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Methods

Accurate and reliable high-throughput detectionof copy number variation in the human genome

¹ The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; ² Department of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; ³ Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, MSG IL7, Canada; ⁴ Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA; ⁵ Harvard Medical School, Boston, Massachusetts 02115, USA

This study describes a new tool for accurate and reliable high-throughput detection of copy number variation in the human genome. We have constructed a large-insert clone DNA microarray covering the entire human genome in tiling path resolution that we have used to identify copy number variation in human populations. Crucial to this study has been the development of a robust array platform and analytic process for the automated identification of copy number variants (CNVs). The array consists of 26,574 clones covering 93.7% of euchromatic regions. Clones were selected primarily from the published "Golden Path," and mapping was confirmed by fingerprinting and BAC-end sequencing. Array performance was extensively tested by a series of validation assays. These included determining the hybridization characteristics of each individual clone on the array by chromosome-specific add-in experiments. Estimation of data reproducibility and false-positive/negative rates was carried out using self–self hybridizations, replicate experiments, and independent validations of CNVs. Based on these studies, we developed a variance-based automatic copy number detection analysis process (CNVfinder) and have demonstrated its robustness by comparison with the SW-ARRAY method.

⁷ Corresponding author.

E-mail npc{at}sanger.ac.uk; fax +44-1223-491919.

Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.5630906

[Supplemental material is available online at www.genome.org.]

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