical metrics, including the "transcriptome-wide impact", an estimator of the overall transcriptional effect of a perturbation which is stable across sampling depths. We analyze new and published large-scale Perturb-seq datasets to show that many true transcriptional effects are not statistically significant, but detectable in aggregate with TRADE. In a genome-scale Perturb-seq screen, we find that a typical gene perturbation affects an estimated 45 genes, whereas a typical essential gene perturbation affects over 500 genes. An advantage of our approach is its ability to compare the transcriptomic effects of genetic perturbations across contexts and dosages despite differences in power. We use this ability to identify perturbations with cell-type dependent effects and to find examples of perturbations where transcriptional responses are not only larger in magnitude, but also qualitatively different, as a function of dosage. Lastly, we expand our analysis to case/control comparison of gene expression for neuropsychiatric conditions, finding that transcriptomic effect correlations are greater than genetic correlations for these diagnoses. TRADE lays an analytic foundation for the systematic comparison of genetic perturbation atlases, as well as differential expression experiments more broadly.

genomics↗

bioRxiv2024

Dopamine D1 receptor expression in dlPFC inhibitory parvalbumin neurons may contribute to higher visuospatial distractibility in marmosets versus macaques

Marmosets and macaques are common non-human primate models of cognition, yet marmosets appear more distractible and perform worse in cognitive tasks. The dorsolateral prefrontal cortex (dlPFC) is pivotal for sustained attention, and prior macaque research suggests that dopaminergic modulation and inhibitory parvalbumin (PV) neurons could contribute to distractibility. Thus, we compared the two species using a visual fixation task with distractors, performed molecular and anatomical analyses in dlPFC, and linked functional microcircuitry with cognitive performance using computational modeling. We found that marmosets are more distractible than macaques, and that marmoset dlPFC PV neurons contain higher levels of dopamine-1 receptor (D1R) transcripts and protein, similar to their levels in mice. The modeling indicated that higher D1R expression in marmoset dlPFC PV neurons may increase distractibility by making dlPFC microcircuits more vulnerable to disruptions of their task-related persistent activity, especially when dopamine is released in dlPFC in response to unexpected salient stimuli. Declaration of InterestsThe authors have nothing to declare. Author ContributionsAFTA, MKPJ, TGI, and SFW designed the study; MKPJ collected and analyzed anatomical data; TGI designed the computational framework with guidance from RG and SFW; TGI performed the modeling simulations and data analysis; FM and SAM collected and analyzed transcriptomics data; GGB and DAL provided macaque brain tissue for transcriptomics performed by FM; SM and NS collected and analyzed phylogenetic transcriptomics dataset; JFM and ASN performed and analyzed the behavioral testing; IW and JMT provided the marmoset tissue for immunofluorescence; MKPJ, TGI, SFW, and AFTA wrote the first draft and all authors revised and edited subsequent drafts of the article.

neuroscience↗

bioRxiv2024

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition

Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimers disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and 7-nicotinic receptors (nic-7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.

neuroscience↗

bioRxiv2024

Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease

Huntington Disease (HD) is a fatal genetic disease in which most striatal projection neurons (SPNs) degenerate. The central biological question about HD pathogenesis has been how the disease-causing DNA repeat expansion (CAGn) in the huntingtin (HTT) gene leads to neurodegeneration after decades of apparent latency. Inherited HTT alleles with a longer CAG repeat hasten disease onset; the length of this repeat also changes over time, generating somatic mosaicism, and genes that regulate DNA-repeat stability can influence HD age-at-onset. To understand the relationship between a cells CAG-repeat length and its biological state, we developed a single-cell method for measuring CAG-repeat length together with genome-wide RNA expression. We found that the HTT CAG repeat expands from 40-45 CAGs to 100-500+ CAGs in HD-vulnerable SPNs but not in other striatal cell types, with these long DNA-repeat expansions acquired at different times by individual SPNs. Surprisingly, somatic expansion from 40 to 150 CAGs had no apparent effect upon gene expression - but neurons with 150-500+ CAGs shared profound gene-expression changes. These expression changes involved hundreds of genes, escalated alongside further CAG-repeat expansion, eroded positive and then negative features of neuronal identity, and culminated in expression of senescence/apoptosis genes. Rates of striatal neuron loss across HD stages reflected the rates at which neurons entered this biologically distorted state. Our results suggest that HTT CAG repeats in striatal neurons undergo decades of biologically quiet expansion, then, as they asynchronously cross a high threshold, cause SPNs to degenerate quickly and asynchronously. We conclude that, at any moment in the course of HD, most neurons have an innocuous (but unstable) huntingtin gene, and that HD pathogenesis is a DNA process for almost all of a neurons life.

genetics↗

bioRxiv2024

Modeling interpretable correspondence between cell state and perturbation response with CellCap

Single-cell transcriptomics, in conjunction with genetic and compound perturbations, offers a robust approach for exploring cellular behaviors in diverse contexts. Such experiments allow un-covering cell-state-specific responses to perturbations, a crucial aspect in unraveling the intricate molecular mechanisms governing cellular behavior and potentially discovering novel regulatory pathways and therapeutic targets. However, prevailing computational methods predominantly focus on predicting average cellular responses, disregarding the inherent response heterogeneity associated with cell state diversity. In this study, we present CellCap, a deep generative model designed for the end-to-end analysis of single-cell perturbation experiments. CellCap employs sparse dictionary learning in a latent space to deconstruct cell-state-specific perturbation responses into a set of transcriptional response programs. These programs are then utilized by each perturbation condition and each cell at varying degrees. The incorporation of specific model design choices, such as dot-product cross-attention between cell states and response programs, along with a linearly-decoded latent space, underlay the interpretation power of CellCap. We evaluate CellCaps model interpretability through multiple simulated scenarios and apply it to two real single-cell perturbation datasets. These datasets feature either heterogeneous cellular populations or a complex experimental setup. Our results demonstrate that CellCap successfully uncovers the relationship between cell state and perturbation response, unveiling novel insights overlooked in previous analyses. The models interpretability, coupled with its effectiveness in capturing heterogeneous responses, positions CellCap as a valuable tool for advancing our understanding of cellular behaviors in the context of perturbation experiments.

bioinformatics↗

bioRxiv2024

Concerted neuron-astrocyte gene expression declines in aging and schizophrenia

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a striking relationship between peoples cortical neurons and cortical astrocytes. We used single-nucleus RNA-seq to analyze the prefrontal cortex of 191 human donors ages 22-97 years, including healthy individuals and persons with schizophrenia. Latent-factor analysis of these data revealed that in persons whose cortical neurons more strongly expressed genes for synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the Synaptic Neuron- and-Astrocyte Program (SNAP). In schizophrenia and aging - two conditions that involve declines in cognitive flexibility and plasticity 1,2 - cells had divested from SNAP: astrocytes, glutamatergic (excitatory) neurons, and GABAergic (inhibitory) neurons all reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy persons of similar age, may underlie many aspects of normal human interindividual differences and be an important point of convergence for multiple kinds of pathophysiology.

neuroscience↗

bioRxiv2023

Sibling chimerism among microglia in marmosets

Chimerism happens rarely among most mammals but is common in marmosets and tamarins, a result of fraternal twin or triplet birth patterns in which in utero connected circulatory systems (through which stem cells transit) lead to persistent blood chimerism (12-80%) throughout life. The presence of Y-chromosome DNA sequences in organs of female marmosets has long suggested that chimerism might also affect these organs. However, a longstanding question is whether this chimerism is driven by blood-derived cells or involves contributions from other cell types. To address this question, we analyzed single-cell RNA-seq data from blood, liver, kidney and many brain regions across a number of marmosets, using transcribed single nucleotide polymorphisms (SNPs) to identify cells with the siblings genome in various cell types within these tissues. Sibling-derived chimerism in all tissues arose entirely from cells of hematopoietic origin (i.e., myeloid and lymphoid lineages). In brain tissue this was reflected as sibling-derived chimerism among microglia (20-52%) and macrophages (18-64%) but not among other resident cell types (neurons, glia or ependymal cells). The percentage of microglia that were sibling-derived showed significant variation across brain regions, even within individual animals, likely reflecting distinct responses by genetic-sibling microglia to local recruitment or proliferation cues or, potentially, distinct clonal expansion histories in different brain areas. In the animals and tissues we analyzed, microglial gene expression profiles bore a much stronger relationship to local/host context than to sibling genetic differences. Naturally occurring marmoset chimerism will provide new ways to recognize the effects of genes, mutations and brain contexts on microglial biology and to distinguish between effects of microglia and other cell types on brain phenotypes.

neuroscience↗