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Human Molecular Genetics Advance Access published online on February 23, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl031
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 6, 2005
Revised February 7, 2006
Accepted February 15, 2006

Article

High-throughput genotyping of intermediate-size structural variation

Tera L. Newman 1, Mark J. Rieder 1, V. Anne Morrison 1, Andrew J. Sharp 1, Joshua D. Smith 1, L. James Sprague 1, Rajinder Kaul 2, Christopher S. Carlson 1, Maynard V. Olson 2, Deborah A. Nickerson 1, and Evan E. Eichler 3 *

1 Department of Genome Sciences, University of Washington School of Medicine, 1705 NE Pacific St., Seattle, WA, 98195
2 University of Washington Genome Center, Department of Medicine, University of Washington, Seattle, Washington 98195, USA
3 Howard Hughes Medical Institute and Department of Genome Sciences, Box 357730; University of Washington School of Medicine, HSB K336B, 1705 NE Pacific St., Seattle, WA, 98195

* To whom correspondence should be addressed.
Evan E. Eichler, E-mail: eee{at}gs.washington.edu


  Abstract

The contribution of large-scale and intermediate-size structural variation 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 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 to PCR/sequence validated genotypes. Using available HapMap data, we observed significant linkage disequilibrium (r2 = 0.74 - 0.95) between each intermediate-size structural variant (ISV) and flanking single nucleotide polymorphisms (SNPs), 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 intermediate-size structural variants is known.


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