Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 50, Pages 20204-20211Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1217659109
Keywords
chromatin architecture; enhancer-promoter interaction
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Funding
- Human Frontier Science Program Organization (HFSPO)
- Ecole Polytechnique Federale de Lausanne (EPFL)
- University of Geneva
- Swiss National Research Fund (SNF)
- National Research Center (NCCR) Frontiers in Genetics
- European Research Council (ERC)
- FP7 European Union Program Integrated research on Developmental determinants of Ageing and Longevity (IDEAL)
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Copy number variations are genomic structural variants that are frequently associated with human diseases. Among these copy number variations, duplications of DNA segments are often assumed to lead to dosage effects by increasing the copy number of either genes or their regulatory elements. We produced a series of large targeted duplications within a conserved gene desert upstream of the murine HoxD locus. This DNA region, syntenic to human 2q31-32, contains a range of regulatory elements required for Hoxd gene transcription, and it is often disrupted and/or reorganized in human genetic conditions collectively known as the 2q31 syndrome. Unexpectedly, one such duplication led to a transcriptional down-regulation in developing digits by impairing physical interactions between the target genes and their upstream regulatory elements, thus phenocopying the effect obtained when these enhancer sequences are deleted. These results illustrate the detrimental consequences of interrupting highly conserved regulatory landscapes and reveal a mechanism where genomic duplications lead to partial loss of function of nearby located genes.
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