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In April 2003, the scientific community announced that a draft sequence of the human genome had been completed. This statement was true only to the extent that many chromosomal regions that resist sequencing by current methods (repetitive sequences, centromeres, and chromosome ends, for example) were ignored. Such sequences may comprise 20 percent, or more, of the human genome. In addition, these elements of genomic sequence contribute disproportionately to programmed and stochastic rearrangements at the DNA level that are involved in diseases and biological evolution. Collaborative efforts between my team and researchigroups here at Stanford use a fusion of biophysical, biochemical, and bioinformatic methods to study such DNA rearrangements; in particular, mechanisms that generate endogenous circular-DNA molecules, termed extrachromosomal-circular DNA (eccDNA). These circular DNAs report on highly dynamic regions of genomes, pointing us to specific regions of linear chromosomes that were previously thought to be stable over time. We have uncovered programmed rearrangements in somatic cells that create variability with respect to tissue type and developmental stage and could be sources of genomic instability. Moreover, information gained from extensive eccDNA profiling of diseased and normal human cells, including stem cells, is yielding insights into molecular aspects of several diseases such as cardiomyopathies and cancers. I will discuss work currently in progress on novel engineering- and bioinformatic-based enabling technologies to accelerate new discoveries in this area.
Dr. Levene was born in New York City and received his A.B. in Chemistry from Columbia University and his Ph.D. in Chemistry from Yale University. His doctoral work demonstrated and quantified the phenomenon of sequence-directed bending in DNA due to adenine-thymine tracts and pioneered the use of Monte Carlo simulation to compute cyclization probabilities of DNA molecules having arbitrary preferred geometries. Upon leaving Yale, Levene became an American Cancer Society postdoctoral fellow at UC San Diego, where he worked on the physical mechanism of gel electrophoresis.
Levene's research interests are broadly in the area of genome architecture and its maintenance by enzyme mechanisms and protein-DNA interactions. His work in this area began from the time he was a Staff Scientist at the Human Genome Center at Lawrence Berkeley National Laboratory, when he worked on the structure and properties of supercoiled DNA and DNA catenanes. Levene's group has made both experimental and theoretical/computational contributions to understanding DNA topology and its relationship to local DNA structures, DNA-loop formation, site-specific DNA recombination, the structure of human telomeres, and extrachromosomal-circular DNA.
