Molecular Mechanisms of Adaptive Evolution in Pathogen Populations

这项研究将解决病原体生物学中一个我们知之甚少的核心问题：什么类型的基因发生了什么类型的变化，导致了宿主特异性的出现？昆虫病原真菌绿僵菌为研究这一问题提供了一个很好的模型系统。它是一种辐射物种，并包含具有广泛和狭窄的宿主范围的通才和专门化谱系。可以选择代表100万年至1100万年进化距离的菌株，它们的自然分子变异允许分析仍在进行的适应性变化和进化分化过程，甚至处于中间状态。为了研究调控变异和基因含量的变化对感染特征的影响，研究人员将通用菌株和特殊菌株的cDNA或DNA与参考菌株在感染过程中表达的数千条ESTs共杂交。这将：1)研究基因复制、分化和降解对致病性特化的贡献；2)鉴定假基因，这将为研究中性序列进化在真菌中的作用及其在不同谱系中的潜在突变过程提供一个独特的数据集。利用基因表达图谱，结合调节mRNA水平的技术，研究者将探索基因表达的控制在多大程度上被用作进化的载体，以确定多种菌株的宿主范围。在进一步的实验中，他将研究调控基因的作用，包括几个可能在宿主转换中起作用的基因。就广泛的影响而言，遗传变异是研究适应的分子基础（进化生物学的“圣杯”之一）的有力工具，这里提出的关于新病原体出现的机制的问题解决了许多基本的，但知之甚少的问题，这些问题跨越了分子进化的许多领域。解决这些问题将大大增加我们对新病原体在广泛或狭窄宿主范围内出现的机制的认识。它还将大大增加我们对真菌基因组动力学的认识，并有助于确定适当的进化距离，以回答突变率、基因降解和基因表达调节等问题。这将有助于为比较基因组学奠定基础，并为更广泛的真菌基因组采样提供最佳选择。该项目还将为来自弱势群体的博士后、研究生和本科生提供研究机会。

This research will address a central question in pathogen biology about which we know little: what types of changes in what types of genes account for the emergence of host specificity? The entomopathogenic fungus Metarhizium anisopliae provides an excellent model system for studying this question. It is a radiating species, and contains both generalist and specialized lineages with broad and narrow host ranges. Strains representing evolutionary distances ranging from 1 to11 million years can be selected and their natural molecular variation allows analysis of processes of both adaptive change and phylectic differentiation still in operation, even in intermediate states. To investigate how regulatory variation and changes in gene content contribute to infection characteristics, cDNA or DNA from generalist and specialist strains will be co-hybridized to thousands of ESTs expressed during infection processes by a reference strain. This will: 1) investigate the contribution to pathogenic specialization of gene duplication, divergence and degradation, and 2) identify pseudogenes that will provide a unique dataset to study the role of neutral sequence evolution in a fungus and its underlying mutational processes in different lineages. Using atlases of gene expression, combined with technologies to modulate mRNA levels, the investigator will explore the extent to which control of gene expression is used as a vehicle by evolution to define the host range of multiple strains. In further experiments he will look at the role of regulatory genes, including several that may play a role in host switching.In terms of broad impact, genetic variation is a powerful tool to study the molecular basis of adaptation (one of the "Holy Grails" of evolutionary biology) and the questions being asked here on the mechanisms by which novel pathogens emerge address many basic, yet poorly understood issues that span much of molecular evolution. Addressing these issues will greatly increase our knowledge of the mechanisms by which new pathogens emerge with either wide or narrow host ranges. It will also greatly increase our knowledge of the dynamics of a fungal genome and help define the appropriate evolutionary distances for answering questions on mutation rates, gene degradation and modulation of gene expression. This will help establish a foundation for comparative genomics and inform optimal choices for broader sampling of fungal genomes. The project will also provide research opportunities for a postdoctoral fellow, graduate students and undergraduate students from underrepresented groups.