High-throughput genotyping of intermediate-size structural variation

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

doi:10.1093/hmg/ddl031

High-throughput genotyping of intermediate-size structural variation

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

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1159-1167
Number of pages	9
Journal	Human Molecular Genetics
Volume	15
Issue number	7
DOIs	https://doi.org/10.1093/hmg/ddl031
State	Published - 1 Apr 2006
Externally published	Yes

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@article{7b65792b757c4ecf9269155829f91006,

title = "High-throughput genotyping of intermediate-size structural variation",

abstract = "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.",

author = "Newman, {Tera L.} and Rieder, {Mark J.} and Morrison, {V. Anne} and Sharp, {Andrew J.} and Smith, {Joshua D.} and Sprague, {L. James} and Rajinder Kaul and Carlson, {Christopher S.} and Olson, {Maynard V.} and Nickerson, {Deborah A.} and Eichler, {Evan E.}",

note = "Funding Information: This work was supported, in part, by NIH grant HD043569 to E.E.E. and by NIEHS grant ES-15478 to D.A.N. and M.J.R.",

year = "2006",

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doi = "10.1093/hmg/ddl031",

language = "English",

volume = "15",

pages = "1159--1167",

journal = "Human Molecular Genetics",

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AU - Newman, Tera L.

AU - Rieder, Mark J.

AU - Morrison, V. Anne

AU - Sharp, Andrew J.

AU - Smith, Joshua D.

AU - Sprague, L. James

AU - Kaul, Rajinder

AU - Carlson, Christopher S.

AU - Olson, Maynard V.

AU - Nickerson, Deborah A.

AU - Eichler, Evan E.

N1 - Funding Information: This work was supported, in part, by NIH grant HD043569 to E.E.E. and by NIEHS grant ES-15478 to D.A.N. and M.J.R.

PY - 2006/4/1

Y1 - 2006/4/1

N2 - 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.

AB - 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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DO - 10.1093/hmg/ddl031

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High-throughput genotyping of intermediate-size structural variation

Abstract

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