Comparative Genomics of Eukaryotes.

This thesis focuses on developing comparative genomics methods in eukaryotes, with an emphasis on applications for gene function prediction and regulatory element detection. In the past, methods have been developed to predict functional associations between gene pairs in prokaryotes. The challenge of this thesis was to extend the genomic association methods to eukaryotes. In the absence of operon structure in eukaryotes,we need a different way to find co-expressed genes. We found co-expressed genes by calculating correlations between expression profiles of individual genes. By applying evolutionary conservation between two species we could make predictions of functional associations between hypothetical genes. Evolutionary conservation was also applied to yeast-2-hybrid interactions; we found that the conserved interactions were more reliable than the unconserved interactions. A second type of conservation relies on the large number of gene duplications in eukaryotes. We start with pairs of genes with co-expression (A and B). Then we investigate wether a pair of paralogous genes exist (A' and B') that also is co-expressed, where A' is homologous to A and B' is homologous to B. Also this type of conserved co-expression could be used to predict functional associations. The overlap of different predictions methods can also be used to predict reliable interactions. We did this for expression datasets of the malaria parasite Plasmodium falciparum. However, we also made more creative integrations between datasets, by not just taking the overlap between existing methods and methods that we developed, but by identifying combinations of scores from different methods that can specifically predict different types of interactions. These predictions will enable experimentalists to design specific experiments to test hypothetical interactions