Advancing genomics through biophysics: Progress toward understanding allelic and copy-number variability

Advancing genomics through biophysics: Progress toward understanding allelic and copy-number variability

Speaker: Professor Stephen Levene, University of Texas, Dallas

Host: Mark Sanderson

Abstract:

Although the notion of genomes as dynamic 3-dimensional structures is not controversial, programmed variability in genome primary structure, i.e., DNA-sequence variation across cells within a multicellular organism, remains largely uncharacterized. A well-studied case of functional, programmed DNA rearrangement is the diversification of the antibody repertoire via V(D)J recombination. This process results in a heterogeneous immunoglobulin locus in pre-lymphocytes and is accompanied by the formation of endogenous, circular DNA molecules or extrachromosomal circular DNA (eccDNA). Our work suggests that the V(D)J locus is not a singular example of variation in otherwise static genomes: eccDNAs are pointing us to specific genomic loci that are dynamic, highly variable, and potential foci of genomic instability. We have taken a whole-genome approach that uses biophysical techniques in conjunction with next-generation sequencing to map endogenous circular DNA in a complete organism (C. elegans) and in human tissue and cell lines. The information gained from extensive eccDNA profiling of diseased and normal cells is yielding insights into critical missing links between the genome and transcriptome. Moreover, the fusion of biophysical and genomic approaches is improving quantitative analyses of allelic copy number. Such novel multi-disciplinary approaches to genome structure and dynamics have the potential to advance the development of biomarkers and lead to new tools for molecular medicine.