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Translational genetics

Structural variation in the 3D genome

Nature Reviews Geneticsvolume 19pages453467 (2018) | Download Citation


Structural and quantitative chromosomal rearrangements, collectively referred to as structural variation (SV), contribute to a large extent to the genetic diversity of the human genome and thus are of high relevance for cancer genetics, rare diseases and evolutionary genetics. Recent studies have shown that SVs can not only affect gene dosage but also modulate basic mechanisms of gene regulation. SVs can alter the copy number of regulatory elements or modify the 3D genome by disrupting higher-order chromatin organization such as topologically associating domains. As a result of these position effects, SVs can influence the expression of genes distant from the SV breakpoints, thereby causing disease. The impact of SVs on the 3D genome and on gene expression regulation has to be considered when interpreting the pathogenic potential of these variant types.

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The authors apologize to colleagues whose work we were unable to discuss or failed to cite owing to space constraints. We thank members of the Mundlos and the Shendure laboratories for helpful discussions. M.S. was supported by a grant from the Deutsche Forschungsgemeinschaft (SP1532/2-1). D.G.L. is supported by a grant from the Deutsche Forschungsgemeinschaft (GA2495/1-1). Work in S.M.’s laboratory is funded by the Deutsche Forschungsgemeinschaft, the Berlin Institute for Health and the Max Planck Foundation.

Author information


  1. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    • Malte Spielmann
  2. Epigenetics and Sex Development Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany

    • Darío G. Lupiáñez
  3. Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany

    • Stefan Mundlos
  4. Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany

    • Stefan Mundlos


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All authors contributed equally to all aspects of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Stefan Mundlos.


Structural variation

(SV). Genetic variation that includes all structural and quantitative chromosomal rearrangements, that is, deletions and duplications, as well as copy-number-neutral aberrations, such as inversions, insertions and translocations.

Copy number variation

(CNV). Genetic variation that refers only to quantitative chromosomal rearrangements, such as deletions and duplications.

Microdeletion and microduplication syndromes

A group of syndromes that are caused by chromosomal microdeletions and microduplications, which make up a subset of copy number variations that are usually smaller than 5 Mb. Classic examples include the 7q11 deletion (Williams–Beuren syndrome), the 15q11–15q13 deletion (Prader–Willi and Angelman syndromes) and the 17p11 deletion (Smith–Magenis syndrome).

Position effects

Effects of structural variation (SV), classically translocations, on the expression of a gene without any changes to its coding sequence or promoter region. These effects can also be observed if a gene is inserted into different regions of the genome or if SVs connect previously unconnected genes and their regulatory units. In these cases, the change in the level of gene expression is thought to result from changes in the position of the gene relative to its normal non-coding cis-regulatory environment.

Chromosome conformation capture

(3C). PCR-based proximity-ligation analysis method of 3D genome organization that allows a reconstruction of the native chromatin structure within the nucleus. 3C employs a PCR-based approach to confirm interactions between two previously known loci (one versus one). The introduction of a second round of digestion and ligation allows the generation of self-circularized DNA fragments (4C-seq), on which inverse PCR can be used to identify all unknown fragments interacting with a specific locus (one versus all). Multiple genomic regions can be investigated in parallel by a multiplexing approach (5C; many versus many). HiC allows the identification of every possible interaction occurring in the nucleus through the introduction of biotin labelling to pull down ligation junctions (all versus all).


A measure of the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance.

Gene dosage

The number of copies of a particular gene, including all its regulatory regions present in a genome.


A state in which one copy of a gene is inactivated or deleted and expression of the remaining functional copy of the gene is not sufficient to preserve normal function.

Topologically associating domains

(TADs). Genomic sequences in the range of megabases in length that are separated by boundary regions and that physically interact with themselves more frequently than with the rest of the genome.

Intra-TAD SVs

Structural variation (SV) that occurs within topologically associating domains (TADs). Within a regulatory domain, SVs of regulatory elements can change the enhancer dosage and may result in a tissue-specific loss of function (deletion) or a gain of function (duplication) of their endogenous target gene, which can be located anywhere within the TAD.

Enhancer adoption

A phenomenon that refers to a regulatory gain of function mutation in which ectopic expression of a gene is driven by an enhancer that normally regulates another gene located in a different regulatory domain; also known as enhancer hijacking.

Inter-TAD SVs

Structural variations (SVs) that occur between topologically associating domains (TADs). Such SVs affect several regulatory domains and have the potential to disrupt and rearrange the complex 3D chromatin organization of a locus by repositioning TAD boundaries, genes and enhancer elements. These position effects may lead to TAD fusion (deletion), neo-TAD formation (duplications) or TAD shuffling (inversion and/or translocation).

TAD shuffling

The reordering of topologically associating domains (TADs) within the genome. Inversions that cross TAD boundaries or translocations can result in the fusion of two regulatory domains that do not naturally belong together, causing enhancer adoption. At the same time, these structural variations can result in regulatory loss of function by removing enhancer elements from their target genes.

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Further reading

  • Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis

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    Nature Genetics (2018)