Position effects in the 3D genome as the cause of neurodevelopmental disorders

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Privatdozent Dr. Malte Spielmann

Charité – Universitätsklinikum
Campus Virchow-Klinikum
Institut für Medizinische Genetik und Humangenetik



Structural variants (SVs) have the potential to disrupt the complex threedimensional (3D) chromatin organization of the genome. This may lead to the repositioning of topologically associating domains (TAD) boundaries and the relocation of enhancer elements in other compartments causing misexpression and disease. So far most cases of TAD-disruption described are associated with extremely rare skeletal phenotypes or cancers. The role of spatial genome architecture in more common phenotypes such as intellectual disability or neurodevelopmental disorders remains poorly understood. Considering that neurodevelopmental disorders are very frequent with a prevalence of up to 1% and often caused by SVs makes it is important to study this disease group in context of the 3D position effects.  The overall aim of the proposed project is to investigate the role of SVs that cause position effects in the 3D genome as a new pathomechanism for neurodevelopmental disorders.  However, several key technical and analytical challenges hinder progress in studying the role of non-coding variation and TAD-disruption in neurodevelopmental disorders: affected tissues and cells of patients are usually not available for functional studies and very few animal models exits since neurological phenotypes are much harder to investigate in animal models. Current pehnotypoing technologies lack the throughput and resolution to obtain a global view of the dynamic molecular processes underway in the diverse and rapidly expanding populations and subpopulations of neurons during development.  To addressed these technical challenges and limitations we propose three experimental approaches:   Work package 1: We aim to generate CRISPR/Ca9 based mouse models of SVs that change the spatial genome architecture and cause neurodevelopmental disorders. We will investigate inter-TAD-SVs that cause autosomal dominant demyelinating leukodystrophy and intra-TADs-deletions associated with severe autism.  Work package 2: We aim to use chromosome conformation capture technologies in mouse models and patients cells to evaluate the effect of SVs causing neurodevelopmental disorders in the 3D genome. We will study inter-TAD-SVs and intra-TADs-deletions.  Work package 3: We aim to use single cell-RNA-seq as a phenotyping tool for mouse models of neurodevelopmental disorders to identify previously overlooked cell type specific phenotypes and misexpression. Sc-RNA-seq provides the necessary resolution to investigate transcriptional changes, molecular states, and trajectories of neuronal cells during development and disease.  Our study will contribute to a better understanding of genotype-phenotype correlations of 3D position effects associated with neurodevelopmental disorders. We also will create an important scientific resources for the study of these very rare diseases, which will ultimately result in better family counselling and patient care.