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Functional screening of an asthma QTL in YAC transgenic mice

Nature Genetics volume 23, pages 241–244 (1999)Cite this article

Abstract

Many quantitative trait loci (QTLs) contributing to genetically complex conditions have been discovered, but few causative genes have been identified. This is mainly due to the large size of QTLs and the subtle connection between genotype and quantitative phenotype associated with these conditions1,2. Transgenic mice have been successfully used to analyse well-characterized genes suspected of contributing to quantitative traits3,4,5. Although this approach is powerful for examining one gene at a time, it can be impractical for surveying the large genomic intervals containing many genes that are typically associated with QTLs. To screen for genes contributing to an asthma QTL mapped to human chromosome 5q3 (refs 6,7), we characterized a panel of large-insert 5q31 transgenics based on studies demonstrating that altering gene dosage frequently affects quantitative phenotypes normally influenced by that gene. This panel of human YAC transgenics, propagating a 1-Mb interval of chromosome 5q31 containing 6 cytokine genes and 17 partially characterized genes8, was screened for quantitative changes in several asthma-associated phenotypes. Multiple independent transgenic lines with altered IgE response to antigen treatment shared a 180-kb region containing 5 genes, including those encoding human interleukin 4 (IL4) and interleukin 13 (IL13 ), which induce IgE class switching in B cells9. Further analysis of these mice and mice transgenic for mouse Il4 and Il13 demonstrated that moderate changes in Il4 and Il13 expression affect asthma-associated phenotypes in vivo. This functional screen of large-insert transgenics enabled us to identify genes that influence the QTL phenotype in vivo.

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Figure 1: Human chromosome 5q31 interval examined in this study.
Figure 2: Interleukin expression by T cells in vitro.
Figure 3: Effect of decreased Il4/Il13 expression on Th2 development.

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Acknowledgements

We thank P. Cooper, P. Upatham and P. Patel for expert technical assistance and R. Coffman for reagents. This work was supported by HHMI and HL56385 from the National Institutes of Health, as well as NIH HL-07279.

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Authors and Affiliations

  1. Genome Science Department, Lawrence Berkeley National Laboratory, Berkeley, 94720, California, USA

    Derek J. Symula, Kelly A. Frazer, Yukihiko Ueda, Mary E. Stevens & Edward M. Rubin

  2. Departments of Medicine and Microbiology/Immunology, University of California-San Francisco, San Francisco, 94143, California, USA

    Zhi-En Wang & Richard Locksley

  3. the Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, 94143, California, USA

    Richard Locksley

  4. Rhone Poulenc Rorer Research-Development, Vitry, France

    Patrice Denefle

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  1. Derek J. Symula
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Correspondence to Edward M. Rubin.

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Symula, D., Frazer, K., Ueda, Y. et al. Functional screening of an asthma QTL in YAC transgenic mice. Nat Genet 23, 241–244 (1999). https://doi.org/10.1038/13880

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