Functional screening of an asthma QTL in YAC transgenic mice

Many quantitative trait loci (QTLs) contributing to genetically complex con ditions have been discovered, but few causative genes have been identified. This is mainly due to the large size of QTLs and the subtle connection bet ween genotype and quantitative phenotype associated with these conditions(1 ,2) Transgenic mice have been successfully used to analyse well-characteriz ed genes suspected of contributing to quantitative traits(3-5). Although th is approach is powerful for examining one gene at a time, it can be impract ical for surveying the large genomic intervals containing many genes that a re typically associated with QTLs. To screen for genes contributing to an a sthma QTL mapped to human chromosome 5q3 (refs 6,7), we characterized a pan el of large-insert 5q31 transgenics based on studies demonstrating that alt ering gene dosage frequently affects quantitative phenotypes normally influ enced by that gene. This panel of human YAC transgenics, propagating a 1Mb interval of chromosome 5q31 containing 6 cytokine genes and 17 partially ch aracterized genes(8), was screened for quantitative changes in several asth ma-associated phenotypes. Multiple independent transgenic lines with altere d IgE response to antigen treatment shared a 180-kb region containing 5 gen es, including those encoding human interleukin 4 (IL4) and interleukin 13(I L 13), which induce IgE class switching in B cells(9). Further analysis of these mice and mice transgenic for mouse Il14 and Il13 demonstrated that mo derate changes in Il4 and Il13 expression affect asthma-associated phenotyp es in vivo. This functional screen of large-insert transgenics enabled us t o identify genes that influence the QTL phenotype in vivo.