1. DEVICES FOR GENOME ANALYSIS
a. Nanopore for rapid sequencing of nucleic acids. Development of a device that can sequence single molecules of nucleic acid, DNA or RNA, at a rate of million bases per second by electrophoresis of the charged polymers through a solid-state nanopore channel of molecular dimensions is the subject under investigation. Pores with a diameter only slightly larger than that of DNA (~2nm) can be used in the detection and discrimination of single molecules of nucleic acid. Nanopore sensor will be made to enable sequencing DNA at a much faster rate than presently possible without the need for extensive sample preparation procedures, such as enzymatic amplification and labeling reactions. It will analyze electronic properties of individual subunits of DNA or RNA, to obtain linear composition of each genetic polymer molecule. The tremendous payoffs of such a nanopore sensor are twofold. Firstly, the complete DNA sequence information underlying the biodiversity of planet Earth will be within reach, thus enabling a complete understanding of the molecular basis of life. Secondly, such a sensor would enable the detection of life on other planets.
b. Application-specific high-density oligonucleotide arrays for detection of nucleic acids.
This work is being done in collaboration with research collaborators at Yale University and commercial partners. This work is largely computational but also includes experimental verification of the array design and use of the arrays for functional genomics, such as mapping of genes in the human genome and in model organisms (see bellow).
2. FUNCTIONAL GENOMICS
a. Functional Genomics.
The association of specific phenotype (such as disease) with variation in DNA sequence is the goal of modern molecular biology. Development of high-density oligonucleotide arrays for probing complex genomes by detection of simple nucleotide variations is the broad subject under investigation.
b. Natural products for genome-wide analysis of yeast Saccharomyces cerevisiae.
A systematic high-density DNA-chip based method called quantitative phenotypic analysis is used to investigate the biological functions of all genes in yeast Saccharomyces cerevisiae. Yeast is used as a model system because it is one of the most genetically and genomically tractable organisms and because it has proven itself a model for the study of human physiology and genetics. Whole-genome studies employing the complete set of yeast deletion strains will address the question not only of assigning function to genes, but also that of elucidating pathways. This work can identify individual gene products that function in any biological function of the yeast cell. The fidelity of protein and RNA biosynthesis as a means of gene function regulation is the broad subject under investigation. The aim is to identify functions of all yeast genes under any growth condition, identify gene targets of natural products synthesized by yeast, and identify natural products from plants and microorganisms that alter functions of yeast gene products. This includes protein- and RNA-coding genes.