RG 2841/1: A Comprehensive Repository of Regulatory Elements and Their Variations in Human Disease (SP 05)

Though the introduction of whole exome sequencing (WES) has enabled the molecular diagnosis rate for patients with rare genetic disorders to rise considerably, it has levelled at a maximum of 50%. WES is limited to the coding regions, meaning that it misses disease-causing variants in the non-coding and regulatory sequences of the genome. Whole genome sequencing (WGS) is the logical next step as sequencing the entire genome should theoretically solve the remaining cases. Despite the inherent promise of WGS, the numerous obstacles that impede the interpretation of the multitudinous variants identified by WGS clearly demonstrate that WGS is not yet ready for routine clinical use. Beyond the Exome has assembled a unique constellation of leading specialists and researchers from clinical medicine, basic sciences, and bioinformatics who will collaborate to improve the interpretation of variants affecting structural and regulatory regions in the non-coding genome. Beyond the Exome researchers aim to (i) improve the processing of whole genome raw data, (ii) evaluate the impact of 3D genome structure on transcription factor binding and on gene regulation, (iii) collect widely dispersed genome regulation information in a central database, (iv) explore the oscillatory expression of transcription factors as a novel mode of gene regulation, and (v) investigate the epigenetic landscape during human thyroid, bone, and muscle development. The required data is unavailable for the human genome and will have to be generated by our research unit (RU). Such data comprise high resolution transcription factor footprints, histone modifications, chromatin contacts, regulatory networks, physical properties of transcription factor: DNA interactions, as well as the effects of larger structural variants on the 3D structure of the genome. We have access to patients from three well-characterized cohorts with developmental disorders of thyroid, bone, and muscle where WES has failed to provide a molecular diagnosis. Data from these patients will be used to develop and test the derived analysis algorithms. Beyond the Exome bioinformaticians will use the experimental data to develop and improve algorithms that will enable the RU’s public domain software to interpret the non-coding genome accurately and reliably. All the RU’s aims depend on the integrated expertise of multiple group leaders, and no aim is attainable by a single group working in isolation. The overarching goal of this translational RU goes beyond simply improving the understanding of gene regulation and transcription; resulting in free, online, user friendly WGS analysis software aimed at geneticists, physicians, and non-bioinformaticians. Beyond the Exome’s ultimate goal is to bring WGS closer to routine clinical application, enabling the remaining half of undiagnosed rare genetic disease patients to receive a molecular diagnosis.

Principal investigators
Leser, Ulf Prof. Dr.-Ing. (Details) (Knowledge Management in Bioinformatics)

Participating organisational units of HU Berlin

Participating external organisations

DFG: Forschergruppen

Duration of project
Start date: 03/2020
End date: 09/2023

Research Areas
Bioinformatics and Theoretical Biology, Human Genetics, Interactive and Intelligent Systems, Image and Language Processing, Computer Graphics and Visualisation

Research Areas
Bioinformatik, Genetik, Maschinelles Lernen

Last updated on 2023-17-07 at 10:27