Analysis of Gene Function by Genome-wide Transcriptional Phenotyping

Baylor College Of Medicine, Houston TX

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Abstract

Global expression profiles are excellent phenotypes. In cancer biology they can be used for diagnosis and[unreadable] prognosis. In yeast and other model organisms they have been used for discovering gene function and[unreadable] drug targets. In the previous funding period we found that expression profiles of Dictyostelium are also[unreadable] useful diagnostics. We also tested and proved the hypothesis that expression profiles can be used as[unreadable] phenotypes for genetic epistasis analysis and pathway construction. In this proposal we will assign function[unreadable] to hundreds of genes by using expression profiles as phenotypes to characterize mutants. We will also test[unreadable] the hypothesis that distinct patterns of global gene expression represent specific, definable biological[unreadable] functions. In a nutshell, we propose that changes in subsets of the expression pattern represent changes[unreadable] in specific biological functions such as cell-cell adhesion or chemotaxis. If this hypothesis were correct, one[unreadable] would be able to identify the specific biological functions that have been affected by mutations or drug[unreadable] treatment, turning the expression profile from an abstract phenotype into a direct diagnostic tool. The[unreadable] applicaiton of this discovery to human health is self evident as it would transform microarray diagnosis of[unreadable] cancer and other diseases from a comparative method into a direct diagnostic method. To reach these[unreadable] goals we will perform microarray analysis of gene expression on several hundred mutants, correlate their[unreadable] expression profiles with other phenotypes, such as chemotaxis, infer which biological functions are[unreadable] represented by which subset of the expression profile and test the functions directly by mutagenesis. In[unreadable] addition, we will analyze selected mutants for specific functions. We will test mutants in 20 of the 66 ABC[unreadable] transporters, all 19 bZIP transcription factors, mutants in a new chemotaxis pathway and mutants with[unreadable] altered sensitivity to the anti-cancer drug cisplatin. Successful completion of these goals will assign[unreadable] function to hundreds of new genes and turn expression profiling into a powerful tool for direct diagnosis of[unreadable] biological function. The data will also be disseminated to the community as a means of expanding the[unreadable] correlation between expression profiles and specific biological functions beyond the scope of this proposal.