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Noncoding copy-number variations are associated with congenital limb malformation.

PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.ConclusionOur findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations.Genetics in Medicine advance online publication, 12 October 2017; doi:10.1038/gim.2017.154.

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International Symposium on Chemical Biology

10.01.2018 09:00, Auditorium (Camps Biotech)

International Symposium on Chemical Biology (List: http://symposium.nccr-chembio.ch/speakers/).
hosted by: Howard RiezmanRobbie LoewithAurélien Roux.

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Our department hosts 12 research laboratories gathering close to 200 scientists, engineers and technical staff. Research topics cover a large variety of topics, such as developmental genetics and neurogenetics, regeneration, evo-devo, physics of biology, phylogenetics or anthropology.

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Teaching life sciences at the University of Geneva is an important duty for all staff scientists. In addition to the bachelor programme, we also propose specific masters and PhD specialisations through various programmes.

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