Genomic studies of antagonistic pleiotropy

描述（由申请人提供）：我的研究项目的长期目标是了解表型变异和进化的分子遗传机制和驱动力。拮抗多效性（Antagonistic pleiotropy， AP）是遗传学中最常见但却鲜为人知的现象之一。它是指一个突变对多个性状的表型效应是相反的。AP被广泛应用于衰老、癌症、遗传疾病、性冲突、合作、进化约束、适应、新功能化和物种形成的解释和模型中。例如，一种流行的衰老理论断言，在生命早期有利于发育和繁殖的突变，在生命后期往往是有害的，并导致衰老。由于致病突变对生活其他方面的益处，AP也被认为会导致一些遗传疾病的意外流行。例如，已知引起亨廷顿氏病的突变会增加繁殖力。AP表明，一个突变不太可能对多个性状或多个环境有利，从而导致不同性状或不同环境的适应之间的妥协。这个基本性质限制了范围和速率

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.