Korbel Group

Previous and current research

We are an interdisciplinary group that combines experimental and computational approaches for studying the extent, functional impact and mutational origins of genetic variation, with a focus on genomic structural variation (SV). SVs, also known as large (>1kb) copy-number variants (CNVs), translocations, and inversions, are responsible for most genetic variation in the human genome. Recent advances in massively parallel DNA sequencing enable us, for example, to decipher the impact of genetic variation by sequencing and analysing entire genomes. Our group has adopted a systems biology rationale in which computational biology research feeds into the experimental laboratory, and vice versa.

We recently developed high-resolution and massive paired-end mapping (PEM), an approach involving next generation DNA sequencing of the end-stretches of genomic fragments and the massive alignment of these against a reference genome to globally map SVs. Our lab uses PEM, and recent extensions of the approach such as breakpoint junction-library analysis, to determine the extent of SVs in the genomes of healthy humans as well as in those suffering from cancer. Our central aims involve inferring the evolutionary and functional impact of SVs, and deducing the molecular mechanisms that cause SV-formation in the genome. For example, we recently learned through sequence analysis that the molecular mechanisms causing SV-formation mainly involve transposable elements as well as meiotic and DNA repair-associated recombination (e.g. non-allelic homologous recombination, as well as mechanisms that do not require homology, such as non-homologous end-joining). Our recent findings further involved the discovery of SVs on chromosome 21 as susceptibility factors for congenital heart disease. Furthermore, we are presently examining at genome-wide scale the effects of human genetic variations, particularly SVs, on the regulation of gene expression.

Future projects and goals

The extent to which genomes of healthy individuals differ due to SVs, the impact of SVs on common phenotypes, and the mutational processes underlying SV-formation are presently poorly understood. We hypothesise that SVs commonly lead to phenotypic variation, e.g. by perturbing tightly regulated cellular processes.We will study the formation mechanisms and the functional impact of SVs in the human genome and in model organisms using high-throughput experiments and data-mining.

Furthermore, as members of the 1000 Genomes Project and the International Cancer Genome Consortium (for which we recently have begun carrying out human genome sequencing and datamining in an effort to analyse paediatric tumours), we are continuing the development of approaches for SV mapping and analysis. One goal is to facilitate the analysis and interpretation of personal genome sequencing data. Furthermore, our approaches may in the near future have an impact on personalised medicine, e.g. in helping facilitate the design and interpretation of next-generation sequencing based studies for associating phenotypes with genetic variation.