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Identification of epistasis through a partial advanced intercross reveals three arthritis loci within the Cia5 QTL in mice

Genes & Immunity volume 6, pages 175–185 (2005)Cite this article

Abstract

Identification of genes controlling complex diseases has proven to be difficult; however, animal models may pave the way to determine how low penetrant genes interact to promote disease development. We have dissected the Cia5/Eae3 susceptibility locus on mouse chromosome 3 previously identified to control disease in experimental models of multiple sclerosis and rheumatoid arthritis. Congenic strains showed significant but small effects on severity of both diseases. To improve the penetrance, we have now used a new strategy that defines the genetic interactions. The QTL interacted with another locus on chromosome 15 and a partial advanced intercross breeding of the two congenic strains for eight generations accumulated enough statistical power to identify interactions with several loci on chromosome 15. Thereby, three separate loci within the original QTL could be identified; Cia5 affected the onset of arthritis by an additive interaction with Cia31 on chromosome 15, whereas the Cia21 and Cia22 affected severity during the chronic phase of the disease through an epistatic interaction with Cia32 on chromosome 15. The definition of genetic interactions was a prerequisite to dissect the Cia5 QTL and we suggest the partial advanced intercross strategy to be helpful also for dissecting other QTL controlling complex phenotypes.

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Acknowledgements

We thank Isabell Bohlin and Carlos Palestro for help with the animal care. This work was supported by grants from the Swedish Medical Research Council, the Swedish Foundation for Strategic Research, the Swedish Association against Rheumatism, the Crafoord, Lundberg, the Kock and Österlund Foundations and EU FP5 (QLG1-CT-2001-01407 ‘EUROME’). Dr Patrik Wernhoff was supported by the EU Grant HPMD-2000-00047.

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Authors and Affiliations

  1. Medical Inflammation Research, BMC I11, Lund University, Lund, Sweden

    M Johannesson, J Karlsson, K S Nandakumar, A-K Lindqvist, L Olsson, Å Andersson & R Holmdahl

  2. Institute for Immunology, University of Rostock, Rostock, Germany

    P Wernhoff

  3. Department of Medicine, and Cooperative Research Center for Chronic Inflammatory Diseases, Arthritis and Inflammation Research Centre, University of Melbourne, Parkville, Victoria, Australia

    A D Cook

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  1. M Johannesson
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Correspondence to M Johannesson.

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Johannesson, M., Karlsson, J., Wernhoff, P. et al. Identification of epistasis through a partial advanced intercross reveals three arthritis loci within the Cia5 QTL in mice. Genes Immun 6, 175–185 (2005). https://doi.org/10.1038/sj.gene.6364155

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