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  • Review Article
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Primer: comparative genetics of animal models of arthritis—a tool to resolve complexity

Nature Clinical Practice Rheumatology volume 3, pages 104–111 (2007)Cite this article

Abstract

Complex traits, including inflammatory rheumatic diseases, have important genetic features, but most of the responsible genes have not been conclusively identified. Genetic analysis of inbred animal models and comparative genetics—the comparison of genes between different species—might help to identify the crucial genes and to investigate more directly the biology involved. Genome-wide linkage analysis of particular genes can be assessed by genetic segregation studies, whereas disease pathways can be delineated by the use of congenic strains. To clone disease genes, the traits need to be transformed so that they are inherited in a more Mendelian manner: achieving this pattern requires isolation of the locus on a genetic background that allows high penetrance by minimization of the size of congenic fragments, genetic manipulations without associated artifacts, or identification of highly penetrant mutations by phenotypic selection. Although almost one hundred quantitative trait loci for arthritis have been identified, only a few genes have so far been positionally cloned. In this Review we highlight the possibilities of using animal models to identify genes associated with complex diseases like arthritis, illustrated with available findings for genes such as those encoding major histocompatibility complex class II, neutrophil cytosolic factor 1 (Ncf1/p47phox) and ZAP70.

Key Points

  • Linkage analysis (i.e. hypothesis-free genetic analysis) is not effective in human complex diseases such as rheumatoid arthritis, but is more effective in animal models

  • Positional identification of genes underlying identified loci is still a difficult task and only a few have been identified in animal models, including major histocompatibility complex class II and Ncf1

  • Identification of genetic polymorphisms provides valuable insight into new molecular pathways leading to disease

  • There are several methods for facilitating the gene search including high density crosses and selection of highly penetrant mutations

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Figure 1: The major histocompatibility complex (MHC) class II Aq as an early example of positional cloning of a gene.
Figure 2: Mice expressing the human class II molecule DRB1*0401 and lacking murine class II molecules are susceptible to collagen-induced arthritis.
Figure 3: Role of identified genes associated with arthritis in T-cell activation.

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Acknowledgements

The author would like to thank the Crafoord Foundation; the Kock and Österlund Foundations; The Swedish Association Against Rheumatism; The Swedish Science Research Council; the Swedish Foundation for Strategic Research and the European Union FP6 scientific grants.

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  1. Medical Inflammation Research, Sölvegatan 19, BMC I11, Lund University, S-22184 Lund, Sweden rikard.holmdahl@med.lu.se

Authors and Affiliations

  1. R Holmdahl is a Professor of Medical Inflammation Research at Lund University, Lund, Sweden.,

    Rikard Holmdahl

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Holmdahl, R. Primer: comparative genetics of animal models of arthritis—a tool to resolve complexity. Nat Rev Rheumatol 3, 104–111 (2007). https://doi.org/10.1038/ncprheum0400

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