Biology subjects

Whitmore, A. C.

Publications and source records attributed to Whitmore, A. C..

3 recordsLinked to original sources

bioRxiv2022

Forward genetic screen of homeostatic antibody levels in the Collaborative Cross identifies MBD1 as a novel regulator of B cell homeostasis

Variation in immune homeostasis, the state in which the immune system is maintained in the absence of stimulation, is highly variable across populations. This variation is attributed to both genetic and environmental factors. However, the identity and function of specific regulators have been difficult to identify in humans. We evaluated homeostatic antibody levels in the serum of the Collaborative Cross (CC) mouse genetic reference population. We found heritable variation in all antibody isotypes and subtypes measured. We identified 4 quantitative trait loci (QTL) associated with 3 IgG subtypes: IgG1, IgG2b, and IgG2c. While 3 of these QTL maps to known immunologically important regions of the genomes, Qih1 (associated with variation in IgG1) mapped to a novel locus on Chromosome 18. We further associated this locus with B cell proportions in the spleen and show that Methyl-CpG binding domain protein 1 is a novel regulator of homeostatic IgG1 levels in the serum and marginal zone B cells (MZB) in the spleen, consistent with a role in MZB differentiation to antibody secreting cells. SummaryHomeostatic antibody levels are highly variable between Collaborative Cross (CC) mouse strains. This forward genetic screen in the CC identifies Methyl-CpG binding domain protein 1 (MBD1) as a regulator of homeostatic IgG1 levels and marginal zone B cell differentiation.

genetics↗

bioRxiv2021

Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice

Variation in immune homeostasis, immune system stability, in organ systems such as the lungs is likely to shape the host response to infection at these exposed tissues. We evaluated immune homeostasis in immune cell populations in the lungs of the Collaborative Cross (CC) mouse genetic reference population. We found vast heritable variation in leukocyte populations with the frequency of many of these cell types showing distinct patterns relative to classic inbred strains C57BL/6J and BALB/cJ. We identified 28 quantitative trait loci (QTL) associated with variation in baseline lung immune cell populations, including several loci that broadly regulate the abundance of immune populations from distinct developmental lineages, and found that many of these loci have predictive value for influenza disease outcomes, demonstrating that genetic determinants of homeostatic immunity in the lungs regulate susceptibility to virus-induced disease. All told, we highlight the need to assess diverse mouse strains in understanding immune homeostasis and resulting immune responses.

genetics↗

bioRxiv2017

Diallel analysis reveals Mx1-dependent and Mx1-independent effects on response to influenza A virus in mice

1.Influenza A virus (IAV) is a respiratory pathogen that causes substantial morbidity and mortality during both seasonal and pandemic outbreaks. Infection outcomes in unexposed populations are affected by host genetics, but this host genetic architecture is not well understood. Here we obtain a broad view of how heritable factors affect a mouse model of response to IAV infection using an 8x8 diallel of the eight inbred founder strains of the Collaborative Cross (CC). Expanding on a prior statistical framework for modeling treatment response in diallels, we explore how a range of heritable effects modify acute host response to IAV through 4 days post-infection. Heritable effects in aggregate explained about 57% of the variance in IAV-induced weight loss. Much of this was attributable to a pattern of additive effects that became more prominent through day 4 post-infection and was consistent with previous reports of anti-influenza myxovirus resistance 1 (Mx1) polymorphisms segregating between these strains; the additive effects largely recapitulated haplotype effects observed at the Mx1 locus in a previous study of the incipient CC (pre-CC), and are also replicated here in a CC recombinant intercross (CC-RIX) population. Genetic dominance of protective Mx1 haplotypes was observed to differ by subspecies origin: relative to the domesticus null Mx1 allele, musculus acts dominantly whereas castaneus acts additively. After controlling for Mx1, heritable effects, though less distinct, accounted for about 34% of the phenotypic variance. Implications for future mapping studies are discussed.

genetics↗