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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.

Kanagaratham C, Marino R, Camateros P, Ren J, Houle D, Sladek R, Vidal SM, Radzioch D - PLoS ONE (2014)

Bottom Line: 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

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.

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Histogram representation of the enhanced pause values of 205 BcA86F2.The distribution of log transformed enhanced pause values (log2(Penh)) of BcA86F2 mice ranges from lower than the average phenotype value of C57BL/6J (solid line) to greater than average phenotype value of BcA86 (dashed line).
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pone-0104234-g002: Histogram representation of the enhanced pause values of 205 BcA86F2.The distribution of log transformed enhanced pause values (log2(Penh)) of BcA86F2 mice ranges from lower than the average phenotype value of C57BL/6J (solid line) to greater than average phenotype value of BcA86 (dashed line).

Mentions: Since Penh measurements are known to be influenced by factors other than airway resistance, we validated our observations from Penh with invasive direct measurements of airway resistance [21]. Our measurements confirmed that the BcA86 strain has a hyperresponsive phenotype similar to A/J strain (Figure 1B). To identify genetic determinants of airway responsiveness in the BcA86 strain, we generated 205 BcA86F2 mice for QTL mapping. The mean log2(Penh) of the BcA86F2 mice shows a transgressive pattern of segregation as their phenotypes range from lower than the mean log2(Penh) of C57BL/6J strain to higher than the mean log2(Penh) of the BcA86 strain (Figure 2). The normal distribution pattern of log2(Penh) values from the F2 mice supports the hypothesis that multiple interacting loci are involved in determining the airway responsiveness phenotype. We also observe that gain of C57BL/6J genomic material results in a greater airway responsiveness phenotype in some BcA86F2 mice in comparison to BcA86. This indicates that in addition to airway responsiveness protective loci, susceptibility loci are also found in the C57BL/6J genome.


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.

Kanagaratham C, Marino R, Camateros P, Ren J, Houle D, Sladek R, Vidal SM, Radzioch D - PLoS ONE (2014)

Histogram representation of the enhanced pause values of 205 BcA86F2.The distribution of log transformed enhanced pause values (log2(Penh)) of BcA86F2 mice ranges from lower than the average phenotype value of C57BL/6J (solid line) to greater than average phenotype value of BcA86 (dashed line).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128649&req=5

pone-0104234-g002: Histogram representation of the enhanced pause values of 205 BcA86F2.The distribution of log transformed enhanced pause values (log2(Penh)) of BcA86F2 mice ranges from lower than the average phenotype value of C57BL/6J (solid line) to greater than average phenotype value of BcA86 (dashed line).
Mentions: Since Penh measurements are known to be influenced by factors other than airway resistance, we validated our observations from Penh with invasive direct measurements of airway resistance [21]. Our measurements confirmed that the BcA86 strain has a hyperresponsive phenotype similar to A/J strain (Figure 1B). To identify genetic determinants of airway responsiveness in the BcA86 strain, we generated 205 BcA86F2 mice for QTL mapping. The mean log2(Penh) of the BcA86F2 mice shows a transgressive pattern of segregation as their phenotypes range from lower than the mean log2(Penh) of C57BL/6J strain to higher than the mean log2(Penh) of the BcA86 strain (Figure 2). The normal distribution pattern of log2(Penh) values from the F2 mice supports the hypothesis that multiple interacting loci are involved in determining the airway responsiveness phenotype. We also observe that gain of C57BL/6J genomic material results in a greater airway responsiveness phenotype in some BcA86F2 mice in comparison to BcA86. This indicates that in addition to airway responsiveness protective loci, susceptibility loci are also found in the C57BL/6J genome.

Bottom Line: 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

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.

Show MeSH
Related in: MedlinePlus