A Unified Model of Gene Regulatory Circuit Evolution

描述(申请人提供)：细胞使用特殊的调控基因控制其基因的时间和表达水平，这些基因在复杂的电路中相互作用，激活或抑制蛋白质编码DNA的转录。我们对复杂的转录电路是如何进化的知之甚少。这个项目的目标是结合多种方法-基因组学、生物化学、分子进化、祖先重建和计算建模-来学习复杂调控电路背后的进化机制。申请者Victor Hanson-Smith博士将使用酵母菌白念珠菌作为研究这一问题的模式生物。白色念珠菌在植入人体的医疗设备上形成表面相关生物膜；与设备相关的生物膜是慢性感染和危及生命的疾病的蓄水池。白色念珠菌通过一个复杂的电路控制生物膜的形成，该电路由六个主调节基因和数千个下游靶基因组成。目前尚不清楚生物膜的形成是如何进化的，也不知道白色念珠菌生物膜网络是否是许多替代方案中的一个进化解决方案。汉森-史密斯博士将使用一种新的定量模型来研究生物膜基因回路的进化，该模型包含了关于基因调控的前所未有的细节。他的方法是从白色念珠菌的分子实验中学习这个模型的经验得出的参数值，然后使用模拟研究来测试生物膜形成的进化模型。汉森-史密斯博士的方法与许多其他类型的进化模拟不同，因为它基于相关分子的真实属性，而不是基因调控的抽象参数。由于这是一个F32培训奖，该项目的一个主要组成部分是对Hanson-Smith博士进行基因组测序和基因表达水平分析技术方面的培训。在这个项目结束时，汉森-史密斯博士将在管理基因调控的分子系统方面接受过出色的培训，因此，结合他的计算背景，他将处于建立和指导自己的研究实验室的有利地位。从科学上讲，这个项目将揭示白色念珠菌获得生物膜形成的进化途径；它还可能揭示临床上控制生物膜形成的新方法，以及未来病原体可能如何进化的一般原理。更广泛地说，这个项目将为理解、甚至预测导致整个生命树上复杂生理特征发展的进化轨迹的类型提供一个框架。

DESCRIPTION (provided by applicant): Cells control the timing and expression levels of their genes using special regulatory genes that interact in complex circuits to activate or repress the transcription of protein-coding DNA. We have little understanding of how complex transcriptional circuits evolve. The goal of this project is to combine multiple approaches - genomics, biochemistry, molecular evolution, ancestral reconstruction, and computational modeling - to learn the evolutionary mechanisms underlying complex regulatory circuits. The applicant, Dr. Victor Hanson-Smith, will use the yeast species Candida albicans as a model organism for studying this problem. C. albicans form surface-associated biofilms on implanted medical devices in humans; device-associated biofilms serve as reservoirs for chronic infection and life-threatening illness. C. albicans control biofilm formation using a complex circuit with six master-regulator genes and thousands of downstream target genes. It is not known how biofilm formation evolved, or if the C. albicans biofilm network is one evolutionary solution among many alternatives. Dr. Hanson-Smith will study the evolution of the biofilm gene circuit using a new quantitative model that incorporates unprecedented detail about gene regulation. His approach is to learn empirically- derived parameter values for this model from molecular experimentation in C. albicans, and then use simulation studies to test models for the evolution of biofilm formation. Dr. Hanson-Smith's approach differs from many other types of evolutionary simulations as it is based on real properties of the relevant molecules involved rather the abstract parameters of gene regulation. Since this is a F32 training award, a major component of this project is the training of Dr. Hanson-Smith in the techniques of genome sequencing and assaying gene expression levels. At the end of this project, Dr. Hanson-Smith will have received outstanding training in the molecular systems governing gene regulation, and therefore - combined with his computational background -- he will be well positioned to establish and direct his own research lab. Scientifically, this project will shed light on the evolutionary pathway by which C. albicans acquired biofilm formation; it may also reveal novel ways of controlling biofilm formation in the clinic, and general principles of how future pathogens might be expected to evolve. More broadly, this project will provide a framework for understanding, and even predicting, the types of evolutionary trajectories that lead to the development of complex physiological traits across the tree of life.