A systems-genetics analyses of complex phenotypes

Complex phenotypes are traits which are influenced by many factors, and not just a single gene, as for classical Mendelian traits. The brain, and its resultant behaviour, gives us a large subset of complex phenotypes to examine. Variation in these traits is affected by a range of different influences, both genetic and environmental, including social interactions and the effects of parents. Systems-genetics provides us with a framework in which to examine these complex traits, seeking to connect genetic variants to the phenotypes they cause, through intermediate phenotypes, such as gene expression and protein levels. This approach has been developed to exploit and analyse massive data sets generated for example in genomics and transcriptomics. In the first half of this thesis, I combine genetic linkage data from the BXD recombinant inbred mouse panel with genome-wide association data from humans to identify novel candidate genes, and use online gene annotations and functional descriptions to support these candidates. Firstly, I discovered MGST3 as a novel regulator of hippocampus size, which may be linked to neurodegenerative disorders. Secondly, I identified that CMYA5, MCTP1, TNR and RXRG are associated with mouse anxiety-like phenotypes and human bipolar disorder, and provide evidence that MCTP1, TNR and RXRG may be acting via inter-cellular signalling in the striatum. The second half of this thesis uses different cross-fostering designs between genetically variable BXD lines and the genetically uniform C57BL/6J strain to identify indirect genetic effects and the loci underlying them. With this, I have found novel loci expressed in mothers that alter offspring behaviour, novel loci expressed in offspring affecting the level of maternal care, and novel loci expressed in offspring, which alter the behaviour of their nestmates, as well as the level of maternal care they receive. Further I provide evidence of co-adaptation between maternal and offspring genotypes, and a positive indirect genetic effect of offspring on their nestmates, supportive of a role for kin selection. Finally, I demonstrate that the BXD lines can be used to investigate genes with parent-of-origin dependent expression, which have an indirect genetic effect on maternal care. In conclusion, this thesis identifies a number of novel loci, and in some cases genes, associated with complex traits. Not only are these techniques applicable to other phenotypes and other questions, but the candidates I identify can now be examined further in vitro or in vivo.