Deletions of chromosomal regulatory boundaries are associated with congenital disease

Abstract

BackgroundRecent data from genome-wide chromosome conformation capture analysis indicate that the human genome is divided into conserved megabase-sized self-interacting regions called topological domains. These topological domains form the regulatory backbone of the genome and are separated by regulatory boundary elements or barriers. Copy-number variations can potentially alter the topological domain architecture by deleting or duplicating the barriers and thereby allowing enhancers from neighboring domains to ectopically activate genes causing misexpression and disease, a mutational mechanism that has recently been termed enhancer adoption.ResultsWe use the Human Phenotype Ontology database to relate the phenotypes of 922 deletion cases recorded in the DECIPHER database to monogenic diseases associated with genes in or adjacent to the deletions. We identify combinations of tissue-specific enhancers and genes adjacent to the deletion and associated with phenotypes in the corresponding tissue, whereby the phenotype matched that observed in the deletion. We compare this computationally with a gene-dosage pathomechanism that attempts to explain the deletion phenotype based on haploinsufficiency of genes located within the deletions. Up to 11.8% of the deletions could be best explained by enhancer adoption or a combination of enhancer adoption and gene-dosage effects.ConclusionsOur results suggest that enhancer adoption caused by deletions of regulatory boundaries may contribute to a substantial minority of copy-number variation phenotypes and should thus be taken into account in their medical interpretation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0423-1) contains supplementary material, which is available to authorized users.

Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations

“…Despite multiple studies, the mechanisms underlying the formation of topological domain boundaries remain unknown. It has been previously suggested that genomic deletions at TAD boundaries in normal cells result in a change in local chromatin organization and in a formation of new domain boundaries (Nora et al 2012;Ibn-Salem et al 2014). We therefore investigated the role of genomic sequence variation in establishing TAD boundaries in cancer cells.…”

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

“…This genomic mechanism is not necessarily limited to these disorders. Recently, losses of cis -regulatory elements, imbalance in coding and noncoding elements, illegitimate adoption of enhancer sequences and the like, resulting from CNVs have been proposed as a general mechanism of 'genomic' disease [Klopocki and Mundlos, 2011;Lettice et al, 2011;Poot and Kas, 2013;Spielmann and Klopocki, 2013;Gordon et al, 2014;Ibn-Salem et al, 2014;Lupiáñez et al, 2015]. CNVs may also cause 'side effects', i.e.…”

“…Next, the phenotypes of model organisms with disruptions of the orthologous genes, and features of breakpoint regions of the human CCRs, such as LINE elements, segmental duplications, 'side effects' on transcription levels of genes in the vicinity of the breakpoints, markers of active promoters (e.g. H3K4Me1, H3K27Ac), and adoption of enhancers or insulators have to be taken into consideration [Reymond et al, 2007;Hehir-Kwa et al, 2010;Spielmann and Mundlos, 2013;Ibn-Salem et al, 2014]. All these sophisticated methods of bioinformatic predictions notwithstanding, experimental confirmation of gene disruption or alteration of mRNA levels in a phenotypically relevant tissue of the patient remains necessary [Kloosterman and Hochstenbach, 2014].…”

3D genomics imposes evolution of the domain model of eukaryotic genome organization

“…Furthermore, replication programs and organization of chromosomes into TADs appear to be reestablished simultaneously after mitosis (Dileep et al 2015a). Finally, disruption of TADs, in particular fusion of the neighboring TADs, results in dramatic changes of promoter-enhancer interactions and may cause various diseases (Ibn-Salem et al 2014;Ji et al 2016;Lupianez et al 2015Lupianez et al , 2016Petrov et al 2006Petrov et al , 2008. Thus, organization of the genome into spatial domains is directly related to the functioning of the genome (Pombo and Dillon 2015;Sexton and Cavalli 2015).…”