Origin and function of genetic variation
The Korbel group combines experimental and computational biology to decipher the function and origin of genetic variation, with a particular focus on genomic structural variants.
Figure 1: (A) Mapping genomic structural variation by paired-end mapping, read-depth analysis, and split-read analysis (Mills et al., Nature 2011). (B) Mutational landscape in a childhood medulloblastoma genome. (C) Catastrophic chromosome rearrangements resulting from chromothripsis (Rausch et al., Cell 2012).
Figure 2: Age-dependent somatic SV landscape in prostate cancer (Weischenfeldt et al. Cancer Cell 2013).
Previous and current research
Genetic variation is a key reason why we differ from one another and can be used as starting point to unravel disease mechanisms. Recent advances in DNA sequencing technology have facilitated the characterisation of genetic variation at genome-wide scale. Our group is devoting efforts to characterising the extent, origin, and functional consequences of DNA variation, with a particular focus on genomic structural variants (SVs) such as deletions, duplications, inversions and translocations – the most consequential type of heritable genetic variation in humans in terms of the sheer number of nucleotides affected. Germline and somatic SV classes have been linked to numerous heritable diseases and different cancer types. We are pursuing research using both laboratory and computational techniques, a ‘hybrid’ approach that allows us to combine data generation and analysis with hypothesis generation and testing in experimental model systems.
A cancer genome study that we recently performed revealed that the development of medulloblastoma, the most common malignant brain tumour in children, frequently involves a remarkable process known as chromothripsis, where localised chromosomal shattering and repair occur in a one-off massive DNA rearrangement event (figure 1). We also recently made progress in understanding the etiology of early onset prostate cancer, the initiation of which we found to be largely driven by androgenmediated somatic SVs (figure 2). Our group also participates in genome research consortia such as the 1000 Genomes Project, with the aim of contributing to the generation of fine-resolution genetic variation maps in humans that can later be related to functional genomics data. We also investigate SVs in non-human species to pursue genetic variation studies in the context of evolution.
Within the Whole Genome Sequencing (WGS) Pan-Cancer Analysis Initiative of the International Cancer Genome Consortium (ICGC) we have begun investigating whole genome, DNA methylome, and transcriptome sequencing data of ~2000 cancer patients. Using integrative analyses we aim to unravel commonalities and discrepancies between cancer types at the molecular level, to facilitate the molecular classification of malignancies with a potential impact on diagnostics and treatment.
Future projects and goals
- Uncovering genetic determinants for the development and progression of cancer in humans, and studying commonalities and differences between tumour types.
- Development of wet-lab and in silico approaches for deciphering the molecular origin and function of SVs in humans and model organisms.
- Constructing near-complete human genome variation maps using second and third generation sequencing technologies.
- Deciphering the mechanistic basis of chromothripsis, an SV process particularly abundant in highly aggressive malignancies.