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      Haplotype Association Mapping Identifies a Candidate Gene Region in Mice Infected With Staphylococcus aureus

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          Abstract

          Exposure to Staphylococcus aureus has a variety of outcomes, from asymptomatic colonization to fatal infection. Strong evidence suggests that host genetics play an important role in susceptibility, but the specific host genetic factors involved are not known. The availability of genome-wide single nucleotide polymorphism (SNP) data for inbred Mus musculus strains means that haplotype association mapping can be used to identify candidate susceptibility genes. We applied haplotype association mapping to Perlegen SNP data and kidney bacterial counts from Staphylococcus aureus-infected mice from 13 inbred strains and detected an associated block on chromosome 7. Strong experimental evidence supports the result: a separate study demonstrated the presence of a susceptibility locus on chromosome 7 using consomic mice. The associated block contains no genes, but lies within the gene cluster of the 26-member extended kallikrein gene family, whose members have well-recognized roles in the generation of antimicrobial peptides and the regulation of inflammation. Efficient mixed-model association (EMMA) testing of all SNPs with two alleles and located within the gene cluster boundaries finds two significant associations: one of the three polymorphisms defining the associated block and one in the gene closest to the block, Klk1b11. In addition, we find that 7 of the 26 kallikrein genes are differentially expressed between susceptible and resistant mice, including the Klk1b11 gene. These genes represent a promising set of candidate genes influencing susceptibility to Staphylococcus aureus.

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          Most cited references 29

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          Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia.

          Induction of pneumonia in C57Bl/6 mice by intranasal inoculation with 10(6) cfu of Streptococcus pneumoniae resulted in sustained expression of interleukin (IL)-6 mRNA in lungs and increases in lung and plasma IL-6 concentrations. In IL-6-deficient (IL-6-/-) mice, pneumonia was associated with higher lung levels of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1beta, and interferon-gamma and of the antiinflammatory cytokine IL-10 than in wild type (IL-6+/+) mice (all P < .05). Also, the plasma concentrations of soluble tumor necrosis factor receptors were higher in IL-6-/- mice (P < .05), while the acute-phase protein response was strongly attenuated (P < .01). Lungs harvested from IL-6-/- mice 40 h after inoculation contained more S. pneumoniae colonies (P < .05). IL-6-/- mice died significantly earlier from pneumococcal pneumonia than did IL-6+/+ mice (P < .05). During pneumococcal pneumonia, IL-6 down-regulates the activation of the cytokine network in the lung and contributes to host defense.
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            Analysing complex genetic traits with chromosome substitution strains.

            Many valuable animal models of human disease are known and new models are continually being generated in existing inbred strains,. Some disease models are simple mendelian traits, but most have a polygenic basis. The current approach to identifying quantitative trait loci (QTLs) that underlie such traits is to localize them in crosses, construct congenic strains carrying individual QTLs, and finally map and clone the genes. This process is time-consuming and expensive, requiring the genotyping of large crosses and many generations of breeding. Here we describe a different approach in which a panel of chromosome substitution strains (CSSs) is used for QTL mapping. Each of these strains has a single chromosome from the donor strain substituting for the corresponding chromosome in the host strain. We discuss the construction, applications and advantages of CSSs compared with conventional crosses for detecting and analysing QTLs, including those that have weak phenotypic effects.
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              Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.

              Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.
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                Author and article information

                Journal
                G3 (Bethesda)
                Genetics
                ggg
                ggg
                ggg
                G3: Genes|Genomes|Genetics
                Genetics Society of America
                2160-1836
                1 June 2012
                June 2012
                : 2
                : 6
                : 693-700
                Affiliations
                [* ]Department of Biostatistics and Bioinformatics and
                []Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
                []Department of Pediatrics, University at Buffalo, Buffalo, New York 14222
                [§ ]Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390
                [** ]Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina 27705
                [†† ]Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida 33136
                Author notes

                Supporting information is available online at http://www.g3journal.org/lookup/suppl/doi:110.1534/g3.112.002501/-/DC1.

                Arrays have been submitted to the GEO database at NCBI as series GSE23584.

                [1 ]Corresponding author : Division of Biomedical Informatics, Department of Clinical Sciences, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9066. E-mail: Lindsay.Cowell@ 123456utsouthwestern.edu
                [2]

                These authors contributed equally to this work.

                Article
                GGG_002501
                10.1534/g3.112.002501
                3362298
                22690378
                Copyright © 2012 Johnson et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Unported License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Genetics

                kallikrein gene family, infectious disease, host genetic susceptibility

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