Biomedical subjects

Rachel B Brem

Publications and source records attributed to Rachel B Brem.

7 recordsLinked to original sources

PubMed2025

Genomic signatures of innovation and selection in the extremotolerant yeast Kluyveromyces marxianus.

Extremophiles can be the product of millions of years of evolutionary engineering and refinement. The underlying mechanisms can be quite distinct from the ones operating at earlier stages of trait innovation. In this work, we have developed the compost yeast Kluyveromyces marxianus, which diverged from its closest relative >20 million years ago, as a model for interspecies comparative biology and genomics. We applied a battery of growth assays to species of the Kluyveromyces genus and found that K. marxianus outperformed its relatives in a battery of heat and chemical stress conditions. We then generated and analyzed genomes from across the genus, to find derived genetic features associated with, and potentially causal for, K. marxianus traits. We found robust expansions in gene families in the K. marxianus genome, most notably among genes annotated as transmembrane transporters and in metabolism. In molecular-evolution tests, we identified adaptive protein variants at hundreds of genes, among which plasma membrane transporters were over-represented. Together, these signals enable a model for the molecular mechanisms and evolutionary pressures underlying K. marxianus traits, including gains in transporter function mediating stress resistance, and metabolic variants contributing to its capacity for rapid growth in challenging conditions. Such oligogenic architectures may be the rule rather than the exception in phenotypes that have evolved over long timescales.

Journal Article↗

PubMed2006

Genomewide evolutionary rates in laboratory and wild yeast.

As wild organisms adapt to the laboratory environment, they become less relevant as biological models. It has been suggested that a commonly used S. cerevisiae strain has rapidly accumulated mutations in the lab. We report a low-to-intermediate rate of protein evolution in this strain relative to wild isolates.

Evolution, Molecular↗

PubMed2005

Local regulatory variation in Saccharomyces cerevisiae.

Naturally occurring sequence variation that affects gene expression is an important source of phenotypic differences among individuals within a species. We and others have previously shown that such regulatory variation can occur both at the same locus as the gene whose expression it affects (local regulatory variation) and elsewhere in the genome at trans-acting factors. Here we present a detailed analysis of genome-wide local regulatory variation in Saccharomyces cerevisiae. We used genetic linkage analysis to show that nearly a quarter of all yeast genes contain local regulatory variation between two divergent strains. We measured allele-specific expression in a diploid hybrid of the two strains for 77 genes showing strong self-linkage and found that in 52%-78% of these genes, local regulatory variation acts directly in cis. We also experimentally confirmed one example in which local regulatory variation in the gene AMN1 acts in trans through a feedback loop. Genome-wide sequence analysis revealed that genes subject to local regulatory variation show increased polymorphism in the promoter regions, and that some but not all of this increase is due to polymorphisms in predicted transcription factor binding sites. Increased polymorphism was also found in the 3' untranslated regions of these genes. These findings point to the importance of cis-acting variation, but also suggest that there is a diverse set of mechanisms through which local variation can affect gene expression levels.

3' Untranslated Regions↗

PubMed2005

Genetic interactions between polymorphisms that affect gene expression in yeast.

Interactions between polymorphisms at different quantitative trait loci (QTLs) are thought to contribute to the genetics of many traits, and can markedly affect the power of genetic studies to detect QTLs. Interacting loci have been identified in many organisms. However, the prevalence of interactions, and the nucleotide changes underlying them, are largely unknown. Here we search for naturally occurring genetic interactions in a large set of quantitative phenotypes--the levels of all transcripts in a cross between two strains of Saccharomyces cerevisiae. For each transcript, we searched for secondary loci interacting with primary QTLs detected by their individual effects. Such locus pairs were estimated to be involved in the inheritance of 57% of transcripts; statistically significant pairs were identified for 225 transcripts. Among these, 67% of secondary loci had individual effects too small to be significant in a genome-wide scan. Engineered polymorphisms in isogenic strains confirmed an interaction between the mating-type locus MAT and the pheromone response gene GPA1. Our results indicate that genetic interactions are widespread in the genetics of transcript levels, and that many QTLs will be missed by single-locus tests but can be detected by two-stage tests that allow for interactions.

Crosses, Genetic↗

PubMed2005

The landscape of genetic complexity across 5,700 gene expression traits in yeast.

Many studies have identified quantitative trait loci (QTLs) that contribute to continuous variation in heritable traits of interest. However, general principles regarding the distribution of QTL numbers, effect sizes, and combined effects of multiple QTLs remain to be elucidated. Here, we characterize complex genetics underlying inheritance of thousands of transcript levels in a cross between two strains of Saccharomyces cerevisiae. Most detected QTLs have weak effects, with a median variance explained of 27% for highly heritable transcripts. Despite the high statistical power of the study, no QTLs were detected for 40% of highly heritable transcripts, indicating extensive genetic complexity. Modeling of QTL detection showed that only 3% of highly heritable transcripts are consistent with single-locus inheritance, 17-18% are consistent with control by one or two loci, and half require more than five loci under additive models. Strikingly, analysis of parent and progeny trait distributions showed that a majority of transcripts exhibit transgressive segregation. Sixteen percent of highly heritable transcripts exhibit evidence of interacting loci. Our results will aid design of future QTL mapping studies and may shed light on the evolution of quantitative traits.

Computer Simulation↗

PubMed2003

Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors.

Natural genetic variation can cause significant differences in gene expression, but little is known about the polymorphisms that affect gene regulation. We analyzed regulatory variation in a cross between laboratory and wild strains of Saccharomyces cerevisiae. Clustering and linkage analysis defined groups of coregulated genes and the loci involved in their regulation. Most expression differences mapped to trans-acting loci. Positional cloning and functional assays showed that polymorphisms in GPA1 and AMN1 affect expression of genes involved in pheromone response and daughter cell separation, respectively. We also asked whether particular classes of genes were more likely to contain trans-regulatory polymorphisms. Notably, transcription factors showed no enrichment, and trans-regulatory variation seems to be broadly dispersed across classes of genes with different molecular functions.

Amino Acid Sequence↗

PubMed2002

Genetic dissection of transcriptional regulation in budding yeast.

To begin to understand the genetic architecture of natural variation in gene expression, we carried out genetic linkage analysis of genomewide expression patterns in a cross between a laboratory strain and a wild strain of Saccharomyces cerevisiae. Over 1500 genes were differentially expressed between the parent strains. Expression levels of 570 genes were linked to one or more different loci, with most expression levels showing complex inheritance patterns. The loci detected by linkage fell largely into two categories: cis-acting modulators of single genes and trans-acting modulators of many genes. We found eight such trans-acting loci, each affecting the expression of a group of 7 to 94 genes of related function.

Chromosome Mapping↗