Figure 1: A. Identification of enhancer hijacking events in cancer genomes; B. IGF2 activation be de novo 3D contact domain formation is mediated by recurrent somatic tandem duplications)

Figure 1: A. Identification of enhancer hijacking events in cancer genomes; B. IGF2 activation be de novo 3D contact domain formation is mediated by recurrent somatic tandem duplications)

Figure 2: A germline genomic hotspot of structural variation with the PSG locus, a pregnancy-associated gene cluster, which we uncovered in the context of the 1000 Genomes Project

Figure 2: A germline genomic hotspot of structural variation with the PSG locus, a pregnancy-associated gene cluster, which we uncovered in the context of the 1000 Genomes Project

The Korbel group combines experimental and computational approaches to unravel determinants and consequences of germline and somatic genetic variation.

Previous and current research

Genetic variation is a fundamental reason why humans differ from one another, and why individuals are susceptible to diseases. Our group is investigating mechanisms and the phenotypic consequences of genetic variation, with a focus on genomic structural variants (SVs). Genome-wide techniques we employ include genome sequencing, single cell and epigenomic assays. Our laboratory uses a ‘hybrid’ approach (integrating laboratory and computational methodology) to combine data generation and analysis with hypothesis generation and experimental testing. Computational methodologies range from computational methods development to analytical integration approaches, with the purpose to uncover biological novelty through development and testing of hypotheses.

Our group plays a key role in a large ongoing “big data” initiative, the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. Integrating data from somatic and germline whole genomes, transcriptomes, and clinical data from more than 2800 cancer patients, we are uncovering commonalities and differences between molecular disease mechanisms in different cancers. We recently uncovered, and recapitulated in vitro, catastrophic DNA alterations known as chromothripsis in the childhood brain tumor medulloblastoma. Additionally, by studying recurrent somatic SVs positioned in intergenic regulatory regions, we recently showed that “enhancer hijacking” – the juxtaposition of active enhancers near proto-oncogenes – is a frequent oncogene activation mechanism in solid tumors (Figure 1). By integration of computational and experimental approaches we recently uncovered numerous novel examples of enhancer hijacking, and showed that recurrent tandem duplications can mediate enhancer hijacking through the de novo formation of 3D contact domains (akin to the somatic formation of de novo topological association domains).

Our group is actively using, and contributing to the development of, “3rd generation” DNA sequencing techniques to obtain insights into the full repertoire of structural variation in the human genome (including SVs in repeat-rich areas of the genome, which are frequently linked with human disease). Recent work by us in the context of the 1000 Genomes Project resulted in a comprehensive catalog of SVs in >2500 individuals and led to novel insights into the origin of diverse SV classes (Figure 2).

Future projects and goals

  • Completion of human genome variation maps by third-generation sequencing.
  • Combining genomic and epigenetic studies to identify determinants for the formation and selection of genetic variation in cancer and normal cells.
  • Deciphering the basis of genomic instability processes using cell-based models.
  • Computational methods development, for example single-cell and single-molecule sequencing, as well as integration of “big data” in omics and health including the use of cloud computing.
ERC INVESTIGATOR