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.

Public Health Relevance

Although antagonistic pleiotropy (AP) is commonly invoked in explanations of aging, cancer, and genetic disease, there is little empirical knowledge about AP. The proposed work characterizes and clarifies the prevalence of AP, extent and mechanisms of AP resolution, and conditions for AP resolution, providing important information for understanding the proximate and ultimate causes of many diseases and biomedical phenomena.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GGG-E (02))
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Krasnewich, Donna M
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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Li, Chuan; Zhang, Jianzhi (2018) Multi-environment fitness landscapes of a tRNA gene. Nat Ecol Evol 2:1025-1032
Yang, Jian-Rong; Maclean, Calum J; Park, Chungoo et al. (2017) Intra and Interspecific Variations of Gene Expression Levels in Yeast Are Largely Neutral: (Nei Lecture, SMBE 2016, Gold Coast). Mol Biol Evol 34:2125-2139
Wei, Xinzhu; Zhang, Jianzhi (2017) The Genomic Architecture of Interactions Between Natural Genetic Polymorphisms and Environments in Yeast Growth. Genetics 205:925-937
Zou, Zhengting; Zhang, Jianzhi (2017) Gene Tree Discordance Does Not Explain Away the Temporal Decline of Convergence in Mammalian Protein Sequence Evolution. Mol Biol Evol 34:1682-1688
Ho, Wei-Chin; Ohya, Yoshikazu; Zhang, Jianzhi (2017) Testing the neutral hypothesis of phenotypic evolution. Proc Natl Acad Sci U S A 114:12219-12224
Wei, Xinzhu; Zhang, Jianzhi (2017) Why Phenotype Robustness Promotes Phenotype Evolvability. Genome Biol Evol 9:3509-3515
Zhang, Jianzhi (2017) Epistasis Analysis Goes Genome-Wide. PLoS Genet 13:e1006558
Xu, Jinrui; Zhang, Jianzhi (2016) Impact of structure space continuity on protein fold classification. Sci Rep 6:23263
Moyers, Bryan A; Zhang, Jianzhi (2016) Evaluating Phylostratigraphic Evidence for Widespread De Novo Gene Birth in Genome Evolution. Mol Biol Evol 33:1245-56
Chen, Xiaoshu; Zhang, Jianzhi (2016) The Genomic Landscape of Position Effects on Protein Expression Level and Noise in Yeast. Cell Syst 2:347-54

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