Korbel Group
Genome dynamics, evolution, and structural variation
Figure 1: Integrating computational methods with population-scale sequencing enables global SV analysis (adapted from Mills et al., Nature 2011).
Figure 2: Protein-DNA binding associated gene regulation displays marked variation among humans, frequently involving SNPs or SVs (Kasowski et al., Science 2010).
Previous and current research
Members of our group apply experimental and/or computational approaches to study the extent, functional impact and mutational origins of genetic variants, particularly genomic structural variants (SVs). SVs, also known as copy-number variants (CNVs), are among the least well studied classes of genetic variation, despite the fact that their net effect on the human genome (in terms of affected base pairs) is higher than the effect of single nucleotide polymorphisms (SNPs). Recent technological advances (e.g. tiling arrays and next-generation DNA sequencing) are enabling us to decipher the impact of SVs through the analysis of entire genomes.
A recent focus of our group has been the development of next-generation sequencing based approaches for SV discovery and genotyping, including paired-end mapping based SV discovery (PEM), breakpoint junction based SV genotyping (BreakSeq), and read-depth based SV genotyping (CopySeq). As a member of the structural variation analysis group of the 1000 Genomes Project, our group recently integrated computational and experimental methods to construct the largest and highest resolution map of SVs developed to date. The study involved the sequencing and analysis of 185 human genomes (figure 1). Based on a new SV clustering approach, we identified over 50 SV formation hotspots-genomic regions in which distinct DNA rearrangement processes (e.g. recombination) appear to operate at an increased rate. Furthermore, we recently assessed the effect of genetic variants (SVs and SNPs) on gene expression regulation, based on coupling chromatin immunoprecipitation sequencing (ChIP-Seq) in several human cell-lines with a computational analysis framework (figure 2). Additional research projects in our lab focus on the de novo formation mechanisms and phenotypic impact of somatic genomic rearrangements occurring in cancer, specifically prostate cancer and pediatric brain tumours.
Future projects and goals
The extent to which genomes differ due to SVs, the impact SVs have on the phenotype, and the mutational processes underlying de novo SV-formation are poorly understood compared to other variation classes (such as SNPs). We believe that SVs commonly cause phenotypic variation by perturbing tightly regulated biological systems. The long-term goals of our group include the study of SV de novo formation mechanisms and the assessment of the impact of SVs on biological systems.
Furthermore, together with collaborators involved in the 1000 Genomes Project and the International Cancer Genome Consortium, we are continuing the development of approaches for SV detection. With human genome sequencing becoming a routinely applied research tool, we foresee that in the not-so-distant future personal genome sequencing will be widely applied to predict specific medical outcomes in patients diagnosed with diseases. Thus, our approaches may in the future have an impact on personalised medicine by enabling predictions relating to the effectiveness of personalised drug treatments.
10 years of the human genome
EMBL scientists mark a decade since the first draft human genome sequence. Click on the image to play.
Duration: 6 mins.