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  • Review Article
  • Published:

Phenotypic impact of genomic structural variation: insights from and for human disease

Nature Reviews Genetics volume 14, pages 125–138 (2013)Cite this article

Subjects

Key Points

  • Recent technological advances in array and sequencing approaches are starting to revolutionize our ability to identify structural variants underlying complex phenotypes.

  • Structural variants are now being associated with an increasing number of normal phenotypic variations, as well as common and rare human diseases.

  • Changes in copy number of genes are overall accompanied by similar changes in mRNA expression, although regulatory mechanisms such as epistasis and autoregulatory feedback mechanisms can buffer against such copy-number changes.

  • Structural variants that are associated with complex phenotypes, such as autism or schizophrenia, can affect both regions associated with variable phenotypes and loci associated with Mendelian disease, which often cause more 'hard-wired' phenotypes.

  • Mice are excellent model systems for delineating the phenotypic consequences of structural variants, owing to their high physiological similarity to (and extensive synteny with) humans, and the availability of advanced genetic tools. They can also be used to analyse developmental, cell-type-specific or tissue-specific phenotypes.

  • Novel integrative approaches, including the use of induced pluripotent stem cells (iPSCs), animal models and computational approaches, will enable the delineation of complex disease phenotypes that are caused by rare de novo structural variants with cell-type-specific effects.

Abstract

Genomic structural variants have long been implicated in phenotypic diversity and human disease, but dissecting the mechanisms by which they exert their functional impact has proven elusive. Recently however, developments in high-throughput DNA sequencing and chromosomal engineering technology have facilitated the analysis of structural variants in human populations and model systems in unprecedented detail. In this Review, we describe how structural variants can affect molecular and cellular processes, leading to complex organismal phenotypes, including human disease. We further present advances in delineating disease-causing elements that are affected by structural variants, and we discuss future directions for research on the functional consequences of structural variants.

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Figure 1: Structural variants: classes and formation mechanisms.
Figure 2: Functional consequences of structural variants.
Figure 3: From genotype to phenotype: buffering and feedback.
Figure 4: Reconstructing the genetic network in DiGeorge syndrome.

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Acknowledgements

We thank R. Weatheritt for critical discussion of the manuscript. We apologize to all colleagues whose contributions could not be cited or highlighted owing to space limitations. J.O.K. was supported by an Emmy Noether Fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft). O.S. was supported by the Louis-Jeantet Foundation.

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  1. Joachim Weischenfeldt and Orsolya Symmons: These authors contributed equally to this work.

Authors and Affiliations

  1. Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, 69117, Germany

    Joachim Weischenfeldt & Jan O. Korbel

  2. Developmental Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, 69117, Germany

    Orsolya Symmons & François Spitz

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  1. Joachim Weischenfeldt
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  2. Orsolya Symmons
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Correspondence to François Spitz or Jan O. Korbel.

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Supplementary information

Supplementary information S1 (table)

Overview of prototypic SV-associated human diseases and traits. (PDF 270 kb)

Supplementary information S2 (table)

Animal models of human disease-causing structural variants (PDF 216 kb)

Glossary

Microarray-based comparative genome hybridization

A technique that allows the detection of copy-number changes. It involves hybridizing differentially labelled test sample DNAs and reference DNAs to microarray slides with genomic probes, and measuring the intensity difference between the two samples.

Paired-end DNA sequencing

A method whereby DNA is fragmented and sequenced from both ends. If the DNA fragments are size-selected, discrepancies in the distance and/or orientation of the two ends compared with a reference genome can reveal the presence of deletions, duplications, inversions and translocations.

Karyotyping

Determining the number, form and size of chromosomes in the nucleus of a cell. Chromosomes are visualised by photomicrographs of isolated and stained chromosomes in metaphase.

Genomic disorders

Diseases that are associated with specific genomic architectures that favour recurrent genomic rearrangements, leading to abnormal dosage or dysregulation of the affected genes.

Positional effects

The effects on expression of a gene or gene region when its genomic context is changed, such as by translocation to another chromosome.

Imprinted gene

A gene for which expression is determined by the parent that contributed it.

Imputation

A technique whereby a genomic variant is not directly genotyped, but instead its presence or absence is inferred on the basis of its association (co-occurrence) with another, genotyped variant.

Epistatic interactions

Modification of the expressivity of an allele by one or several other genes (known as 'modifier genes'). In Crohn's disease, epistatic interactions may explain up to 80% of the so-called 'missing heritability'.

cis-regulatory elements

Genomic regions (for example, enhancers) that regulate the expression of genes on the same chromosome.

Expression quantitative trait locus (eQTL)

A genomic locus that regulates the mRNA expression level of a gene.

Effect size

The percentage of phenotypic variance that can be attributed to a given genomic variant.

Synteny

Shared genomic organization between related species. It is usually seen as a shared relative order of genes or other functional elements on a portion of a chromosome.

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Weischenfeldt, J., Symmons, O., Spitz, F. et al. Phenotypic impact of genomic structural variation: insights from and for human disease. Nat Rev Genet 14, 125–138 (2013). https://doi.org/10.1038/nrg3373

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