Biology subjects

George, A. M.

Publications and source records attributed to George, A. M..

8 recordsLinked to original sources

bioRxiv2026

Genomic SEM reveals shared genetic architecture and expands locus discovery for locomotor activity in heterogeneous stock rats

Locomotor response to a novel environment is a heritable, addiction-relevant behavioral phenotype in rodents. We characterized its genetic basis in 9,341 male and female heterogeneous stock (HS) rats from eight studies. Locomotor activity was heritable across studies, while pairwise genetic correlations were positive but variable, indicating shared yet nonidentical genetic influences. Given nonuniform genetic architecture, we compared three complementary approaches to locus discovery that analyzed SNP effects 1) on a pooled locomotor phenotype (MEGA), 2) across studies under a fixed-effect model (METAL), or 3) on a shared genetic factor (Genomic SEM). To ensure comparability, all three locus-discovery approaches were applied to a common subset of seven studies. Together, these approaches identified 38 loci, with both convergence and method-specific discovery across analyses. Genomic SEM identified 31 loci, compared to 8 for MEGA and 13 for METAL. To interpret the loci, we integrated brain molecular QTLs, predicted coding and splice consequences, and open-field locomotor phenotypes from knockouts of orthologous mouse genes. Our results highlighted established neurobehavioral candidates spanning locomotor and reward-related biology (Negr1 and Lmo4), serotonergic signaling (Htr1b), and GABAergic signaling (Gabrg2), as well as relatively novel genes including Tcerg1l, Pcdh10, and Tmem132e. Our results illustrate how Genomic SEM can integrate genetically correlated yet heterogeneous behavioral measures and enable discovery of loci underlying their shared genetic architecture, highlighting its utility for complex-trait studies in rodents.

genetics↗

bioRxiv2026

Radiological Patterns in Maxillofacial Ewing Sarcoma: A systematic review with pooled patient-level descriptive analysis

BackgroundEwing sarcoma (ES) is a rare malignant bone tumor with predilection for the mandible and maxilla in the head and neck region. However, existing literature comprises fragmented case reports and small case series that fail to establish consolidated, evidence-based understanding of characteristic radiological patterns in the maxillofacial region, hindering timely diagnosis and potentially leading to misdiagnosis or delayed intervention. MethodologyA systematic review and pooled patient-level descriptive analysis were conducted according to the PRISMA guidelines and pre-registered on PROSPERO. Comprehensive searches of PubMed, OVID, and Cochrane databases (inception to July 2025) identified studies reporting radiological findings of biopsy-confirmed maxillofacial Ewing sarcoma. Quality assessment using Joanna-Briggs Institute criteria ensured inclusion of only high-quality cases (quality score [≥]4/5). Synthesis Without Meta-analysis (SWiM) methodology with pooled prevalence estimation and binomial vote-counting analysis were employed for 68 published cases. ResultsFour radiological features demonstrated consistent predominance across pooled cases: soft tissue mass presence (100%, 95% CI: 94.7-100.0%), enhancing soft tissue (77.6%, 95% CI: 65.8-86.9%), cortical destruction (69.0%, 95% CI: 55.5-80.5%), and notably, absence of periosteal reaction (84.7%, 95% CI: 73.0-92.8%). Location-specific radiological phenotypes were evident: maxillary tumors demonstrated near-universal sinus involvement (100%) with high soft tissue enhancement (92.3%), whereas mandibular tumors showed predominant cortical destruction (80.0%) and teeth involvement (81.2%). ConclusionMRI and CT are essential for characterizing the distinctive radiological profile of maxillofacial Ewing sarcoma, enabling early identification and improving patient outcomes in this rare malignancy. HighlightsO_LIFirst pooled review to summarize imaging features of maxillofacial Ewing sarcoma C_LIO_LIAnalysis of 68 published cases reveals consistent imaging patterns. C_LIO_LIMost tumors show soft tissue mass and bone damage without surface reaction. C_LIO_LIJaw tumors differ from long bone tumors in their imaging appearance. C_LIO_LIUpper and lower jaw tumors show distinct location-specific features. C_LI

cancer biology↗

bioRxiv2025

The DLX/Notch axis is necessary for spatiotemporal regulation of neural cell fate

The neuronal-glial cell fate switch during forebrain development is highly regulated. DLX transcription factors are necessary for promoting GABAergic interneuron differentiation and migration but the mechanisms for concomitant repression of glial fate in neural progenitors remain elusive. Here, the DLX2 regulatory network dynamic in the developing ventral telencephalon was characterised using a multi-omic approach at single-cell resolution, including single-cell whole genome spatial transcriptomics. We identified a secondary proliferative zone in the ventral subventricular zone and spatiotemporal-context dependent Notch pathway repression by DLX2 in maintaining progenitor populations and facilitating neural differentiation. We found that DLX2 controls cell fate determination by directly repressing Notch signalling genes as well as glial fate promoting transcription factors, thereby inhibiting early adoption of oligodendroglial differentiation during neurogenesis. Thus, temporal cell fate switch mediated by DLX2 via a multilayer gene regulatory network redefines our current understanding of neuronal-glial cell specification mechanisms in the developing telencephalon.

developmental biology↗

bioRxiv2025

Novel insights into the genetic architecture and mechanisms of host/microbiome interactions from a multi-cohort analysis of outbred laboratory rats

The intestinal microbiome influences health and disease. Its composition is affected by host genetics and environmental exposures. Understanding host genetic effects is critical but challenging in humans, due to the difficulty of detecting, mapping and interpreting them. To address this, we analysed host genetic effects in four cohorts of outbred laboratory rats exposed to distinct but controlled environments. We found that polygenic host genetic effects were consistent across environments. We identified three replicated microbiome-associated loci, one of which involved a sialyltransferase gene and Paraprevotella. We found a similar association in a human cohort, between ST6GAL1 and Paraprevotella, both of which have been linked with immune and infectious diseases. Moreover, we found evidence of indirect genetic effects on microbiome phenotypes, which substantially increased their total genetic variance. Finally, we identified a novel mechanism whereby indirect genetic effects can contribute to "missing heritability".

genetics↗

bioRxiv2023

Environmental enrichment promotes adaptive responding during tests of behavioral regulation in male heterogeneous stock rats

Organisms must regulate their behavior flexibly in the face of environmental challenges. Failure can lead to a host of maladaptive behavioral traits associated with a range of neuropsychiatric disorders, including attention deficit hyperactivity disorder, autism, and substance use disorders. This maladaptive dysregulation of behavior is influenced by genetic and environmental factors. For example, environmental enrichment produces beneficial neurobehavioral effects in animal models of such disorders. The present study determined the effects of environmental enrichment on a range of measures related to behavioral regulation using a large cohort of male, outbred heterogeneous stock (HS) rats as subjects to mimic the genetic variability found in the human population. Subjects were reared from late adolescence onwards either in pairs in standard housing with minimal enrichment (n=200) or in groups of 16 in a highly enriched environment consisting of a large multi-level cage filled with toys, running wheels, and shelters (n=64). Rats were subjected to a battery of tests, including: (i) locomotor response to novelty, (iI) light reinforcement, (iii) social reinforcement, (iv) reaction time, (v) a patch-depletion foraging test, (vi) Pavlovian conditioned approach, (vii) conditioned reinforcement, and (viii) cocaine conditioned cue preference. Results indicated that rats housed in the enriched environment were able to filter out irrelevant stimuli more effectively and thereby regulate their behavior more efficiently than standard-housing rats. The dramatic impact of environmental enrichment suggests that behavioral studies using standard housing conditions may not generalize to more complex environments that may be more ethologically relevant.

animal behavior and cognition↗

bioRxiv2022

Polygenic Transcriptome Risk Scores Can Translate Genetic Results Between Species

Genome-wide association studies (GWAS) have implicated specific alleles and genes as risk factors for numerous complex traits. However, translating GWAS results into biologically and therapeutically meaningful discoveries remains extremely challenging. Most GWAS results identify noncoding regions of the genome, suggesting that differences in gene regulation are the major driver of trait variability. To better integrate GWAS results with gene regulatory polymorphisms, we previously developed PrediXcan (also known as "transcriptome-wide association studies" or TWAS), which maps SNPs to predicted gene expression using GWAS data. In this study, we developed RatXcan, a framework that extends this methodology to outbred heterogeneous stock (HS) rats. RatXcan accounts for the close familial relationships among HS rats by modeling the relatedness with a random effect that encodes the genetic relatedness. RatXcan also corrects for polygenic-driven inflation because of the equivalence between a relatedness random effect and the infinitesimal polygenic model. To develop RatXcan, we trained transcript predictors for 8,934 genes using reference genotype and expression data from five rat brain regions. We found that the cis genetic architecture of gene expression in both rats and humans was sparse and similar across brain tissues. We tested the association between predicted expression in rats and two example traits (body length and BMI) using phenotype and genotype data from 5,401 densely genotyped HS rats and identified a significant enrichment between the genes associated with rat and human body length and BMI. Thus, RatXcan represents a valuable tool for identifying the relationship between gene expression and phenotypes across species and paves the way to explore shared biological mechanisms of complex traits. Author SummaryUnderstanding how genetic variation affects phenotypic variation is critical to leveraging the wealth of genetic studies to make biologically and therapeutically useful discoveries. Since most of the genetic loci associated with complex diseases are regulatory in nature--meaning that they do not alter protein coding but rather subtly affect gene expression--transcriptome-wide association studies have been developed. However, these apply only to human data where large samples of unrelated individuals are available. For animal models, relatedness is much higher, causing higher false-positive rates. We propose a computationally efficient method to address this problem and find shared biology between humans and rats. Taken together, our development paves the way to further explore shared biological mechanisms of complex traits across species.

genomics↗

bioRxiv2021

A novel and highly divergent Canine Distemper Virus lineage causing distemper in ferrets in Australia

Canine distemper virus (CDV) is a highly contagious systemic viral disease of dogs, that regularly spills-over into other animal species. Despite widespread vaccination, CDV remains endemic in many parts of the world. In this study we report an outbreak of distemper in ferrets in two independent research facilities in Australia. We found that disease severity varied, although most animals had mild to moderate disease signs. Histopathology results of animals with severe disease presented the typical profile of distemper pathology with multi-system virus replication. Through the development of a discriminatory PCR paired with full genome sequencing we revealed that the outbreak at both facilities was caused by a single, novel lineage of CDV. This lineage was highly divergent across the H gene, F signal peptide and full genome and had less than 93% similarity across the H gene to other described lineages, including the vaccine strain. Molecular analysis indicates that this strain belongs to a distinct lineage that diverged from other clades approximately 140 to 400 years ago, and appears to be unique to Australia. Given the differences in key viral proteins of this novel CDV strain, a review of the efficacy of the CDV vaccines currently in use in Australia is warranted to ensure maximum protection of dogs and other vulnerable species. In addition, enhanced surveillance to determine the prevalence of CDV in ferrets, dogs and other at-risk species in Australia would be useful to better understand the diversity of CDV in Australia. ImportanceCanine distemper virus (CDV) is highly contagious and while dogs are the main reservoir, it may spill over into a number of other animal species. In this study we report an outbreak of distemper in ferrets in two research facilities in Australia. Outcomes of pathology and histopathology suggest ferrets have widespread multi-systemic infection, consistent with previously reported distemper infections in ferrets and dogs. Critically, through sequencing and phylogenetic analysis, we revealed that the outbreak at both facilities was caused by a single, novel and highly divergent lineage of CDV. This virus had less than 93% nucleotide similarity to other described lineages and the vaccine strain. This manuscript adds considerably to the epidemiology, ecology and evolution of this virus, and is one of few reports of distemper in Australia in the literature.

microbiology↗

bioRxiv2020

The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome

Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network-Breast project (SCAN-B; ClinicalTrials.gov NCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such as PIK3CA, TP53, and ERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible at http://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.

cancer biology↗