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Human Molecular Genetics 2006 15(Review Issue 1):R57-R66; doi:10.1093/hmg/ddl057
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Structural variants: changing the landscape of chromosomes and design of disease studies

Lars Feuk, Christian R. Marshall, Richard F. Wintle and Stephen W. Scherer*

The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Department of Molecular and Medical Genetics, University of Toronto, Ontario, Canada

* To whom correspondence should be addressed at: The Centre for Applied Genomics, The Hospital for Sick Children, MaRS Centre—East Tower, 101 College Street, Room 14-701, Toronto, Ontario, Canada M5G 1L7. Tel: +1 4168137613; Fax: +1 4168138319; Email: swscherer{at}sickkids.ca

Received February 23, 2006; Accepted March 9, 2006

The near completeness of human chromosome sequences is facilitating accurate characterization and assessment of all classes of genomic variation. Particularly, using the DNA reference sequence as a guide, genome scanning technologies, such as microarray-based comparative genomic hybridization (array CGH) and genome-wide single nucleotide polymorphism (SNP) platforms, have now enabled the detection of a previously unrecognized degree of larger-sized (non-SNP) variability in all genomes. This heterogeneity can include copy number variations (CNVs), inversions, insertions, deletions and other complex rearrangements, most of which are not detected by standard cytogenetics or DNA sequencing. Although these genomic alterations (collectively termed structural variants or polymorphisms) have been described previously, mainly through locus-specific studies, they are now known to be more global in occurrence. Moreover, as just one example, CNVs can contain entire genes and their number can correlate with the level of gene expression. It is also plausible that structural variants may commonly influence nearby genes through chromosomal positional or domain effects. Here, we discuss what is known of the prevalence of structural variants in the human genome and how they might influence phenotype, including the continuum of etiologic events underlying monogenic to complex diseases. Particularly, we highlight the newest studies and some classic examples of how structural variants might have adverse genetic consequences. We also discuss why analysis of structural variants should become a vital step in any genetic study going forward. All these progresses have set the stage for a golden era of combined microscopic and sub-microscopic (cytogenomic)-based research of chromosomes leading to a more complete understanding of the human genome.


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