We sequenced the genome of Saccharomyces cerevisiae strain YJM789, which was derived from a yeast isolated from the lung of an AIDS patient with pneumonia. The strain is used for studies of fungal infections and quantitative genetics because of its extensive phenotypic differences to the laboratory reference strain, including growth at high temperature and deadly virulence in mouse models. Here we show that the Ϸ12-Mb genome of YJM789 contains Ϸ60,000 SNPs and Ϸ6,000 indels with respect to the reference S288c genome, leading to protein polymorphisms with a few known cases of phenotypic changes. Several ORFs are found to be unique to YJM789, some of which might have been acquired through horizontal transfer. Localized regions of high polymorphism density are scattered over the genome, in some cases spanning multiple ORFs and in others concentrated within single genes. The sequence of YJM789 contains clues to pathogenicity and spurs the development of more powerful approaches to dissecting the genetic basis of complex hereditary traits.comparative genomics ͉ genome architecture ͉ introgression ͉ lateral gene transfer T here is extensive genetic and phenotypic diversity within species. Determining which of the vast amounts of sequence differences that are found among individuals of a species contribute to heritable traits will allow diseases to be tackled at the molecular level and aid in the development of novel therapies. Saccharomyces cerevisiae, commonly known as baker's or brewer's yeast, plays a central role in food production and is one of the most studied genetic model species. It is not only widely used in biotechnology but also is a powerful model system that has been applied to identify multigenetic factors of hereditary traits (1-7). The genome sequence of one laboratory strain, a derivative of S288c, was the first genome of a free-living eukaryotic organism to be sequenced (8). Over the last 10 years, this genome has served as the reference for the S. cerevisiae species and has catalyzed the development of whole-genome approaches to biology (9, 10). Despite frequent laboratory use of alternative strains, sequence information for S. cerevisiae beyond the domesticated strain S288c has been fragmentary. S288c, which originated from a strain isolated from a rotten fig, was chosen for sequencing because it possesses properties that make it easy to work with, such as minimal colony morphology switching, consistent growth rates in glucose media, and no flocculence (11). At several loci, S288c contains polymorphisms not found in natural isolates, which could be hallmarks of domestication (12,13). A growing number of S. cerevisiae infections in humans have recently been reported (14). As a result, S. cerevisiae is also regarded as an emerging opportunistic pathogen that can cause clinically relevant infections in different patient types and body sites (15)(16)(17). One clinical strain (YJM145), derived from a yeast isolated from an AIDS patient with S. cerevisiae pneumonia (18), has been studied extensively as ...