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  • Review Article
  • Published:

Comparing whole genomes using DNA microarrays

Nature Reviews Genetics volume 9, pages 291–302 (2008)Cite this article

Key Points

  • Hybridization between complementary strands of DNA enables the interrogation of unknown DNA by comparison with DNA of known sequence or genomic context.

  • DNA microarrays containing hundreds of thousands or millions of probes can be used to interrogate genomic sequence. Advances in array-based approaches have enabled detection of the main forms of genomic variation: amplifications, deletions, insertions, rearrangements and base-pair changes.

  • Structural variation in the genome — deletions and duplications, copy number variation, insertions, inversions and chromosomal translocations — can be detected using array comparative genome hybridization. For this application it is often sufficient to have large probes (such as PCR products, cDNA clones or long oligonucleotides) that allow for hybridization despite some sequence differences.

  • When DNA probes are short, hybridization efficiency is acutely sensitive to mismatches; such probes therefore facilitate comparison of genomes at the nucleotide level.

  • Global mapping of insertion sites is performed by isolating the insertion element and its immediately neighbouring DNA. The DNA is then hybridized to a whole-genome array to identify its genomic location.

  • Comprehensive detection of mutations in a complex genome is carried out using whole-genome overlapping tiling arrays, which provide multiple measurements of the effect of an SNP on hybridization.

  • Resequencing arrays use at least four probes per interrogated base and have been used to resequence small genomes.

  • Microarrays offer a relatively inexpensive and efficient means of comparing all known classes of genomic diversity between closely related genomes. However, they are not appropriate for some applications, such as detecting unknown sequences or interrogating highly repetitive or low-complexity sequences.

Abstract

The rapid accumulation of complete genomic sequences offers the opportunity to carry out an analysis of inter- and intra-individual genome variation within a species on a routine basis. Sequencing whole genomes requires resources that are currently beyond those of a single laboratory and therefore it is not a practical approach for resequencing hundreds of individual genomes. DNA microarrays present an alternative way to study differences between closely related genomes. Advances in microarray-based approaches have enabled the main forms of genomic variation (amplifications, deletions, insertions, rearrangements and base-pair changes) to be detected using techniques that are readily performed in individual laboratories using simple experimental approaches.

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Figure 1: Identifying copy number variation in genomes using array comparative genome hybridization.
Figure 2: Detecting SNP variation using microarrays.
Figure 3: Genome-wide mapping of loci by selective enrichment and detection using microarrays.

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Acknowledgements

We thank members of the Botstein and Dunham laboratories. Research is supported by the National Institute of General Medical Sciences Center for Quantitative Biology (GM-071508) grant.

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Authors and Affiliations

  1. Lewis–Sigler Institute for Integrative Genomics, Carl Icahn Laboratory, Princeton University, Princeton, 08544, New Jersey, USA

    David Gresham, Maitreya J. Dunham & David Botstein

  2. Department of Molecular Biology, Carl Icahn Laboratory, Princeton University, Princeton, 08544, New Jersey, USA

    David Gresham, Maitreya J. Dunham & David Botstein

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  1. David Gresham
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Glossary

Experimental evolution

The long-term selection of microorganisms or populations under laboratory conditions to model simple evolutionary scenarios.

Detect

The identification of a genomic variant, the actual state of which is not known until further analysis.

DNA probe

In the context of microarrays, DNA probe refers to the DNA oligonucleotide, PCR product or genomic clone that is attached to a microarray in order to probe a labelled genomic DNA sample that is added in solution. In the context of Southern blotting, DNA probe refers to the labelled DNA oligonucleotide that is added in solution to probe the genomic DNA sample that is immobilized on a membrane.

Photolithography

The use of masks to selectively deprotect nascent oligonucleotides using light, allowing the parallel synthesis of millions of probes.

Ink-jet deposition

The use of print cartridge heads to deposit one of the four DNA bases at a probe site on the microarray.

Fluorescent in situ hybridization

(FISH). A technique in which a fluorescently labelled DNA probe is used to detect a particular chromosome or gene using fluorescence microscopy.

Quantitative PCR

A procedure in which the products of a PCR reaction are measured by monitoring the signal that is produced by a fluorescent dye, which accumulates during each PCR cycle.

Tm

The Tm (melting temperature) of an oligonucleotide is the temperature at which 50% of the duplex strands are separated.

Suppressor mutations

Mutations that suppress, or alleviate, the phenotypic effect of another mutation.

Genome complexity

The number of different DNA sequences in a genome, originally measured by the rate of re-association of heat-denatured DNA.

Paired-end sequencing

Determination of the sequence at both ends of a fragment of DNA of known size.

Resequencing

The determination of the exact DNA sequence by comparison with a known reference.

Parametric tests

Statistical tests that assume an underlying distribution, which is usually Gaussian. The term Gaussian describes a continuous probability distribution that is symmetrical around a defined mean value, the shape of which is determined by the variance.

Chromatin immunoprecipitation

(ChIP). Fractionation of DNA that is bound to a protein of interest by means of an antibody.

Ratiometric approach

The use of methods that include an internal reference so that the ratio between sample and control is the metric of interest.

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Gresham, D., Dunham, M. & Botstein, D. Comparing whole genomes using DNA microarrays. Nat Rev Genet 9, 291–302 (2008). https://doi.org/10.1038/nrg2335

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