Genomic studies of antagonistic pleiotropy

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): The long-term objective of my research program is to understand the molecular genetic mechanisms and driving forces of phenotypic variation and evolution. Antagonistic pleiotropy (AP) is one of the most common yet least understood phenomena in genetics. It refers to the observation that the phenotypic effects of a mutation on multiple traits are opposite. AP is widely invoked in explanations and models of senescence, cancer, genetic disease, sexual conflict, cooperation, evolutionary constraint, adaptation, neofunctionalization, and speciation. For instance, a prevailing theory of aging asserts that mutations beneficial to development and reproduction in early stages of life tend to be deleterious later in life and cause senescence. AP is also believed to cause the unexpected prevalence of some genetic diseases, due to the benefits conferred by the disease-causing mutations to other aspects of life. For instance, mutations causing Huntington's disease are known to increase fecundity. AP dictates that a mutation is unlikely to be advantageous to multiple traits or in multiple environments, leading to compromises among adaptations of different traits or in different environments. This fundamental property limits the extent and rate of adaptation and guarantees that no species or genotype would outperform all others in all environments. In contrast to the importance of AP in many theories as well as human health issues, our empirical knowledge and understanding of AP is extremely limited. It is unknown (i) how prevalent AP is at the genomic scale, (ii) what genes tend to be subject to AP and under what conditions, and (iii) whether, to what extent, and by what genetic mechanisms AP can be evolutionarily resolved. Three studies, involving functional genomics, molecular genetics, and theoretical population genetics, are proposed to address the above questions at the genomic scale using the baker's yeast Saccharomyces cerevisiae as a model. This project represents the first genome-wide characterization of AP and is expected to expand substantially our knowledge of the patterns and mechanisms of AP. Such knowledge is critically needed for evaluating the validity of all AP-dependent theories and for understanding and solving AP-related health issues.