Broad advances in DNA sequencing have radically transformed the scale and nature of genetics making it possible to analyze genomic changes across species, individuals, cell-types, and as mutations accrue and are subject to natural selection. Diverse phenotypic datasets have also grown rapidly, not only for sequencing-based assays such as gene expression and protein-nucleic acid interactions, but also other types including metabolomic, clinical, and drug-screening data. My lab is interested in computational and mathematical approaches to analyzing such large data sources, to understand how genomes function and evolve. Since moving to the Jackson Laboratory for Genomic Medicine in 2012, the lab been focusing on cancer genomics and RNA-level gene regulation.

Cancer Genomics Our lab is currently involved in multiple projects in cancer genomics, with a focus on the genomics of patient-derived xenografts. We are especially interested in tumor heterogeneity.

RNA-level Gene Regulation Our lab is currently involved in multiple projects in RNA-level gene regulation, with a focus on processes regulation translation, protein-RNA binding, and splicing. These works are related to our prior studies of the functions and neutral evolutionary behavior of synonymous sites in coding sequences. Such sequences contain a substantial amount of selection in a variety of phylogenies (Kural et al 2009). We have shown for example that coding sequences are replete with binding sites for microRNAs, as well as other types of functional sequences such as exonic splicing enhancers. Such sites exhibit a strong selective pressure on the synonymous sites of coding regions.

Functions of Highly Conserved Enhancer Sequences In a given phylogeny, comparative sequence data can be used to infer the functional sequences within genomes. Just as morphological features shared among species (e.g. all vertebrates have a spine) are likely to be important to those species, DNA sequences shared among species are likely to be functional. One of the organisms we focus on is the model vertebrate Danio rerio, i.e. the zebrafish. Our lab collaborates with the Guo lab at UCSF to study conserved noncoding elements, sequences with conservation far beyond what would be expected by neutral mutation in vertebrate intergenic regions. For example, at a threshold of at least 50 bp and at least 50% sequence identity, there are 73187 strand-specific CNEs conserved between zebrafish and human. A major challenge in understanding these CNEs is to organize them in a meaningful way, analogous to the organization of genes provided by the Gene Ontology. We have recently developed a tool for organizing CNEs based on the expression of nearby genes (cneviewer.zebrafishcne.org, Persampieri et al 2008), as this may provide a key to understanding the tissue-specific enhancer behavior of CNEs. We are also exploring the relative importance of cis- and trans- regulatory effects on the functional behavior of enhancers (Ritter et al 2010).

Other Prior Interests Other model organisms with which we have expertise are the malaria parasite Plasmodium falciparum and the yeast S. cerevisiae. A central mystery of the malaria genome is how transcription is regulated. We have observed that there is far less intergenic sequence apparently under purifying selection in malaria than in yeast genomes, suggesting that transcription regulation is simpler in malaria (Imamura, Persampieri and Chuang, 2007). We have also applied comparative techniques to identify functional sites in the promoters of the Saccharomyces genus of yeasts, to estimate the complexity of gene regulation and the types of genes likely to be under the strictest regulation (Chin, Chuang, and Li 2005).

Our lab is also interested in a variety of issues in molecular evolution related to the balance of functional and neutral pressures in genomes. For example, one puzzle is why mutation rates are uniform in some species, such as the sensu stricto yeasts, while rates vary by location in other species, such as mouse and human. We have found that all mammalian species have regional mutation biases, typically on a scale of several megabases. In contrast, all yeasts have uniform mutation rates, with the exception of the Candida clade (Fox et al 2008; Chuang and Li 2004; Chuang and Li 2007; Chin, Chuang, and Li 2005). In species where the mutation rate is non-uniform, we are interested in questions such as what structural or sequence features affect mutation rates, and whether gene locations have evolved to make use of mutational heterogeneity.

Previously the lab also has worked on the analysis of high-throughput lipidomic data. Our lab has collaborated with the Seyfried Lab (Boston College) and the Han Lab (Washington University in St. Louis) to analyze lipid content in cancerous vs. non-cancerous tissues. Our group is developing tools to analyze which aspects of lipid content are important to cancer phenotypes (Kiebish et al 2008). This work is closely tied to evaluating the Warburg theory of cancer, as described in this report. We have also developed both equilibrum and dynamic models to explain the distributions of lipids found in normal and cancerous tissues (Kiebish et al 2010).

Accepting Lab Rotation Students: Fall Block 2024, Spring 1 and 2 Block 2025

We are currently seeking graduate students interested in a variety of problems in post-transcriptional regulation and cancer genomics. Our lab is a computational lab and students should have expertise/interest in programming and quantitative approaches.

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