Koning, D.J. de

Haley, Chris

Knott, Sara

Lam, Alex C.

Genus / PIC

Biotechnology and Biological Sciences Research Council (BBSRC)

Genesis Faraday Partnership

2010-10-13T08:25:31Z

2010-10-13T08:25:31Z

2009

Quantitative Trait Loci (QTL) mapping has been widely used to identify genetic loci attributable to the variation observed in complex traits. In recent years, gene expression phenotypes have emerged as a new type of quantitative trait for which QTL can be mapped. Locating sequence variation that has an effect on gene expression (eQTL) is thought to be a promising way to elucidate the genetic architecture of quantitative traits. This thesis explores a number of methodological aspects of eQTL mapping (also known as “genetical genomics”) and considers some practical strategies for applying this approach to livestock populations. One of the exciting prospects of genetical genomics is that the combination of expression studies with fine mapping of functional trait loci can guide the reconstruction of gene networks. The thesis begins with an analysis in which correlations between gene expression and meat quality traits in pigs are investigated in relation to a pork meat quality QTL previously identified. The influence on power due to factors including sample size and records of matched subjects is discussed. An efficient experimental design for two-colour microarrays is then put forward, and it is shown to be an effective use of microarrays for mapping additive eQTL in outbred crosses under simulation. However, designs optimised for detecting both additive and dominance eQTL are found to be less effective. Data collected from livestock populations usually have a pedigreed structure. Many family-based association mapping methods are rather computationally intensive, hence are time-consuming when analysing very large numbers of traits. The application of a novel family-based association method is demonstrated; it is shown to be fast, accurate and flexible for genetical genomics. Furthermore, the results show that multiple testing correction alone is not sufficient to control type I errors in genetical genomics and that careful data filtering is essential. While it is important to limit false positives, it is desirable not to miss many true signals. A multi-trait analysis based on grouping of functionally related genes is devised to detect some of the signals overlooked by a univariate analysis. Using an inbred rat dataset, 13 loci are identified with significant linkage to gene sets of various functions defined by Gene Ontology. Applying this method to livestock species is possible, but the current level of annotations is a limiting factor. Finally, the thesis concludes with some current opinions on the development of genetical genomics and its impact on livestock genetics research.

http://hdl.handle.net/1842/3950

en

The University of Edinburgh

Lam, A.C., Fu, J., Jansen, R.C., Haley, C.S., and de Koning, D.J. 2008. Optimal design of genetic studies of gene expression with two-colour microarrays in outbred crosses. Genetics.180(3): 1691-8.

Lam, A.C., Powell, J., Wei, W.H., de Koning, D.J., and Haley, C.S. 2008. A combined strategy for quantitative trait loci detection by genome-wide association. in press.

Lam, A.C., Schouten, M., Aulchenko, Y.S., Haley, C.S., and de Koning, D.J. 2007. Rapid and robust association mapping of expression QTL. BMC Proceedings 1 Suppl 1:S144.

Lam, A.C., Sorensen, P., Petretto, E., Aitman, T.J., Haley, C.S., and de Koning, D.J. 2008. Pathway-based approach for genetic analysis of gene expression. 7th Annual Meeting of the Complex Trait Consortium. Abstract A3.

Lam, A.C., Massault, C., Dornan, S., Wilkinson, J.M., Davey, G., Tilley, R., Blott, S.C., Sargent, Cairns, M., Evans, G., Plastow, G.S., Knott, S.A., Haley, C.S., and de Koning, D.J. 2006. Pathway inference using genetical genomics in pigs. 8th World Congress on Genetics Applied to Livestock Production. Communication 23-14.

genetical genomics

quantitative trait loci

eQTL

Design and analysis of genetical genomics studies and their potential applications in livestock research

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy