Genetic interactions and the evolution of complex traits in yeast

项目摘要/摘要 适应性进化是生物学中的一个基本过程。在其最简单的随机突变中产生 选择所作用的表型变异，丰富有利的表型，清除较少的表型-- 有利的。这一过程造就了地球上生命的多样性。但与此同时，自适应 进化是人类健康中一些最令人烦恼的问题的罪魁祸首，从不断增长的问题 抗生素耐药性对病毒病原体的实时进化到抵抗药物治疗的癌症和 逃避免疫系统。尽管如此，我们缺乏对基因组如何 响应选择。一个主要的未知数是，自适应进化是如何从 在众多可能的选择中。另一个主要的未知数是基因变异如何产生新的 选择所依据的表型。实验进化为解决这两个问题提供了一条前进的道路 我们知识中的这些重大差距。随着高通量生物学的进步，我们可以进化出数百个 最初相同的种群在几千代人中平行存在，并对 实验参数。这种多才多艺的技术使我们能够通过 不可能在自然种群中进行的实验。同时，实验进化 是功能基因组学的有力工具。通过识别响应选择的基因和途径 压力，以及这些突变如何相互作用来改变表型，实验室进化实验发现 以前不为人知的细胞连接。在过去的五年里，我的实验室改进了一种机械 对适应性进化的理解。未来的研究将确定基因变化如何引起复杂的 表型。我们将在遗传背景和基因扰动后进行进化实验 在不断变化的环境中。除了增进我们对适应性进化的理解外，我们预计， 在我们先前工作的基础上，为了鉴定以前未知的核-核、核质和基因- 环境相互作用。最后，我们将开发一种快速可靠的方法来执行多轮 我们将使用这种方法来系统地分析遗传交互作用 那些被其他方法遗漏的。通过在进化的背景下将基因型与表型联系起来， 我们的工作将提供对复杂特征如何进化的机械性理解。这项工作将会取得进展 我们对适应性进化和复杂性状在较难处理的系统中的遗传基础的理解， 包括人类和人类病原体。

PROJECT SUMMARY/ABSTRACT Adaptive evolution is a fundamental process in biology. At its simplest random mutation produces phenotypic variation on which selection acts, enriching for favorable phenotypes and purging the less- favorable ones. This process has produced the diversity of life on Earth. Yet at the same time, adaptive evolution is responsible for some of the most vexing problems in human health, from the growing problem of antibiotic resistance to real-time evolution of viral pathogens to cancers that resist drug treatments and evade the immune system. Despite this, we lack a basic mechanistic understanding of how genomes respond to selection. One major unknown is how adaptive evolution “chooses” one particular path from among a vast number of possible ones. Another major unknown is how genetic variation produces new phenotypes on which selection acts. Experimental Evolution provides a way forward to address both of these significant gaps in our knowledge. With advances in high-throughput biology we can evolve hundreds of initially identical populations in parallel for thousands of generations, with exquisite control over experimental parameters. This versatile technique makes it possible to test evolutionary theory through experiments that are impossible to perform in natural populations. At the same time, experimental evolution is powerful tool for functional genomics. By identifying the genes and pathways that respond to selective pressures, and how these mutations interact to alter phenotype, laboratory evolution experiments identify previously unknown cellular connections. In the past five years my laboratory has advanced a mechanistic understanding of adaptive evolution. Future work will determine how genetic changes give rise to complex phenotypes. We will perform evolution experiments following perturbation of the genetic background and in shifting environments. In addition to advancing our understanding of adaptive evolution, we expect, based on our prior work, to identify previously unknown nuclear-nuclear, nuclear-cytoplasmic, and gene- environment interactions. Finally, we will develop a fast and reliable method for performing multiple rounds of pooled gene editing in yeast, and we will use this method to systematically assay genetic interactions that have been missed by other methods. By connecting genotype to phenotype in an evolutionary context, our work will provide a mechanistic understanding of how complex traits evolve. This work will advance our understanding of adaptive evolution and the genetic basis of complex traits in less tractable systems, including humans and human pathogens.