Figure 1: A germline genomic hotspot of structural variation with the PSG locus, a pregnancy-associated gene cluster.
Figure 2: The CAST approach providing insights into determinants of chromothripsis.
The Korbel group combines experimental and computational approaches to decipher determinants and consequences of germline and somatic DNA variation.
Previous and current research
Genetic variation is a fundamental reason why humans differ from one another and why some individuals are more susceptible to diseases than others. Our group is investigating mechanisms and the phenotypic consequences of genetic variation, with a focus on genomic structural variations (SVs). Genome-wide techniques we employ include genome sequencing, single cell and epigenomic assays (including ChIP-Seq, ATAC-Seq, and Hi-C). 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 analytical integration approaches (with the purpose to uncover biological novelty) to statistically-oriented methods development.
Our group plays leadership roles in research consortia, including currently the largest ongoing global “big data” initiative – the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. Integrating data from somatic and germline whole genomes, DNA methylomes, transcriptomes, and clinical data from more than 2800 cancer patients, we aim to unravel commonalities and discrepancies between the emergence of cancer types and subtypes at the molecular level, to facilitate the molecular classification of malignancies with impact on diagnostics and treatment, and to uncover causalities linking genotype, environment, and phenotype.
Within the 1000 Genomes Project and its follow-up studies, we are conducting further human deep population surveys using short-read and single-molecule long DNA read sequencing. Recent work by us uncovered the most comprehensive catalogue of genetic variation to date, providing insights into the origin of diverse structural variation classes (Figure 1).
We are also making progress in understanding the occurrence of complex genetic variants with experimental model systems, especially with regard to a process known as chromothripsis – a cellular catastrophe causing massive simultaneous DNA rearrangements. We recently developed an integrative method termed ‘Complex Alterations after Selection and Transformation’ (CAST) allowing mechanistic dissection of chromothripsis (Figure 2). CAST revealed an increased rate of chromothripsis in hyperploid cells and following telomere shortening (through siRNA induced silencing of a shelterin complex component), findings that we verified by genome sequencing in primary brain tumours.
Future projects and goals
- Completion of human genome variation maps by third-generation sequencing.
- Combining genomic and epigenetic studies to identify molecular determinants for 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.