Home Faculty and Research Faculty by Name Rachel Brem

Rachel Brem

Assistant Professor of Genetics, Genomics and Development

Full Directory Information

Research Interests

Individuals within a species differ in many ways, from eye color to disease susceptibility.  Much of this variation is controlled by sequence differences in genomic DNA.  Recent successes in quantitative genetics have made clear that most such sequence variants give rise to subtle regulatory changes rather than to qualitative gains or losses.  How these changes propagate through the regulatory network and manifest phenotypically is not well understood.  Despite the elegance and power of general principles that have emerged from systems biology research, in most cases we cannot predict how subtle genetic changes lead to dramatic cellular consequences, let alone design therapeutics that interfere with these effects in human genetic disease.

The work in our lab is based on the idea that many sequence differences between outbred individuals affect regulatory cascades quantitatively—their RNA and protein output, their sensitivity to input signal, kinetics of output production, stochastic noise, adaptation, and other fine-scale parameters.  Sequence variants affecting quantitative behavior can be identified by forward-genetic methods for any circuit, even when the total molecular parts list of the circuit is unknown.  Their mapping allows us to discover novel circuit components, and their effects tell us how changes in these components can perturb the circuit yet be tolerated in the wild.  We aim to understand the mechanisms by which our mapped alleles exert their effects:  how they alter biomolecule structure, function, expression and abundance, and how these changes perturb the network.  We also want to know how many variants impinge on a given pathway, and we want to assess the selective pressure on these variants in outbred populations.

Our lab group uses genetically distinct strains of budding yeast, and increasingly of other fungi, as a model for the study of natural variation in RNA expression and quantitative regulatory biochemistry.  We assay these parameters experimentally, and we write and implement statistical genetics software to identify the polymorphisms responsible for differences between the strains.  To test these loci, we use the toolkit of yeast molecular biology.

Current Projects

Natural variation in the yeast unfolded protein response.  We are launching a project on the well-conserved transcriptional cascade in S. cerevisiae called the unfolded protein response.  We are investigating how yeast strains tune the quantitative relationship between the inducer of the cascade—the level of unprocessed polypeptides in the endoplasmic reticulum—and its transcriptional output.  

Natural variation in yeast replication initiation.  We are dissecting the way sites of initiation of DNA replication are stochastically chosen in the S phase of mitosis in S. cerevisiae.  We want to understand the quantitative regulation of this process, following up on a preliminary observation of noncoding transcription at initiation sites that differs between yeast strains.

Natural variation in gene expression in N. crassa.  We are collaborating with UCB mycologists John Taylor and Louise Glass to study genetic variation between strains of the filamentous fungus, Neurospora crassa.  Our work focuses on ways to harness mRNA expression variation to infer the function of unknown open reading frames in this emerging model organism.

Selected Publications

Zhu J, Zhang B, Smith EN, Drees B, Brem RB, Kruglyak L, Bumgarner RE, Schadt EE.  Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks.  Nature Genetics, in press. 

Ronald J, Tang H, Brem RB.  Genome-wide evolutionary rates in laboratory and wild yeast.  Genetics 174(1):541-4, 2006. 

Ronald J, Brem RB, Whittle J, Kruglyak L.  Local Regulatory Variation in Saccharomyces cerevisiae.  PLoS Genet. 1(2):e25, 2005.

Brem RB, Storey JD, Whittle J, Kruglyak L.  Genetic interactions between polymorphisms that affect gene expression in yeast.  Nature 436(7051):701-3, 2005.

Brem RB, Kruglyak L.  The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc Natl Acad Sci U S A. 102(5):1572-7, 2005.

Yvert G, Brem RB, Whittle J, Akey JM, Foss E, Smith EN, Mackelprang R, Kruglyak L.  Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors.  Nat Genet. 35(1):57-64, 2003.

Brem RB, Yvert G, Clinton R, Kruglyak L.  Genetic dissection of transcriptional regulation in budding yeast.  Science 296(5568):752-5, 2002.

Last Updated 2008-06-10