The genetics of variation in gene expression

The majority of genetic differences between species and individuals have been hypothesised to impact on the regulation, rather than the structure, of genes. As the details of genetic variation are uncovered by the various genome sequencing projects, understanding the functional effects on gene regulation will be key to uncovering the molecular mechanisms underying the genesis and inheritance of common phenotypes, such as complex human disease and commercially important traits in plants and animals. Unlike coding sequence polymorphisms, genetic variants affecting gene expression will reside in the transcriptional machinery and its regulatory inputs. As these are largely specific tocell- or tissue-types, we would expect that regulatory variants will also affect final mRNA levels in a tissue specific manner. Genetic variation between individuals may therefore be more complex than the sum total of sequence differences between them. Demonstrating this hypothesis is the main focus of this thesis. We use microarrays to measure mRNA levels of approximately 22,000 transcripts in inbred and recombinant inbred strains of mice, and present compelling evidence that the genetic influences on these levels are tissue-specific in at least 85% of cases.We uncover two loci which apparently influence transcript levels of multiple genes in a tissue-specific manner. We also present evidence that failure of microarray data normalisation may cause spurious linkage of expression phenotypes leading to erroneous biological conclusions, and detail a novel, extensible mathematical framework for performing tailored normalisation which can remove such systematic bias. The wider context of these results is then discussed