GENETIC DIVERSITY AND COMPLEX TRAITS IN S CEREVISIAE

这项提议的具体目标是克隆、鉴定和排序负责一种复杂遗传性状的基因，即在42度下生长的能力。相关基因序列将从能够在42度下生长的菌株中确定，并与S288c参考菌株（不能在42度下生长）序列进行比较。克隆的基因将用于制造一系列在高温生长位点不同的确定的等基因菌株。这些等基因菌株将进行高温生长测试，以确定每个等位基因/位点对表型的贡献，以及位点之间的相互作用（显性与隐性，加性与上位性），以精确的遗传和分子术语。这个提议在三个方面与健康有关。首先，在高温下生长的能力是酿酒酵母和其他真菌的一种毒力特性。了解在高温下生长的能力将有助于我们了解真菌的发病机制。其次，这项对一种毒力性状的研究是对其他真菌毒力性状的解剖和酿酒葡萄球菌作为致病真菌模型的发展的前奏。这项研究将告诉我们机会性病原体是如何从无害腐生植物的基因库中出现的。更好地了解真菌的发病机制也将有助于抗真菌药物的开发。最后，本建议解决了遗传学中的一个主要问题——复杂的多基因性状和遗传多样性。复杂的多基因性状尚未得到很好的理解。许多人类遗传疾病本质上是定量的。复杂多基因性状的微生物模型的发展将使这些性状在精确的遗传和分子术语中得到理解，从而有助于理解高等生物的数量性状。本研究的长期目标是：1 .)开发酿酒葡萄球菌作为分析复杂多基因性状的微生物模型；2.)鉴定允许特定酿酒葡萄球菌菌株在高温下生长的遗传机制；3.)开发酿酒葡萄球菌作为致病真菌的遗传可操作模型和作为真菌毒力种间重构的宿主。

The specific aims of this proposal are to clone, identify and sequence the genes responsible for one genetically complex trait, the ability to grow at 42 degrees. The sequences of the relevant genes will be determined from strains able to grow at 42 degrees and compared with the S288c reference strain (unable to grow at 42 degrees) sequence. The cloned genes will be used to make a series of defined isogenic strains which differ at the high temperature growth loci. These isogenic strains will be tested for high temperature growth to determine the contribution of each allele/locus to phenotype as well as the interactions of the loci (dominant vs. recessive, additive vs. epistatic) i precise genetic and molecular terms. This proposal is health related in three ways. First, the ability to grow at high temperatures is a virulence trait in S. cerevisiae and other fungi. Understanding the ability to grow at high temperatures will aid our understanding of fungal pathogenesis. Second, this study on one virulence trait is a prelude to a dissection of other fungal virulence traits and to the development of S. cerevisiae as a model for the pathogenic fungi. This study will tell us how an opportunistic pathogen has emerged from the gene pool of a harmless saprophyte. A better understanding of fungal pathogenesis will also aid the development of antifungal drugs. Finally, this proposal addresses a major problem in genetics -- complex polygenic traits and genetic diversity. Complex polygenic traits are not well understood. Many human genetic diseases are quantitative in nature. The development of a microbial model for complex polygenic traits will allow these traits to be understood in precise genetic and molecular terms and thereby aid the understanding of quantitative traits in higher organisms. The broad long term objectives of this proposal are: l.) the development of S. cerevisiae as a microbial model for the analysis of complex polygenic traits, 2.) the identification of the genetic mechanisms which allow specific S. cerevisiae strains to grow at very high temperatures, and 3.) the development of S. cerevisiae as genetically manipulable model for the pathogenic fungi and as a host for the interspecific reconstitution of fungal virulence.