title: Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus.
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.
authors.affiliation: National Research Centre Frontiers in Genetics, School of Life Sciences,  Ecole Polytechnique Fédérale, 1015 Lausanne,  Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Montavon
authors.forename: Laurie
authors.initials: L
authors.lastname: Thevenet
authors.forename: Denis
authors.initials: D
authors.lastname: Duboule
mesh_terms: D000818:Animals; D001483:Base Sequence; D007446:Chromosome Inversion; D056915:DNA Copy Number Variations; D017931:DNA Primers / Q000235:genetics; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005121:Extremities / Q000196:embryology; D005260:Female; D020440:Gene Duplication; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D005810:Multigene Family; D011247:Pregnancy
chemical_list: D017931:DNA Primers