Human Molecular Genomics
Spielmann Lab
The Spielmann Lab investigates how non-coding mutations and structural variants contribute to human disease by perturbing gene regulation during development. Our central aim is to understand the pleiotropic effects of genetic variation during embryogenesis and to uncover how alterations in genome structure shape the three-dimensional (3D) organization of the genome.
To address these questions, we combine mouse developmental models with state-of-the-art high-throughput technologies, including single-cell genomics, lineage tracing, chromosome conformation capture approaches, and massively parallel reporter assays. By integrating these methods, we study gene regulation at scale—from individual regulatory elements to whole-embryo analyses.
Our long-term goal is to develop a virtual embryo that enables in silico modeling of human Mendelian disease at whole-embryo resolution.
The Spielmann Lab works in close collaboration with the Institute for Medical and Human Genetics (IMG) at the Charité – Universitätsmedizin Berlin. The IMG provides a direct clinical connection to our work and the possibility of translating the knowledge gained into clinical practice.
Project 01: Single-cell human genetics of embryonic development
A major focus of the lab is the analysis of mutations and structural variants at single-cell resolution during embryonic development. We apply single-cell RNA sequencing and single-cell ATAC sequencing to mouse embryos carrying patient-derived genetic alterations.
This approach enables, for the first time, the systematic single-cell analysis of entire embryos, allowing us to investigate how identical genetic variants lead to distinct cellular outcomes across tissues and cell types. Our work reveals pronounced cell-type–specific responses to genetic perturbations, providing a mechanistic framework for understanding pleiotropy and variable expressivity in genetic disease.
Project 02: Structural variants and 3D genome architecture
Structural variants such as deletions, duplications, and inversions can disrupt the regulatory architecture of the non-coding genome by reshaping topologically associating domains (TADs) and their boundaries. These changes can lead to inappropriate enhancer–gene interactions and altered gene expression during development.
We study how such position effects influence developmental gene regulation, with a particular emphasis on congenital malformations. Using whole-genome sequencing in combination with functional analyses in mouse models, we aim to define general principles by which genome structure controls gene regulation in development.
Project 03: High-throughput functional interrogation of non-coding variation
Whole-genome sequencing identifies large numbers of non-coding variants whose functional impact is often unknown. To systematically address this challenge, we develop and apply massively parallel reporter assays (MPRAs) and CRISPR-based screening approaches to test thousands of regulatory elements and sequence variants in parallel.
These high-throughput functional approaches enable the direct assessment of regulatory activity and provide a scalable framework for interpreting non-coding variation. More broadly, this work contributes to a mechanistic understanding of gene regulation and genome function in development and disease.
