The Causes and Consequences of Complementation and Selfishness in Viruses

描述（由申请人提供）：当两种病毒感染单个宿主细胞时，它们以影响其进化和发病机制的方式相互作用。我将研究两种这样的相互作用：1)互补，一个病毒携带的等位基因被另一个病毒携带的同源等位基因掩盖；2)自私，一个等位基因以牺牲同源等位基因为代价利用共享资源。这些相互作用允许降低适应性的突变（即有害和自私的突变）的持续存在，并减缓有益突变的固定。虽然已观察到互补和自私在特定情况下影响耐药性和毒力的演变，但尚未研究这些相互作用的一般性质及其在病毒中出现的频率。我将进行进化实验来研究噬菌体96中互补和自私的原因和适应性后果。具体目标确定优势生理理论是否准确地预测了病毒中的互补效应。我将进行两组实验来验证这一点。第一部分将研究显性和有害突变选择系数之间的关系，以确定是否如显性生理学理论所预测的那样，它们是负相关的。第二篇将研究在病毒为单倍体的种群中积累的有益突变的关系。特定目标2：确定适应的遗传基础在单倍体和二倍体群体之间是否不同。我将从两个方面来检验这个问题。首先，我将确定在二倍体群体中积累的适应性突变是否比在单倍体群体中积累的适应性突变更自私。其次，我将测量在病毒有效为二倍体（即宿主细胞通常被两种病毒感染）的种群中积累的有益突变的优势系数。然后，我将使用第二个实验的数据来测试二倍体群体中积累的适应性突变是否如霍尔丹筛子所预测的那样，比单倍体群体中积累的突变更占优势。相关性：双重感染期间病毒之间的相互作用可能影响感染的毒力和耐药性的演变。因此，了解噬菌体中的这些相互作用可能为人类病毒病原体的进化和发病机制提供见解。

DESCRIPTION (provided by applicant): When two viruses infect a single host cell, they interact in ways that influence their evolution and pathogenesis. I will investigate two such interactions: 1) complementation, the masking of an allele carried by one virus by the homologous allele carried by the other virus, and 2) selfishness, the exploitation of a shared resource by one allele at a cost to the homologous allele. These interactions allow the persistence of mutations that reduce fitness (i.e. deleterious and selfish mutations), and slow the fixation of beneficial mutations. Although complementation and selfishness have been observed to affect the evolution of drug resistance and virulence in particular cases, the general nature of these interactions and the frequency with which they arise in viruses has not been studied. I will conduct evolution experiments to examine the causes and fitness consequences of complementation and selfishness in the bacteriophage 96. Specific Aim 1. Determine whether the physiological theory of dominance accurately predicts the effects of complementation in viruses. I will perform two sets of experiments to test this. The first will examine the relationship between dominance and selection coefficients of deleterious mutations to determine whether, as predicted by the physiological theory of dominance, they are negatively correlated. The second will examine this relationship for beneficial mutations accumulated in populations where viruses are haploid. Specific Aim 2: Determine whether the genetic basis of adaptation differs between haploid and diploid populations. I will examine this in two ways. First, I will determine whether adaptive mutations accumulated in diploid populations are more often selfish than those accumulated in haploid populations. Second, I will measure the dominance coefficients of beneficial mutations accumulated in populations where viruses are effectively diploid (i.e. host cells are typically infected by two viruses). I will then use data from this second experiment to test whether adaptive mutations accumulated in diploid populations are, as predicted by Haldane's Sieve, more dominant that mutations accumulated in haploid populations. Relevance: Interactions between viruses during dual infections may affect the virulence of infections and the evolution of drug resistance. As a result, understanding these interactions in bacteriophage may provide insights into the evolution and pathogenesis of viral pathogens of humans.