title: Mapping of a chromosome 12 region associated with airway hyperresponsiveness in a recombinant congenic mouse strain and selection of potential candidate genes by expression and sequence variation analyses.
abstract: In a previous study we determined that BcA86 mice, a strain belonging to a panel of AcB/BcA recombinant congenic strains, have an airway responsiveness phenotype resembling mice from the airway hyperresponsive A/J strain. The majority of the BcA86 genome is however from the hyporesponsive C57BL/6J strain. The aim of this study was to identify candidate regions and genes associated with airway hyperresponsiveness (AHR) by quantitative trait locus (QTL) analysis using the BcA86 strain. Airway responsiveness of 205 F2 mice generated from backcrossing BcA86 strain to C57BL/6J strain was measured and used for QTL analysis to identify genomic regions in linkage with AHR. Consomic mice for the QTL containing chromosomes were phenotyped to study the contribution of each chromosome to lung responsiveness. Candidate genes within the QTL were selected based on expression differences in mRNA from whole lungs, and the presence of coding non-synonymous mutations that were predicted to have a functional effect by amino acid substitution prediction tools. One QTL for AHR was identified on Chromosome 12 with its 95% confidence interval ranging from 54.6 to 82.6 Mbp and a maximum LOD score of 5.11 (p = 3.68 × 10(-3)). We confirmed that the genotype of mouse Chromosome 12 is an important determinant of lung responsiveness using a Chromosome 12 substitution strain. Mice with an A/J Chromosome 12 on a C57BL/6J background have an AHR phenotype similar to hyperresponsive strains A/J and BcA86. Within the QTL, genes with deleterious coding variants, such as Foxa1, and genes with expression differences, such as Mettl21d and Snapc1, were selected as possible candidates for the AHR phenotype. Overall, through QTL analysis of a recombinant congenic strain, microarray analysis and coding variant analysis we identified Chromosome 12 and three potential candidate genes to be in linkage with airway responsiveness.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Kanagaratham
authors.affiliation: Faculty of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Rafael
authors.initials: R
authors.lastname: Marino
authors.affiliation: Faculty of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Camateros
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Ren
authors.affiliation: Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Houle
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Faculty of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Sladek
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Vidal
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Faculty of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Danuta
authors.initials: D
authors.lastname: Radzioch
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation; D006967:Hypersensitivity / Q000235:genetics*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D040641:Quantitative Trait Loci / Q000235:genetics*; D012140:Respiratory Tract Diseases / Q000235:genetics*; D013045:Species Specificity
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