Beyond the exome

DFG funded Research Group (FOR 2841)

P08: High resolution mapping and network analysis of myogenic transcription factors for the detection of non-coding disease-causing variants in congenital myopathy.

Open postions: 1 PhD student

Principal investigator: Prof. Dr. Markus Schuelke

P01 Congenital myopathies (CMs) are a heterogeneous group of disorders often manifesting as fetal akinesia (lack of in utero movement). Most severe forms of the disease are associated with Arthrogryposis multiplex congenita (AMC), a syndrome characterized by multiple congenital joint contractures. The underlying molecular causes are manifold, affecting muscle development and the composition of contractile elements of the muscle. The fact that whole exome sequencing (WES) is able to provide a molecular diagnosis to only half of severe CM cases raises the distinct possibility that disease-causing variants in the non-coding genome, i.e. regions that can be studied using whole genome sequencing (WGS), contribute to CM pathogenesis. In order to interpret the very large number of non-coding alterations and structural variants in the non-coding genome, we need basic data on the sites of epigenetic modification and gene regulation during early fetal muscle development. We will investigate this in iPSC-derived myogenic cells at different stages of myogenic development in collaboration with other groups of the RU to develop a bioinformatic model of muscle development. To this end we will search for regions of open chromatin, chromatin contacts, histone modifications, and transcription factor binding sites (TFBSs). Our group will determine TFBSs for three important myogenic transcription factors in the human genome, i.e. PAX7, MYOD, and MYOG. The ChIP-exo approach will enable us to interpret mutations at and around TF footprints with base pair precision. We will perform linked-read sequencing on WGS trios in combination with RNA-sequencing of muscle RNA from our unsolved patients with severe CM and AMC. We will use our updated variant annotation tools MutationTaster and RegulationSpotter to interpret their non-coding and structural variants in light of our newfound data on epigenetic modification. This project will improve our understanding of human muscle development, help to find the genetic basis for unsolved CM cases, and improve the genetic counseling for affected families; resulting in an often long awaited diagnosis.