GENETIC DIVERSITY AND COMPLEX TRAITS IN S CEREVISIAE

这项提议的具体目标是克隆、鉴定和测序负责一种基因复杂特征的基因，即42度生长的能力。相关基因的序列将从能够在42度生长的菌株中确定，并与S288c参考菌株(不能在42度生长)序列进行比较。克隆的基因将被用来制造一系列定义的同基因菌株，这些菌株在高温生长位置上存在差异。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/基因座对表型的贡献，以及这些基因座(显性与隐性、加性与上位性)之间的相互作用。这项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征。了解真菌在高温下生长的能力将有助于我们理解真菌的发病机制。其次，对一种致病性状的研究是剖析其他致病性状的前奏，也是发展酿酒酵母作为致病真菌模式的前奏。这项研究将告诉我们，一种条件致病菌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，这项建议解决了遗传学中的一个主要问题--复杂的多基因特征和遗传多样性。复杂的多基因特征还没有被很好地理解。许多人类遗传病在本质上是定量的。针对复杂多基因性状的微生物模型的发展将使人们能够从精确的遗传和分子角度理解这些性状，从而有助于理解高等生物中的数量性状。这项建议的长远目标是：L。)酿酒酵母作为分析复杂多基因性状的微生物模型的发展，2。鉴定允许特定酿酒酵母菌株在非常高的温度下生长的遗传机制，以及3.酿酒酵母作为病原真菌的遗传操作模型和真菌毒力种间重组的宿主的发展。

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.