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Updated: May 17, 2026

HOX Loci Focused CRISPR/sgRNA Library Screening Identifying Critical CTCF Boundaries
Published on: March 31, 2019
Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus
Thomas Montavon1, Laurie Thevenet, Denis Duboule
1National Research Centre Frontiers in Genetics, School of Life Sciences, Ecole Polytechnique Fédérale, 1015 Lausanne, Switzerland.
Abstract:
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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