Biology subjects

Bubier, J.

Publications and source records attributed to Bubier, J..

4 recordsLinked to original sources

bioRxiv2026

A novel wild-derived MHC-linked locus regulates host immunity to gammaherpesvirus infection

Inefficient host control of infection by gammaherpesviruses is a risk factor for lymphoproliferative disease, autoimmunity, and cancer, yet naturally occurring genetic determinants of viral control remain poorly defined. Previously, we discovered that wild-derived PWD/PhJ (PWD) mice exhibit markedly improved control of murine gammaherpesvirus 68 (MHV-68) replication compared with C57BL/6J (B6) mice. This elite control of viral replication was linked to muted T cell responses, but partially dependent on NK cells. Here, we used genetic approaches to identify host determinants controlling MHV-68 resistance in PWD mice. Analysis of B6PWDF1 and B6PWDF2 populations suggested the existence of a major locus in the PWD genome contributing to MHV-68 resistance. Using B6.ChrPWD chromosome substitution (consomic) mice, we mapped a major resistance locus to Chr 17 and refined the required interval to 27.6-49.4 Mb, including the MHC locus. While B6.Chr17PWD mice recapitulated muted T cell responses observed in PWD mice, they controlled viral burden independent of NK cells and without reduced frequencies of infected germinal center B cells, indicating that resistance of PWD mice comprises multiple genetically and mechanistically distinct pathways. While the NK cell receptor complex on PWD chromosome 6 did not provide protection, genotype-phenotype analysis of the B6PWDF2 cohort revealed additional non-Chr 17-linked loci contributing to viral control. Together, our results identify a novel MHC-linked locus regulating gammaherpesvirus burden with minimal cytotoxic T cell expansion, demonstrating that effective host control of gammaherpesviruses can be achieved by diverse immune mechanisms. ImportancePoor host control of human gammaherpesvirus infection is linked to cancer and autoimmunity, but how natural genetic variation impacts immune mechanism of control is poorly defined. In this study, we examined genetic mechanisms linked to superior control of gammaherpesvirus infection. We identified a novel MHC-linked locus that regulates gammaherpesvirus burden without a large expansion of cytotoxic T cells and independent of NK cells. These findings show that host control of gammaherpesviruses can be achieved through diverse immune mechanisms that are driven by variation in host genetic background.

immunology↗

bioRxiv2025

Genetic mapping in Collaborative Cross mouse strains identifies loci that affect initial sensitivity to cocaine

We identified two Collaborative Cross (CC) strains, CC004/TauUncJ (CC004) and CC041/TauUncJ (CC041), that differ significantly for locomotor response and self-administration of cocaine. In the current study, we crossed each of these strains to C57BL/6NJ (B6N) mice to produce two F2 populations and identify genetic loci that influence locomotor response to cocaine. We identified three significant loci on chromosomes 7, 11 and 14 in the CC041 F2 mapping cross that collectively explain 14% of the phenotypic variance for locomotor response to cocaine. We used a bioinformatic approach to identify high quality candidate genes that are genetically plausible, have functional relevance and are suitable for further exploration. Our study is the first to use CC strains to perform QTL mapping for addiction-related phenotypes and proposes several candidate genes for follow-up analyses.

genetics↗

bioRxiv2021

An allelic series of spontaneous mutations in Rorb cause a gait phenotype, retinal abnormalities, and transcriptomic changes relevant to human neurodevelopmental conditions

Rorb encodes the Retinoic Acid Receptor-related orphan receptor beta. Mutations in either of the two transcripts of Rorb cause defects in multiple systems, including abnormal photoreceptor abundance and morphology in the retina and a characteristic "high-stepper" or "duck-like" gait arising from dysfunction of interneurons in the spinal cord. Rorb is also important for cortical development and cell fate specification in mice. Rorb variants segregate with epilepsy and comorbidities such as intellectual disability in numerous clinical cases. Here we describe five mouse strains with spontaneous mutations in Rorb identified by their gait phenotype. These mutations affect different domains and isoforms of Rorb, which correspond to the spectrum of anatomical and physiological phenotypes exhibited by these mice. Gene set analysis in Rorb mutants implicates pathways associated with development and nervous system function, and differential gene expression analysis indicates changes in numerous genes related to epilepsy, bipolar disorder, and autism spectrum disorder (ASD). Many of these genes and their protein products are known to interact during synapse formation and neuronal activity. These findings further illuminate the role of Rorb in nervous system development, provide further evidence for an association between Rorb and several neurological conditions, and describe an allelic series of Rorb mutant mice that will be useful for dissecting thalamocortical afferent (TCA) development, neural cell fate determination, and as animal models exhibiting transcriptomic shifts in neurological conditions such as epilepsy, bipolar disorder, and ASD. {blacksquare}Five mutant mice with a characteristic high-stepper gait phenotype have mutations in Rorb {blacksquare}These allelic series mutations manifest in a spectrum of anatomical and physiological abnormalities {blacksquare}Gene expression data suggest involvement of pathways related to neurodevelopmental disorders

genetics↗

bioRxiv2018

Systems genetic discovery of host-microbiome interactions reveals mechanisms of microbial involvement in disease

The role of the microbiome in health and disease involves complex networks of host genetics, genomics, microbes and environment. Identifying the mechanisms of these interactions has remained challenging. Systems genetics in the laboratory mouse enables data-driven discovery of network components and mechanisms of host-microbial interactions underlying multiple disease phenotypes. To examine the interplay among the whole host genome, transcriptome and microbiome, we mapped quantitative trait loci and correlated the abundance of cecal mRNA, luminal microflora, physiology and behavior in incipient strains of the highly diverse Collaborative Cross mouse population. The relationships that are extracted can be tested experimentally to ascribe causality among host and microbe in behavior and physiology, providing insight into disease. Application of this strategy in the Collaborative Cross population revealed experimentally validated mechanisms of microbial involvement in models of autism, inflammatory bowel disease and sleep disorder.\n\neTOC BlurbHost genetic diversity provides a variable selection environment and physiological context for microbiota and their interaction with host physiology. Using a highly diverse mouse population Bubier et al. identified a variety of host, microbe and potentially disease interactions.\n\nHighlights* 18 significant species-specific QTL regulating microbial abundance were identified\n* Cis and trans eQTL for 1,600 cecal transcripts were mapped in the Collaborative Cross\n* Sleep phenotypes were highly correlated with the abundance of B.P. Odoribacter\n* Elimination of sleep-associated microbes restored normal sleep patterns in mice.

genetics↗