We are interested in defining and understanding evolutionary phenomena at the molecular level. What mutations are adaptive? Does the spectum of adaptive mutations differ between haploids and diploids? Do mutations that provide an adaptive advantage under one condition provide an advantage under another? Or a disadvantage (antagonistic pleiotropy). What is the underlying nature of clonal interference? To answer these questions, we use experimental evolution, and the budding yeast, S. cerevisiae as a model organism.

When yeast is grown in continuous culture in a chemostat, with a limiting nutrient, then adaptive mutations that arise will be selected for, and thus may increase in allele frequency. We are using Illumina and ABI sequencing to sequence both individual adaptive clones, as well as to sequence evolving populations, to discover the adaptive mutational spectrum, and to follow the dynamics of different alleles in the population.

We are also interested in the speciation process itself - what makes two yeast species incompatible? Do Dobzhansky-Muller determinants of speciation exist, and if so, did they cause the speciation, or did they arise after speciation? Is speciation the result of sequence differences that lead to antirecombination, or incompatible networks, or are specific genes involved that led to the speciation event?

• Kao, K.C., Schwartz, K., Sherlock, G. (2010). A Genome-Wide Analysis Reveals No Nuclear Dobzhansky-Muller Pairs of Determinants of Speciation between S. cerevisiae and S. paradoxus, but Suggests More Complex Incompatibilities. PLoS Genetics 6(7), e1001038.
  
• Kao, K.C. and Sherlock, G. (2008). Molecular characterization of clonal interference during adaptive evolution in asexual populations of Saccharomyces cerevisiae. Nature Genetics 40, 1499 - 1504.
  

C. albicans is a significant cause of morbidity and mortality, and has become the third or fourth most common nosocomial bloodstream isolate; mortality rates are high (35% or greater) and treatment is costly. Although many antifungal compunds do exist, there has been an emergence of antifungal resistance in a clinical setting. For all these reasons, it is important that we understand the full set of transcribed sequences produced by the C. albicans genome, as well as how they are regulated. In collaboration with Anja Forche at Bowdoin College, we are using high throughput sequencing of RNA from both drug resistant and drug sensitive isolates of C. albicans under various conditions to better determine the transcriptome itself, and how it is regulated. Because C. albicans is an obligate diploid, we are particularly interested to see whether there are cases where different alleles show different regulation, depending on the condition.

• Bruno, V.M., Wang, Z., Marjani, S.L., Euskirchen, G.M., Martin, J., Sherlock, G. and Snyder, M. (2010). Comprehensive annotation of the transcriptome of the human fungal pathogen Candida albicans using RNA-seq. Genome Research 20, 1451-1458.
  

We are using high throughput sequencing to characterize the transcriptome of S. cerevisiae and a number of closely related species under a variety of different conditions. How do different species wire their transcriptional networks, and how do they evolve? What kind of regulation do we see at this precise molecular level between conditions - is splicing efficiency altered? are UTR lengths different? Do "novel" transcripts in one species also get produced from the syntenic location in other species grown in the same condition, even if the syntenic region is diverged? What does this tell us about how new genes evolve?

• Lee, A., Hansen, K.D., Bullard, J., Dudoit, S. and Sherlock, G. (2008). Novel Low Abundance and Transient RNAs in Yeast Revealed by Tiling Microarrays and Ultra High-Throughput Sequencing Are Not Conserved Across Closely Related Yeast Species. PLoS Genet 4(12): e1000299.