Genomics - Quantitative & Computational Biology

http://helix-web.stanford.edu/people/altman/

Pharmacogenomics is the study of how genetic variation impacts drug response phenotypes.   We have been building the PharmGKB (http://www.pharmgkb.org) to catalog human pharmacogenomic knowledge since 2000.  As a result, we are very interested in informatics methods to catalyze discovery of drug effects and molecular mechanisms, in order to study how variations in the relevant genes can be used to understand and optimize the use and design of drugs.  There are multiple exciting sources of data relevant to the interactions of drugs and genes at the molecular and cellular level, and there is information in the published literature and population based clinical data sources that can be integrated to generate and test hypotheses about drug action and mechanism.  These can be used individually, but the real promise is in their integrated use.

http://www.cchem.berkeley.edu/crbgrp/

The glycome is dynamically regulated during development and disease progression.  The ability to detect changes in protein glycosylation, in tissue and serum samples as well as in vivo, is of considerable interest for biomarker identification and disease monitoring.  This presentation will focus on our work toward profiling glycomic changes using proteomics and in vivo imaging techniques.  Bioorthogonal chemistry is central to our approaches, which involve metabolic labeling of glycans with bioorthogonal functional groups followed by chemical tagging with affinity reagents, mass spectrometry tags or imaging probes.  Fundamental principles of bioorthogonal reaction development will be discussed, along with applications in cancer biomarker discovery and glycan imaging during embryonic development.

http://biodynamics.ucsd.edu/

Departments of Molecular Biology and Bioengineering
BioCircuits Institute
University of California, San Diego

Synthetic biology can be broadly parsed into the “top-down” synthesis of genomes and the “bottom-up” engineering of relatively small genetic circuits. In the genetic circuits arena, toggle switches and oscillators have progressed into triggers, counters and synchronized clocks. Sensors have arisen as a major fo-cus in the context of biotechnology, while oscillators have provided insights into the basic-science functionality of cyclic regulatory processes. A common theme is the concurrent development of mathematical modeling that can be used for experimental design and characterization, as in physics and the engineering dis-ciplines. In this talk, I will describe the development of genetic oscillators over increasingly longer length scales. I will first describe an engineered intracellular oscillator that is fast, robust, and persistent, with tunable oscillatory periods as fast as 13 minutes. Experiments show remarkable robustness and persistence of oscillations in the designed circuit; almost every cell exhibits large-amplitude fluorescence oscillations throughout each experiment. Computational modeling reveals that the key design principle for constructing a robust oscillator is a smal l time delay in the negative feedback loop, which can mechanistically arise from the cascade of cellular processes involved in forming a functional transcription factor. I will then describe an engineered network with intercellular coupling that is capable of generating synchronized oscillations in a growing population of cells. Microfluidic devices tailored for cellular populations at differing length scales are used to demonstrate collective synchronization properties along with spatiotemporal waves occurring on millimeter scales. While quorum sensing proves to be a promising design strategy for reducing variability through coordi-nation across a cellular population, the length scales are limited by the diffusion time of the small molecule governing the intercellular communication. I will con-clude with our recent progress in engineering the synchronization of thousands of oscillating colony “biopixels” over centimeter length scales through the use of redox signaling that is mediated by hydrogen peroxide vapor. We have used the redox communication to construct a frequency modulated biosensor by coupling the synchronized oscillators to the output of an arsenic sensitive promoter that modulates the frequency of colony-level oscillations due to quorum sensing.

http://selab.janelia.org/

Department of Genome Sciences and Howard Hughes Medical Institute, University of Washington, Seattle.

Duplicated sequences are important sources for the evolution of new gene function within species and are also hotspots of genomic rearrangement. Humans and great apes have a preponderance of intrachromosomal duplications organized in an interspersed fashion as opposed to tandem which is the archetype in most other mammalian genomes. We have used this architectural feature to discover copy number variation associated with neurodevelopmental disease and rapidly evolving gene families. We have reconstructed the evolutionary history of these regions within the primate lineage. All of these data point to a burst of segmental duplication in the common ancestor of human and the apes in contrast to other mutational processes, which have slowed. I will show that much of the interspersed human duplication architecture is focused around core duplicons corresponding to the expansion of gene families that show strong signatures of positive selection and lack orthologs in other mammalian species. I will provide examples of potentially novel genes that have evolved within the human lineage and may be important in terms of brain function.  Paradoxically, the duplication architecture has led to a high background rate of copy number variation mutations associated with neuropsychiatric and neurodevelopmental disease in the human species suggesting that novel adaptations and increased disease burden in our lineage are linked.

http://buttelab.stanford.edu/

Dr. Butte’s lab at Stanford builds and applies tools that convert more than 300 billion points of molecular, clinical, and epidemiological data measured by researchers and clinicians over the past decade into diagnostics, therapeutics, and new insights into disease.  Dr. Butte, a bioinformatician and pediatric endocrinologist, will highlight his lab’s work on environment-wide association studies, evolution and disease, and evaluations of patients presenting with personal genomes.

http://www.sabetilab.org/

We are in the midst of a revolution in the fields of genomics and public health. The completion of the human genome sequence, the availability of genome sequence from increasing numbers of related species, the availability of genome-wide human variation data, and the ability to rapidly generate new data have created unprecedented opportunities to study human biology, evolution, and disease. These same tools are also making it possible to carry out unprecedented studies in the microbial pathogens that affect humans. With a background in both biology and medicine, my research goals are to use the rapidly emerging resources to:  (1) Develop and apply methods to detect natural selection in the human genome; (2) Investigate the underlying functional changes driving human evolution; (3) Study the genomic evolution of the microbial pathogens that affect humans; and (4) Build new computational tools for studies of genomics and public health. The key infectious diseases of my labs’s current studies are Plasmodium Falciparum malaria, Vibrio Cholerae cholera, and Lassa virus fever.