The Causes and Consequences of Complementation and Selfishness in Viruses

描述(申请人提供)：当两种病毒感染一个宿主细胞时，它们以影响其进化和致病的方式相互作用。我将研究两种相互作用：1)互补，一种病毒携带的等位基因被另一种病毒携带的同源等位基因掩盖；2)自私，一种等位基因以牺牲同源等位基因为代价利用共享的资源。这些相互作用允许降低适合度的突变(即有害和自私的突变)的持续存在，并减缓有益突变的固定。虽然已经观察到互补和自私在特定情况下影响耐药性和毒力的进化，但这些相互作用的一般性质和它们在病毒中出现的频率尚未被研究。我将进行进化实验，以研究噬菌体96中互补和自私的原因和健康后果。具体目标1。确定显性生理理论是否准确地预测了病毒中的互补效应。我将执行两组实验来测试这一点。第一项研究将考察有害突变的显性和选择系数之间的关系，以确定它们是否如显性生理学理论所预测的那样是负相关的。第二项研究将研究在病毒为单倍体的种群中积累的有益突变的这种关系。具体目标2：确定单倍体和二倍体种群适应的遗传基础是否不同。我将从两个方面来研究这一点。首先，我将确定二倍体种群中积累的适应性突变是否比单倍体种群中积累的适应性突变更自私。其次，我将测量在病毒有效二倍体(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显性系数。然后，我将使用第二个实验的数据来测试二倍体种群中积累的适应性突变是否像霍尔丹筛子预测的那样，比单倍体种群中积累的突变更显性。相关性：双重感染期间病毒之间的相互作用可能会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有助于深入了解人类病毒病原体的进化和发病机制。

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.