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Bioinformatics Advance Access published online on August 8, 2008
Bioinformatics, doi:10.1093/bioinformatics/btn421
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© The Author (2008). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

On the frequency of Copy Number Variants

Iuliana Ionita-Laza 1,*, Nan M. Laird 1, Benjamin A. Raby 2, Scott T. Weiss 2 and Christoph Lange 1

1Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA
2Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA

*To whom correspondence should be addressed. Dr. Iuliana Ionita-Laza, E-mail: iionita{at}hsph.harvard.edu


  Abstract

Motivation: Estimating the frequency distribution of copy number variants (CNVs) is an important aspect of the effort to characterize this new type of genetic variation. Currently, most studies report a strong skew toward low frequency CNVs. In this paper, our goal is to investigate the frequencies of CNVs. We employ a two-step procedure for the CNV frequency estimation process. We use family information a posteriori to select only the most reliable CNV regions, i.e. those showing high rates of mendelian transmission.

Results: Our results suggest that the current skew toward low frequency CNVs may not be representative of the true frequency distribution, but may be due, among other reasons, to the non-negligible false-negative rates that characterize CNV detection methods. Moreover, false-positives are also likely, as low frequency CNVs are hard to detect with small sample sizes and technologies that are not ideally suited for their detection. Without appropriate validation methods, such as incorporation of biologically relevant information (for example, in our case, the transmission of heritable CNVs from parents to offspring), it is difficult to assess the validity of specific CNVs, and even harder to obtain reliable frequency estimates.

Availability: Software implementing the methods described in this manuscript is available for download at the following address: http://www.isites.harvard.edu/icb/icb.do?keyword=k36162

Contact: iionita{at}hsph.harvard.edu

Associate Editor: Dr. Alex Bateman

Received on May 27, 2008; revised on August 4, 2008; accepted on August 7, 2008

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