The effects of non-coding duplications on gene regulation and disease pathology

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Structural variants are a frequent cause of human disease that are often ignored if they are located in non-coding regions of the genome and/or are considered not to be related to gene dosage. We will investigate the effect of a small (5 kb) duplication containing two enhancer elements next to BMP2 that is associated with brachydactyly. Chromosome conformation capture (HiC) has shown that the locus consists of one large topologically associated domain (TAD) likely to contain the entirety of BMP2 regulatory elements. To investigate the pathomechanism of the duplication we will re-engineer the human brachydactyly-associated duplication in mice and investigate its pathology in regard to gene expression and digit development. We will determine the importance of position of the enhancers within the TAD for gene expression and analyze the effect of duplications on chromatin contacts. We will determine factors that bind to the BMP2 enhancer element to understand how it gets activated. Finally, we will investigate a cohort of brachydactyly patients for non-coding mutations. The project will provide in depth data about a single locus that will be taken paradigmatically for the bioinformatic evaluation of structural variants in other loci affected by enhancer duplication or reshuffling.