Intraspecific variation in growth

My postdoctoral research has focused on mapping and studying the effects of quantitative trait loci (QTL) that affect body size in mice, i.e., regions of the genome that contribute to continuous variation rather than major mutations that cause serious abnormalities. 

In one project, we demonstrated that a previously-identified growth QTL has a general effect on skeletal size, affecting the length of various bones (e.g., humerus, femur, tibia, mandible, scapula, pelvic girdle) in addition to tail length and body mass (Christians et al. 2003).  In subsequent work, we showed that this QTL is actually composed of multiple, linked QTL; although most of the effect is due to one main QTL, there are also other QTL with smaller effects located on either side (Christians and Keightley 2004).  A similar result was found with a different QTL that affects obesity (Stylianou et al. 2004).

More recently I have been working on a different growth QTL.  By fine mapping, examining the expression patterns and the transcript levels of genes within the QTL region, as well as searching for sequence polymorphisms, we showed that Gpc3 is the gene responsible for the effect of an X-linked QTL (Oliver et al. 2005).  The finding that Gpc3 was the gene responsible was particularly interesting because in humans, loss-of-function mutations in Gpc3 lead to Simpson-Golabi-Behmel syndrome (SGBS), a disorder with numerous phenotypic effects, including overgrowth.  This study therefore shows that a gene underlying a Mendelian disease in humans can contribute to quantitative variation in mice.  Another important result was that the QTL was caused by a ~15% difference in Gpc3 expression, showing that relatively small changes in expression levels can have a substantial effect on phenotype. 

In a third project, we examined the effect of yet another QTL in two genetic backgrounds.  Specifically, we introgressed the high-growth allele of the QTL onto a low-growth line of mice, and vice-versa (Christians et al. 2004).  This work demonstrated that the QTL had similar effects in very different genetic backgrounds.  This issue is of relevance to whether disease susceptibility alleles will have similar effects in different ethnic groups, and whether the introgression of beneficial alleles in agricultural species will be successful. 

References

Christians, J.K., Rance, K.A., Knott, S.A., Pignatelli, P.M., Oliver, F. and Bünger, L. (2004)  Identification and reciprocal introgression of a QTL affecting body mass in mice.  Genetics Selection Evolution 36: 577-591.

Christians, J.K. and Keightley, P.D. (2004) Fine mapping of a murine growth locus to a 1.4 cM region and resolution of linked QTL.  Mammalian Genome 15: 482-491.

Christians, J.K., Bingham, V., Oliver, F., Heath, T.T. and Keightley, P.D. (2003) Characterisation of a QTL affecting skeletal size in mice.  Mammalian Genome 14: 175-183.

Oliver, F. *, Christians, J.K. *, Liu, X, Rhind, S., Verma, V., Davison, C., Brown, S.D.M, Denny, P., and Keightley, P.D. (2005) Regulatory variation at glypican-3 underlies a major growth QTL in mice.  PLoS Biology 3: e135. * equal contribution.  [PDF]  

Stylianou, I.M., Christians, J.K., Keightley, P.D., Bünger, L., Clinton, M., Bulfield, G., Horvat, S. (2004) Genetic complexity of an obesity QTL (Fob3) revealed by detailed genetic mapping.  Mammalian Genome 15: 472-481.