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Human Molecular Genetics Advance Access originally published online on February 23, 2006
Human Molecular Genetics 2006 15(7):1159-1167; doi:10.1093/hmg/ddl031
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

High-throughput genotyping of intermediate-size structural variation

Tera L. Newman1, Mark J. Rieder1, V. Anne Morrison1, Andrew J. Sharp1, Joshua D. Smith1, L. James Sprague1, Rajinder Kaul3, Christopher S. Carlson1, Maynard V. Olson2, Deborah A. Nickerson1 and Evan E. Eichler1,*

1Department of Genome Sciences and 2Howard Hughes Medical Institute, University of Washington School of Medicine, 1705 NE Pacific Street, Seattle, WA 98195, USA and 3University of Washington Genome Center, Department of Medicine, University of Washington, Seattle, WA 98195, USA

* To whom correspondence should be addressed at: Howard Hughes Medical Institute, Department of Genome Sciences, Box 357730, University of Washington School of Medicine, HSB K336B, 1705 NE Pacific Street, Seattle, WA 98195, USA. Email: eee{at}gs.washington.edu

Received December 6, 2005; Revised February 7, 2006; Accepted February 15, 2006

The contribution of large-scale and intermediate-size structural variation (ISV) to human genetic disease and disease susceptibility is only beginning to be understood. The development of high-throughput genotyping technologies is one of the most critical aspects for future studies of linkage disequilibrium (LD) and disease association. Using a simple PCR-based method designed to assay the junctions of the breakpoints, we genotyped seven simple insertion and deletion polymorphisms ranging in size from 6.3 to 24.7 kb among 90 CEPH individuals. We then extended this analysis to a larger collection of samples (n=460) by application of an oligonucleotide extension–ligation genotyping assay. The analysis showed a high level of concordance (~99%) when compared with PCR/sequence-validated genotypes. Using the available HapMap data, we observed significant LD (r2=0.74–0.95) between each ISV and flanking single nucleotide polymorphisms, but this observation is likely to hold only for similar simple insertion/deletion events. The approach we describe may be used to characterize a large number of individuals in a cost-effective manner once the sequence organization of ISVs is known.


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