High-throughput genotyping of intermediate-size structural variation

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 disequ...

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Bibliographic Details
Published in:Human molecular genetics 2006-04, Vol.15 (7), p.1159-1167
Main Authors: Newman, Tera L., Rieder, Mark J., Morrison, V. Anne, Sharp, Andrew J., Smith, Joshua D., Sprague, L. James, Kaul, Rajinder, Carlson, Christopher S., Olson, Maynard V., Nickerson, Deborah A., Eichler, Evan E.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cohort Studies
Female
Fundamental and applied biological sciences. Psychology
Genetic Testing - methods
Genetic Variation
Genetics of eukaryotes. Biological and molecular evolution
Genotype
Humans
Linkage Disequilibrium
Male
Microarray Analysis
Models, Genetic
Molecular and cellular biology
Polymorphism, Single Nucleotide
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddl031