DESCRIPTION (provided by applicant): The long-term objective of my laboratory is to understand how new genes with novel functions originate and how these molecular innovations contribute to the survival, adaptation, and evolution of organisms. Gene duplication is wildly regarded as the primary source of new genes, but the general patterns and mechanisms of functional divergence of duplicate genes are not well understood. Taking advantage of high-throughput genomic technologies and unprecedented amount of functional genomic data, we propose experimental and computational functional genomic approaches to duplicate gene evolution, with four specific aims. First, using protein-protein interaction (PPI) as a measure of protein function, we plan to study the rate of protein functional change in duplicated and unduplicated genes between the budding yeast Saccharomyces cerevisiae and its relative Kluyveromyces waltii. The S. cerevisiae lineage experienced a whole-genome duplication (WGD) shortly after its separation from K. waltii and has retained ~450 pairs of WGD-duplicates. PPI information from S. cerevisiae is publicly available, while the corresponding PPIs in K. waltii will be experimentally tested. Second, we propose to make custom gene expression microarrays of K. waltii and compare its genome- wide gene expression pattern with that of S. cerevisiae to study how expression patterns of unduplicated and duplicated genes change in evolution. A similar analysis will also be conducted on the publicly available high-quality microarray data of the human and mouse. Third, competing hypotheses exist on whether gene duplication in an individual organism causes an immediate fitness gain by providing extra protein products, an immediate fitness loss by wasting energy for making extra products that are not needed, or no fitness change. Using publicly available functional genomic data of yeast and mammals, we will examine these hypotheses computationally. We will then experimentally measure in yeast the fitness cost of protein production at various levels, using foreign proteins that are not needed in yeast. Fourth, it is controversial as whether a gene can functionally compensate the loss of its duplicate copy. We propose a critical examination of this compensation hypothesis by a yeast experiment in which we measure the fitness change caused by replacing the coding region of a gene with that of its paralog. Complete protein compensation predicts no fitness change whereas an absence of compensation leads to fitness reduction. Together, these studies are expected to improve significantly our understanding of the patterns and mechanisms of duplicate gene evolution. PUBLIC HEALTH RELEVANCE: Our projects will increase understanding of mechanisms of gene evolution and aid many studies of how new biological functions arise. Our study is of human health relevance, because many gene copy number variations, generated by gene duplication, are involved in human diseases. Furthermore, different functional relationships among duplicate genes (e.g., completely redundant, partially overlapping, or distinctly different) would predict different consequences of mutations to the likelihood and severity of genetic diseases. A clear understanding of these relationships helps clarify the exact molecular basis of human diseases, a necessary step in the treatment and prevention of these diseases.

NARRATIVE ON PROJECT RELEVANCE Our projects will increase understanding of mechanisms of gene evolution and aid many studies of how new biological functions arise. Our study is of human health relevance, because many gene copy number variations, generated by gene duplication, are involved in human diseases. Furthermore, different functional relationships among duplicate genes (e.g., completely redundant, partially overlapping, or distinctly different) would predict different consequences of mutations to the likelihood and severity of genetic diseases. A clear understanding of these relationships helps clarify the exact molecular basis of human diseases, a necessary step in the treatment and prevention of these diseases.