Origin and function of genetic variation
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: Human cancers commonly develop as a consequence of chromothripsis, a structural rearrangement mechanism linked with predisposing TP53 mutations. Chromothripsis frequently leads to the formation of complex circular mini-chromosomes (‘double minute chromosomes’) harbouring proto-oncogenes (Rausch et al., Cell 2012)
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.
Previous and current research
Heritable structural variations (SVs) represent a major class of genetic variation in humans and are responsible for more heritable nucleotide sequence differences between individuals than other genetic variant classes, such as single-nucleotide polymorphisms. One of our main focuses has been on developing next-generation DNA sequencing-based approaches for the discovery and genotyping of SVs (see figure). In the 1000 Genomes Project we are contributing to the generation of a fineresolution SV map across more than 2000 humans: early versions have provided insights into the mechanistic origins of SVs, enabling the delineation of SV formation hotspots in the human genome. Integrating genetic variation maps with cellular (such as transcriptome and protein-DNA binding) and clinical phenotypes will allow us to decipher the functional impact of genetic variants by uncovering genotypephenotype relationships.
Our group also contributes to the International Cancer Genome Consortium: currently, we are investigating the genomes, epigenomes and transcriptomes of hundreds of patients diagnosed with early-onset prostate cancer, lymphoma, and paediatric brain tumours. Recently, we observed that childhood medulloblastoma patients harbour very few point mutations, raising the question of which molecular events lead to the development of these tumours. Using whole-genome sequencing, we found that medulloblastoma frequently develops in conjunction with a remarkable process termed ‘chromothripsis’, where localised chromosomal shattering and repair occur in a one-off structural variation catastrophe and leads to massive DNA rearrangement (see figure). Our recent studies have linked chromothripsis in medulloblastoma with germline mutations of the TP53 gene, encoding the p53 protein. We are currently expanding our panel of completely sequenced cancer genomes to intensify the discovery of links between mutational mechanisms and genotype-phenotype relationships in cancer and are performing complementary molecular and cell biology experiments to identify factors instigating chromothripsis, with the aim of uncovering the mechanistic basis of this catastrophic rearrangement process.
Future projects and goals
- Constructing a near-complete map of human genome variation, including difficult-to-ascertain genomic regions, using novel DNA sequencing approaches.
- Development of wet-lab and in silico approaches for deciphering the molecular origin and function of SVs in humans and model systems (including yeast and non-human primates).
- Uncovering genetic determinants for the development and progression of cancer in humans.
- Deciphering the mechanistic basis of ‘chromothripsis’, a rearrangement process observed in 2-3% of human cancers, which is particularly abundant in some highly aggressive malignancies.
- Dissecting the effect of genetic variation on biological systems in healthy states and in cancer, by integrating ‘variomes’ with cellular phenotype (such as transcriptome and epigenome) data.