Biology subjects

Anderson, H.

Publications and source records attributed to Anderson, H..

12 recordsLinked to original sources

bioRxiv2026

A multimodal interrogation of Broca's area in the pediatric and adult human brain

Language is a defining trait of our species, and disruptions in language acquisition can have profound consequences to the individuals affected. Uncovering the neurodevelopmental basis of this complex trait requires detailed molecular and cellular insights into the neocortical areas that support linguistic abilities. Here we performed joint gene expression and chromatin accessibility profiling at single-nucleus resolution (10x Genomics Single cell Multiome) and spatial transcriptomic profiling (Xenium high-plex in situ spatial transcriptomics) of Brocas area alongside adjacent motor cortical areas. We profiled individuals from different ancestries (European and African) and developmental stages (infancy, childhood, adolescence, and adulthood). We provide a high-resolution dissection of the cellular and molecular architecture of Brocas and motor cortical areas across early life stages and anchor the trajectories to the cellular states found in the adult human brain. We identify distinct area- and stage-specific cellular signatures, including a prominent role of glia populations and interneuron subtypes contributing to cytoarchitectonic specializations. Using longitudinal single cell spatial transcriptomic profiling, we orthogonally validate our consensus cell taxonomy and spatially resolve layer enrichment of neuronal and astrocyte subtypes that distinguish Brocas area and motor cortex. We also uncover cell type-specific molecular signatures that distinguish cell developmental trajectories in these cortical areas, including an early molecular code established by differential expression of cadherin genes that might contribute to area-specific intercellular communication. We also identify cell type-specific vulnerabilities to language- related neurodevelopmental and neuropsychiatric disorders, with selective susceptibility of particular somatostatin-positive interneuron subtypes to ASD/ADHD. Finally, evolutionary analysis of differentially accessible regions between Brocas area and motor cortex suggests that genetic mutations that might have contributed to the emergence of linguistic abilities accumulated over the course of million years following the divergence of human and chimpanzee lineages. Together, our study provides a comprehensive molecular, cellular and spatial definition of Brocas area and motor cortex, laying the groundwork for investigations into unique aspects of human cognition and related neurodevelopmental and neuropsychiatric disorders.

neuroscience↗

bioRxiv2026

Spatial lung niches shape Pseudomonas aeruginosa persistence

Chronic Pseudomonas aeruginosa lung infection is a major cause of morbidity and mortality in people with pre-existing lung disease. Once established, infection is rarely eradicated and often persists despite prolonged antimicrobial therapy, but the underlying mechanisms remain poorly understood. To define how P. aeruginosa occupies and adapts to diseased lung tissue, we applied host-pathogen spatial transcriptomics to profile over 23 million lung cells from explanted and resected lungs from people with Cystic Fibrosis (CF) and chronic obstructive pulmonary disease (COPD), mapping bacterial niches and transcriptional states in situ. We found that P. aeruginosa adopted distinct niche-linked states across chronically infected human lung tissue. Bacterial burden was highest in airway lumens, but bacteria also occupied submucosal glands, parenchyma and, unexpectedly, blood vessel lumens in CF tissue. Within airway lumens, two coupled host-pathogen states emerged: an alginate-rich biofilm-like state linked to PI3-positive neutrophil inflammation and host chemical-sensing programmes; and a motile, quorum-sensing state with activated type 6 secretion linked to human ciliary stress, epithelial remodelling and proteolytic injury. Intravascular bacteria co-localised with neutrophils, fibrin and vascular-remodelling signatures, suggesting local breach of barrier integrity and subsequent immune containment. P. aeruginosa also displayed disease-specific cellular associations, with neutrophil-dominated interactions in CF and greater association with macrophages and dendritic cells in COPD. Together, these data reveal chronic P. aeruginosa infection as a spatially partitioned ecosystem in which anatomical microenvironments impose distinct bacterial lifestyles and host inflammatory states. This niche-resolved framework helps explain how persistent infection can diversify within a single lung and suggests that eradication therapies may need to target multiple anatomical and cellular niches to be effective.

immunology↗

bioRxiv2026

Urbanization effects are trait-specific and city-dependent across a widespread spider's global range

Urban environments impose strong selective pressures through biotic and abiotic factors, driving changes in behavior, physiology, and morphology. Yet, responses vary across taxa and cities, and it remains unclear which traits respond consistently and what factors moderate this variation. We addressed these questions using the widespread European garden spider (Araneus diadematus) as a model, measuring size, color, and web-building traits along urban-rural transects in 22 cities across its distribution range. Using a meta-analytic framework, we assessed how city-specific characteristics influenced trait variation. Urbanization consistently reduced relative abdomen surface area, a proxy for body condition. Exploratory meta-regressions suggest that web-building response was predicted by temperature: compared to their non-urban surroundings, urban webs are larger in colder regions and smaller in warmer regions. In contrast, body size and abdomen brightness varied among cities without clear environmental predictors. These findings show that urbanization effects are trait- and context-dependent, likely influenced by local factors such as heat island intensity, microclimate, or prey availability. Linking within- and between-city variation will improve understanding of species phenotypic responses to urban environments.

ecology↗

bioRxiv2025

Neurocomputational impairments in disambiguation of context as a key determinant of post-traumatic psychopathology

We combine theoretical biology and systems neuroscience to relate the mechanisms of post-traumatic stress disorder (PTSD) models to biopsychosocial complexity. Moving beyond fear conditioning, extinction and habits formed by associative learning, we consider conserved neuromodulatory mechanisms related to harm expectation, defensive mobilisation, and context (in)sensitivity. Our account of harm-mitigating, neurobehavioural responses furnishes a mechanistic understanding of maladaptive behaviour and impaired belief-updating, which are often underspecified in conceptual analyses. Grounded in neurobiological evidence, we specify PTSD-related impairment in terms of Bayesian belief-updating and establish an adaptive/maladaptive boundary using active inference simulation studies. The ensuing model plausibly illustrates PTSD pathogenesis, which remains understudied relative to aetiology. We locate pathogenesis in maladaptive precision following trauma, characterised by a distortion of ideal Bayesian updating via aberrant credit assignment. Future scientific and clinical studies can test the validity of these insights, which could underwrite our understanding of the phenomenology, diagnostics and ultimately treatment intervention in post-traumatic disorders.

neuroscience↗

bioRxiv2024

Variant classification guidelines for animals to objectively evaluate genetic variant pathogenicity

Assessing the pathogenicity of a disease-associated variant in animals accurately is vital, both on a population and individual scale. At the population level, breeding decisions based on invalid DNA tests can lead to the incorrect exclusion of animals and compromise the long- term health of a population, and at the level of the individual animal, lead to incorrect treatment and even life-ending decisions. Criteria to determine pathogenicity are not standardized, hence no guidelines for animal variants are available. Here, we developed and optimized the animal variant classification guidelines, based on those developed for humans by The American College of Medical Genetics and Genomics, and demonstrated a superior classification in animals. We described methods to develop datasets for benchmarking the criteria and identified the most optimal in silico variant effect predictor tools. As the reproducibility was high, we classified 72 known disease-associated variants in cats and 40 other disease-associated variants in eight additional species.

genetics↗

bioRxiv2023

Successful placentation in human pregnancy is regulated by reciprocal interactions between maternal uterine NK cells and fetal placental trophoblast

Fetal growth and development during human pregnancy depends on delivery of adequate maternal oxygen and nutrients to the fetus via the placenta. In humans, the balanced invasion of fetal placental trophoblast cells into the maternal uterine lining, where they interact with uterine natural killer cells (uNK), is thought to be critical for a successful pregnancy but exactly how this influences reproductive outcomes remains undefined. Here, we used our trophoblast organoid model and primary tissue samples to determine how uNK affect placentation. By locating potential interaction axes between primary trophoblast cells and uNK using single cell transcriptomics, and in vitro modelling of these interactions in trophoblast organoids, we identify a uNK-derived cytokine signal that promotes trophoblast differentiation by enhancing epithelial-mesenchymal transition and increasing trophoblast cells at the late stage of the invasive pathway. Moreover, it affects transcriptional programs involved in increasing blood flow, placental access to nutrients, and dampening inflammatory and adaptive immune responses, as well as gene signatures associated with disorders of pregnancy such as pre-eclampsia. Our findings shed new light on how optimal immunological interactions between maternal uNK cells and fetal trophoblast enhance reproductive success.

developmental biology↗

bioRxiv2022

Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs

Hundreds of genetic variants linked to Mendelian disease have been characterized in dogs to date, and commercial screening is being offered for most of them worldwide. There typically remains a paucity of information regarding the broader population frequency of newly discovered variants, as well as uncertainty regarding their functional and clinical impact on additional genomic ancestry backgrounds beyond the discovery breed. Panel screening of disease variants, commercially offered as direct-to-consumer genetic testing, provides an opportunity to establish large-scale cohorts with both genotype and phenotype data available to address open questions related to variant prevalence and relevance. In this study, we screened the largest canine cohort examined in a single study to date (1,054,293 representative dogs from our existing cohort of more than three million dogs; a total of 811,628 mixed breed dogs and 242,665 purebreds from more than 150 countries and territories) for 250 genetic disease-associated variants to understand their prevalence and distribution in the general population. Electronic medical records from veterinary clinics were available for 43.5% of the genotyped dogs, enabling follow up on the clinical impact of variants. We provide detailed frequencies for all tested variants across breeds and find that 57% of dogs carry at least one copy of a studied Mendelian disease-linked variant. We provide evidence of full penetrance for 10 variants, and at minimum plausible evidence for the clinical significance of 22 variants, on a wide variety of breed backgrounds. We further show that a reduction in genome-wide heterozygosity is associated with an increased Mendelian disease load and assess genome-wide heterozygosity levels in over 100 breeds. The accumulated knowledge represents a resource to guide discussions on disease variant presence and genetic test relevance by breed.

genetics↗

bioRxiv2021

Genetic epidemiology of blood type, disease and trait variants, and genome-wide genetic diversity in over 11,000 domestic cats

In the largest DNA-based study of domestic cat to date, 11,036 individuals (10,419 pedigreed cats from 91 breeds and breed types and 617 non-pedigreed cats) were genotyped via commercial panel testing, elucidating the distribution and frequency of known genetic variants associated with blood type, disease and physical traits across cat breeds. Blood group determining variants, which are relevant clinically and in cat breeding, were genotyped to assess the across breed distribution of blood types A, B and AB. Extensive panel testing identified 13 disease-associated variants in 48 breeds or breed types for which the variant had not previously been observed, strengthening the argument for panel testing across populations. The study also indicates that multiple breed clubs have effectively used DNA testing to reduce disease-associated genetic variants within certain pedigreed cat populations. Appearance-associated genetic variation in all cats is also discussed. Additionally, we combined genotypic data with phenotype information and clinical documentation, actively conducted owner and veterinarian interviews, and recruited cats for clinical examination to investigate the causality of a number of tested variants across different breed backgrounds. Lastly, genome-wide informative SNP heterozygosity levels were calculated to obtain a comparable measure of the genetic diversity in different cat breeds. This study represents the first comprehensive exploration of informative Mendelian variants in felines by screening over 10,000 domestic cats. The results qualitatively contribute to the understanding of feline variant heritage and genetic diversity and demonstrate the clinical utility and importance of such information in supporting breeding programs and the research community. The work also highlights the crucial commitment of pedigreed cat breeders and registries in supporting the establishment of large genomic databases that when combined with phenotype information can advance scientific understanding and provide insights that can be applied to improve the health and welfare of cats.

genetics↗

bioRxiv2021

Targeted Protein Acetylation in Cells Using Heterobifunctional Molecules

Protein acetylation is a central event in orchestrating diverse cellular processes. However, current strategies to investigate protein acetylation in cells are often non-specific or lack temporal and magnitude control. Here, we developed an acetylation tagging system, AceTAG, to induce acetylation of targeted proteins. The AceTAG system utilizes bifunctional molecules to direct the lysine acetyltransferase p300/CBP to proteins fused with the small protein tag FKBP12F36V, resulting in their induced acetylation. Using AceTAG, we induced targeted acetylation of a diverse array of proteins in cells, specifically histone H3.3, the NF-{kappa}B subunit p65/RelA, and the tumor suppressor p53. We demonstrate that targeted acetylation with the AceTAG system is rapid, selective, reversible, and can be controlled in a dose-dependent fashion. AceTAG represents a useful strategy to modulate protein acetylation and will enable the exploration of targeted acetylation in basic biological and therapeutic contexts. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/454011v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@e7eeddorg.highwire.dtl.DTLVardef@f2fbf1org.highwire.dtl.DTLVardef@7a9d23org.highwire.dtl.DTLVardef@1e2a5b4_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2020

Vertical transmission at the pathogen-symbiont interface: Serratia symbiotica and aphids

Many insects possess beneficial bacterial symbionts that occupy specialized host cells and are maternally transmitted. As a consequence of their host-restricted lifestyle, these symbionts often possess reduced genomes and cannot be cultured outside hosts, limiting their study. The bacterial species Serratia symbiotica was originally described by noncultured strains that live as mutualistic symbionts of aphids and are vertically transmitted through transovarial endocytosis within the mothers body. More recently, culturable strains of S. symbiotica were discovered that retain a larger set of ancestral Serratia genes, are gut pathogens in aphid hosts, and are principally transmitted via a fecal-oral route. We find that these culturable strains, when injected into pea aphids, replicate in the hemolymph and are pathogenic. Unexpectedly, they are also capable of maternal transmission via transovarial endocytosis: using GFP-tagged strains, we observe that pathogenic S. symbiotica, but not Escherichia coli, are endocytosed into early embryos. Furthermore, pathogenic S. symbiotica strains are compartmentalized into specialized aphid cells in a similar fashion to mutualistic S. symbiotica strains during later stages of embryonic development. Thus, cultured, pathogenic strains of S. symbiotica have the latent capacity to transition to lifestyles as mutualistic symbionts of aphid hosts. This capacity is blocked by pathogenicity: their hosts die before infected progeny are born. To transition into stably inherited symbionts, culturable S. symbiotica strains may need to adapt to regulate their titer, limit their pathogenicity, and/or provide benefits to aphids that outweigh their cost. ImportanceInsects have evolved various mechanisms to reliably transmit their beneficial bacterial symbionts to the next generation. Sap-sucking insects, including aphids, transmit symbionts by endocytosis of the symbiont into cells of the early embryo within the mothers body. Experimental studies of this process are hampered by the inability to culture or genetically manipulate host-restricted, symbiotic bacteria. Serratia symbiotica is a bacterial species that includes strains ranging from obligate, heritable symbionts to culturable gut pathogens. We demonstrate that culturable S. symbiotica strains, that are aphid gut pathogens, can be maternally transmitted by endocytosis. Cultured S. symbiotica therefore possess a latent capacity for evolving a host-restricted lifestyle and can be used to understand the transition from pathogenicity to beneficial symbiosis.

microbiology↗

bioRxiv2020

Intradermal-delivered DNA vaccine provides anamnestic protection in a rhesus macaque SARS-CoV-2 challenge model

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a dramatic global impact on public health, social, and economic infrastructures. Here, we assess immunogenicity and anamnestic protective efficacy in rhesus macaques of the intradermal (ID)-delivered SARS-CoV-2 spike DNA vaccine, INO-4800. INO-4800 is an ID-delivered DNA vaccine currently being evaluated in clinical trials. Vaccination with INO-4800 induced T cell responses and neutralizing antibody responses against both the D614 and G614 SARS-CoV-2 spike proteins. Several months after vaccination, animals were challenged with SARS-CoV-2 resulting in rapid recall of anti-SARS-CoV-2 spike protein T and B cell responses. These responses were associated with lower viral loads in the lung and with faster nasal clearance of virus. These studies support the immune impact of INO-4800 for inducing both humoral and cellular arms of the adaptive immune system which are likely important for providing durable protection against COVID-19 disease.

immunology↗

bioRxiv2019

True Colors: commercially-acquired morphological genotypes reveal hidden allele variation among dog breeds, informing both trait ancestry and breed potential

Direct-to-consumer canine genetic testing is becoming increasingly popular among dog owners. The data collected therein provides intriguing insight into the current status of morphological variation present within purebred populations. Mars WISDOM PANELTM data from 11,790 anonymized dogs, representing 212 breeds and 4 wild canine species, were evaluated at genes associated with 7 coat color traits and 5 physical characteristics. Frequencies for all tested alleles at these 12 genes were determined by breed and by phylogenetic grouping. A sub-set of the data, consisting of 30 breeds, was divided into separate same-breed populations based on country of collection, body size, coat variation, or lineages selected for working or conformation traits. Significantly different (p [≤] 0.00167) allele frequencies were observed between populations for at least one of the tested genes in 26 of the 30 breeds. Next, standard breed descriptions from major American and international registries were used to determine colors and tail lengths (e.g. genetic bobtail) accepted within each breed. Alleles capable of producing traits incongruous with breed descriptions were observed in 143 breeds, such that random mating within breeds has probabilities of between 4.9e-7 and 0.25 of creating undesirable phenotypes. Finally, the presence of rare alleles within breeds, such as those for the recessive black coloration and natural bobtail, was combined with previously published identity-by-decent haplotype sharing levels to propose pathways by which the alleles may have spread throughout dog breeds. Taken together, this work demonstrates that: 1) the occurrence of low frequency alleles within breeds can reveal the influence of regional or functional selection practices; 2) it is possible to trace the mode by which characteristics have spread across breeds during historical breed formation; and 3) the necessity of addressing conflicting ideals in breed descriptions relative to actual genetic potential is crucial.\n\nAuthor SummaryFrom the sleek Doberman Pinscher to the coifed Poodle, the sunny Golden Retriever to the aristocratic Pekingese, the world of purebred dogs offers options that appeal to nearly all aesthetics. Pure dog breeds, of which there are over 400 worldwide, are created through selective breeding over multiple generations, toward an ideal goal of temperament, behavior, and physical appearance. Written descriptions of these breed-specific ideals are produced and maintained by dedicated breed enthusiasts, and provide guidelines that direct breeders in their selection choices. However, the genetic mechanisms that produce the spectrum of canine colors and patterns, sculpt the small triangular ears of a Siberian Husky or the long soft ears of a Basset Hound, are complicated and intertwined. This means that some breeds can carry rare, hidden traits for many generations, hampering selection efforts toward uniformity. We have determined the genotypes of >11,000 dogs, representing >200 breeds, at 12 genes that impact coat color and physical characteristics. In doing so, we can now present realistic trait frequencies within each breed, report occurrences of gene variants that can produce undesirable traits, and draw conclusions about the historic spread of characteristics across modern related breeds and those with distant shared ancestry.

genetics↗