Genomic studies of antagonistic pleiotropy

描述(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(AP)是遗传学中最常见但最不了解的现象之一。它指的是观察到一种突变对多个性状的表型效应是相反的。AP在衰老、癌症、遗传病、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被广泛引用。例如，一种流行的衰老理论断言，在生命早期有利于发育和生殖的突变往往在晚年有害，并导致衰老。AP还被认为导致了一些遗传疾病的意外流行，因为致病突变给生活的其他方面带来了好处。例如，众所周知，导致亨廷顿病的突变会增加生育能力。AP规定，突变不太可能对多种特征或多种环境有利，导致不同特征或不同环境的适应之间的妥协。这一基本属性限制了范围和速度 并保证没有任何物种或基因在所有环境中的表现都优于其他所有物种或基因。与AP在许多理论和人类健康问题上的重要性相比，我们对AP的经验知识和理解极其有限。目前尚不清楚(I)AP在基因组水平上的普遍程度，(Ii)哪些基因往往受到AP的影响，在什么条件下，以及(Iii)AP是否可以在多大程度上通过什么遗传机制进化解决。本文以面包酵母为模型，从功能基因组学、分子遗传学和理论群体遗传学三个方面对上述问题进行了研究。这个项目代表了AP的第一个全基因组特征，并有望极大地扩展我们对AP模式和机制的知识。这些知识对于评估所有AP依赖理论的有效性以及理解和解决AP相关的健康问题至关重要。

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.