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Structural variation in the human genome

Key Points

  • Structural variants in the human genome include cytogenetically detectable and submicroscopic deletions, duplications, large-scale copy-number variants, inversions and translocations.

  • The ability to detect and characterize structural variants in the 1-kb to 3-Mb size range in a robust manner across the genome has not been possible until recently.

  • New developments in genome-scanning technologies and computational methodologies, and the availability of a reference sequence for comparison, have made possible the large-scale discovery of structural variants.

  • Many studies are revealing that the total content of structural variants in the human genome could equal or exceed that of SNPs.

  • Structural variants often coincide with low-copy repeat DNA (also called segmental duplications), as these highly related sequences are more likely to undergo non-allelic recombination and subsequent rearrangement.

  • Structural variation in the genome can directly or indirectly influence gene dosage through different mechanisms, and therefore influence phenotypic variation and disease.

  • The cataloguing of structural variants and their frequencies in populations will be important for disease-mapping studies and for proper interpretation of clinical diagnostic-testing data.

Abstract

The first wave of information from the analysis of the human genome revealed SNPs to be the main source of genetic and phenotypic human variation. However, the advent of genome-scanning technologies has now uncovered an unexpectedly large extent of what we term 'structural variation' in the human genome. This comprises microscopic and, more commonly, submicroscopic variants, which include deletions, duplications and large-scale copy-number variants — collectively termed copy-number variants or copy-number polymorphisms — as well as insertions, inversions and translocations. Rapidly accumulating evidence indicates that structural variants can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.

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Figure 1: Cytogenetic detection and confirmation of structural variants.
Figure 2: Array-based, genome-wide methods for the identification of copy-number variants.
Figure 3: Multiplex PCR-based methods for the identification of copy-number variants.
Figure 4: The complexity of segmental duplications and copy-number variants.
Figure 5: Influence of structural variants on phenotype.

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Acknowledgements

The authors thank R. Khaja, J. MacDonald, J. Zhang and M. Shago (from The Centre for Applied Genomics, Hospital for Sick Children), N. Carter and M. Hurles (Wellcome Trust Sanger Institute), K. Jones (Affymetrix), and C. Lee (Brigham and Woman's Hospital, Harvard Medical School) for discussions. The work was supported from grants from Genome Canada/Ontario Genomics Institute, the Canadian Institutes of Health Research (CIHR), and the McLaughlin Centre for Molecular Medicine. A.R.C. is supported by the Natural Science and Engineering Research Council and L.F. is supported by the Swedish Medical Research Council. S.W.S. is an Investigator of CIHR and International Scholar of the Howard Hughes Medical Institute.

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Correspondence to Stephen W. Scherer.

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DATABASES

OMIM

Angelman syndrome

Hunter syndrome

Sotos syndrome

Williams–Beuren syndrome

Wolf–Hirschhorn syndrome

FURTHER INFORMATION

Affymetrix

Agilent Technologies

Celera Genomics

Chromosome Abnormality Database

Database of Chromosomal Imbalance and Phenotypes in Humans using Ensembl Resources (DECIPHER)

Database of Genomic Variants

Human Genome Segmental Duplication Database

Human Structural Variation Database

Mendelian Cytogenetics Network Online Database

Mitelman Database of Chromosome Aberrations in Cancer

NIGMS Human Genetic Cell Repository

NimbleGen

The European Collection of Cell Cultures (ECACC)

The International HapMap Project

Nature Genetics

Glossary

Aneuploidy

The presence of an abnormal number of chromosomes within a cell.

Heteromorphism

A microscopically visible region of a chromosome that varies in size, morphology or staining properties. They include euchromatic and non-euchromatic variation, such as satellite–satellite stalk variation and heterochromatic variation (centromeres and other C-band positive regions).

Fragile site

A small break or a constriction of a chromosome that can be visualized under special cell-culture conditions. Some fragile sites are universal, others are normal structural variants, and two are associated with mental retardation syndromes (FRAXA and FRAXE).

Isochromosome

A chromosome that has two genetically and morphologically identical arms.

Double minute

Acentric, extra-chromosomally amplified chromatin, which usually contains a particular chromosomal segment or gene; common in cancer cells.

Marker chromosome

(Also known as an extra-structurally abnormal chromosome or 'supernumerary' chromosome.) Chromosomes that are seen in addition to the normal chromosome complement in fluorescence in situ hybridization experiments.

Secondary constriction

A thin chromatic filament that connects a chromosomal satellite with the rest of the chromosome.

Acrocentric chromosome

A chromosome that has a centromere at or close to one end. Human acrocentric chromosomes are 13, 14, 15, 21 and 22.

Chromosome banding

A method of defining chromosome structure by staining with Giemsa and looking at the banding pattern in the heterochromatin of the centromeric regions.

Fluorescence in situ hybridization

A technique in which fluorescently labelled DNA probes are hybridized to interphase cells, metaphase chromosome preparations or DNA fibres, as a means to determine the presence and relative location of target sequences.

Unbalanced rearrangement

A genomic variant that involves gain or loss of DNA, such as deletion and duplication.

Euchromatic variant

A subset of cytogenetic heteromorphisms that involve microscopically visible variations of the euchromatic regions of chromosomes.

Derivative chromosome

An abnormal chromosome consisting of segments of two or more chromosomes joined together as a result of a translocation of other rearrangement.

Segmental duplications

Segments of chromosomal DNA that are >1 kb in size and have >90% inter-copy sequence identity (also called low-copy repeats or duplicons). They have been shown to constitute 5% of the reference sequence of the human genome, where they are thought to have arisen over the past 35 million years of primate evolution.

Balanced variant

A genomic variant that involves no net loss or gain of genetic material. They include perfect inversions and translocations.

COT-1 DNA

DNA that is mainly composed of repetitive sequences. It is produced when short fragments of denatured genomic DNA are re-annealed.

Fosmid

A bacterially propagated phagemid vector system that is suitable for cloning genomic inserts of approximately 40 kb in size.

Cryptic translocation

A translocation, particularly one that involves DNA near telomeres, that is too small to be detectable by traditional chromosome-banding analysis.

Gene conversion

A process in which one sequence directs the sequence conversion of a partner allele or paralogous sequence into its own form.

Constitutional translocations

Chromosome abnormalities that occur before fertilization (during meiosis) or early in embryogenesis (during mitosis), such that essentially all cells in the individual harbour the same abnormality.

Position effect

A change in the expression of a gene that is produced by changing its location within a genome.

Genomic disorders

A group of human diseases that are caused by recurrent genomic rearrangements of unstable genomic regions. These give rise to phenotypes as a result of abnormal gene dosage within the rearranged genomic region. Segmental duplications are often involved in the rearrangement event.

Haplotype

A tightly linked group of genetic markers, which tend to be inherited as a unit because of their close proximity.

Gene Ontology

A project that provides sets of controlled vocabularies that have been developed to help describe and categorize genes. They describe the molecular function, biological process and cellular localization of gene products.

Optical mapping

A technology that uses in situ restriction digests of individual DNA molecules from genomic DNA to produce detailed optical-restriction maps of genomes.

Tiling-path array

An array that contains a set of clones that represents the sequence of a chromosome or a portion of a genome with minimum overlap.

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Feuk, L., Carson, A. & Scherer, S. Structural variation in the human genome. Nat Rev Genet 7, 85–97 (2006). https://doi.org/10.1038/nrg1767

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