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

结构变异是人类疾病的常见原因，如果它们位于基因组的非编码区和/或被认为与基因剂量无关，则通常被忽视。我们将研究与短指畸形相关的BMP 2旁含有两个增强子元件的小（5 kb）重复的影响。染色体构象捕获（HiC）表明，该基因座由一个大的拓扑相关结构域组成（CRN），可能包含整个BMP 2调控元件。为了研究重复的病理机制，我们将在小鼠中重新设计人类短趾相关重复，并研究其在基因表达和手指发育方面的病理学。我们将确定的重要性的增强子的位置内的基因表达的重复和分析的影响，染色质接触。我们将确定与BMP 2增强子元件结合的因素，以了解它是如何被激活的。最后，我们将调查一组短指（趾）畸形患者的非编码突变。该项目将提供有关单个基因座的深入数据，这些数据将被用于受增强子复制或重组影响的其他基因座中结构变异的生物信息学评估。

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.