Molecular Cytogenetics Group

Scientific overview

Structural variants of the genome, in particular those that are associated with loss or gain of DNA, represent the greatest portion of genomic variability in humans. They are important forces of evolution, but at the same time, they pose a considerable threat to individual health. Structural variants are the underlying cause of many congenital disorders and their accumulation in somatic cells is a hallmark of tumor development.

Predicting the biological consequences of structural variants is challenging in many cases. Importantly, a specific genetic change that appears to have no effect at all in one individual may cause severe health problems in another one. These individual differences in response to structural variants result from the complex interplay of diverse regulatory mechanisms at the genetic and epigenetic level. Our current research is dedicated to improving our understanding of these influences.

We have identified and published numerous rare genomic variants as the underlying genetic cause of various diseases, including autism, schizophrenia, amyotrophic lateral sclerosis, ADHD and congenital malformations of the heart, thyroid and brain. Furthermore, we have investigated the patterns of somatic DNA copy number changes in tumors of the breast and the hematopoietic system. We have developed strategies using the gene content of rare structural variants identified in a cohort of patients suffering of brain malformations to learn more about the regulatory networks involved in brain development. Currently, we are applying the same bioinformatics approach to somatic mutations identified in T cell-lymphomas. Proceeding on the assumption that the tumor-specific patterns of chromosomal aberrations reflect the selective pressure favoring the observed combination of mutations, we have employed network analysis to identify recurrently mutated genes that have a high likelihood to act in concert to promote T-cell lymphoma progression. The relevance of the predicted interactions will be tested in vitro by combinatorial deregulation of gene dosage either by knock down or over-expression in a project funded by the Wilhelm Sander foundation. For a more comprehensive view on the causes of structural variants and their variable phenotypic consequences, we have started to integrate information on higher order chromatin organization and the three dimensional structure of the nucleus into our analysis. In this context, we are developing appropriate software tools (funded by the DFG) and are in the process of establishing a technique called Hi-C, which is a sequencing-based method that has been developed to elucidate the three-dimensional organization of the nucleus with unprecedented resolution.

Co-operations within the department

My group has been part of the department´s initiative to decipher the genetic causes of autosomal recessive intellectual disability. We have established the techniques and performed the experiments that have allowed the region specific sequencing of all the selected genomic intervals of interest. Furthermore we are continuing our fruitful cooperation with the group of Vera Kalscheuer to fine-map the breakpoints of balanced chromosomal translocations