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Journal article
Identification of genetic determinants of the sexual dimorphism in CNS autoimmunity
PloS one, v 10(2), pp e0117993-e0117993
2015
PMID: 25671658
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Multiple sclerosis (MS) is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, with higher prevalence in females, and a strong genetic component. While over 200 MS susceptibility loci have been identified in GWAS, the underlying mechanisms whereby they contribute to disease susceptibility remains ill-defined. Forward genetics approaches using conventional laboratory mouse strains are useful in identifying and functionally dissecting genes controlling disease-relevant phenotypes, but are hindered by the limited genetic diversity represented in such strains. To address this, we have combined the powerful chromosome substitution (consomic) strain approach with the genetic diversity of a wild-derived inbred mouse strain. Using experimental allergic encephalomyelitis (EAE), a mouse model of MS, we evaluated genetic control of disease course among a panel of 26 consomic strains of mice inheriting chromosomes from the wild-derived PWD strain on the C57BL/6J background, which models the genetic diversity seen in human populations. Nineteen linkages on 18 chromosomes were found to harbor loci controlling EAE. Of these 19 linkages, six were male-specific, four were female-specific, and nine were non-sex-specific, consistent with a differential genetic control of disease course between males and females. An MS-GWAS candidate-driven bioinformatic analysis using orthologous genes linked to EAE course identified sex-specific and non-sex-specific gene networks underlying disease pathogenesis. An analysis of sex hormone regulation of genes within these networks identified several key molecules, prominently including the MAP kinase family, known hormone-dependent regulators of sex differences in EAE course. Importantly, our results provide the framework by which consomic mouse strains with overall genome-wide genetic diversity, approximating that seen in humans, can be used as a rapid and powerful tool for modeling the genetic architecture of MS. Moreover, our data represent the first step towards mechanistic dissection of genetic control of sexual dimorphism in CNS autoimmunity.
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Details
- Title
- Identification of genetic determinants of the sexual dimorphism in CNS autoimmunity
- Creators
- Frank Bearoff - Drexel UniversityLaure K Case - University of VermontDimitry N Krementsov - University of VermontEmma H Wall - University of VermontNaresha Saligrama - University of VermontElizabeth P Blankenhorn - Drexel UniversityCory Teuscher - University of Vermont
- Publication Details
- PloS one, v 10(2), pp e0117993-e0117993
- Publisher
- Public LIbrary of Science (PLOS)
- Grant note
- R21 NS076200 / NINDS NIH HHS NS069628 / NINDS NIH HHS NS036526 / NINDS NIH HHS R01 NS060901 / NINDS NIH HHS P20 GM103496 / NIGMS NIH HHS R01 NS036526 / NINDS NIH HHS R01 NS069628 / NINDS NIH HHS R01 NS061014 / NINDS NIH HHS NS060901 / NINDS NIH HHS NS061014 / NINDS NIH HHS NS076200 / NINDS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000349545300077
- Scopus ID
- 2-s2.0-84923253381
- Other Identifier
- 991019168997704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Genetics & Heredity