CHRISTIANS, Julian K*; HOEFLICH, Andreas; KEIGHTLEY, Peter D; Simon Fraser University; Ludwig-Maximilians Universitaet; University of Edinburgh: Investigation of the causal gene underlying a quantitative trait locus (QTL) contributing to genetic variation in growth

Within all species, many traits show continuous variation between individuals, with phenotype determined by both the environment and a potentially large number of genes. Understanding the genetic basis of intraspecific variation is of fundamental importance to medicine, evolutionary biology and agriculture. In the past decade, enormous effort has focused on identifying genes underlying quantitative trait loci (QTL), i.e., naturally occurring genetic variation that contributes to �normal� variation within species. Our recent work has focused on a QTL with a general effect on size in mice; the QTL affects the length of the tail and various bones, and has a weaker effect on mass. We have refined the location of this QTL to a chromosomal region containing only four genes, one of which is a strong candidate: the mouse orthologue of the human PAPPA2 gene. The protein product of this gene is known to cleave insulin-like growth factor-binding protein 5 (IGFBP-5) in vitro, but its physiological role is poorly understood. To evaluate whether this candidate gene is responsible for the effect of the QTL, we have examined coding sequence variation between QTL alleles and found a number of amino-acid changing differences. We are also examining the tissue expression profile of this gene, and whether its expression levels differ between QTL genotypes. Furthermore, effects on potential downstream pathways (e.g., IGFBP-5) are also being investigated. This system promises a powerful model for exploring the physiological pathways by which genetic variation leads to phenotypic variation.