Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus

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 produ...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-12, Vol.109 (50), p.20204-20211
Main Authors: Montavon, Thomas, Thevenet, Laurie, Duboule, Denis
Format: Article
Language:English
Subjects:
Alleles
Animals
Archipelagos
Base Sequence
Biological Sciences
Chromosome Inversion
Deoxyribonucleic acid
DNA
DNA Copy Number Variations
DNA Primers - genetics
dose response
Embryos
enhancer elements
Enhancer Elements, Genetic
Evolution, Molecular
Extremities - embryology
Female
Gene Duplication
Gene expression
gene expression regulation
Gene Expression Regulation, Developmental
Genes
Genes, Homeobox
Genetic loci
genetic variation
Genomics
Genotype & phenotype
human diseases
Humans
loci
Mice
Mice, Transgenic
Models, Genetic
Multigene Family
Phenotypes
Pregnancy
regulator genes
transcription (genetics)
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1217659109