Multiplexed variation scanning for 1,000 amplicons in hundreds of patients using mismatch repair detection (MRD) on tag arrays
- Malek Faham*,‡,†,
- Jianbiao Zheng*,‡,
- Martin Moorhead*,‡,
- Hossein Fakhrai-Rad*,‡,
- Eugeni Namsaraev*,‡,
- Kee Wong*,‡,
- Zhiyong Wang*,‡,
- Shu G. Chow*,‡,
- Liana Lee*,‡,
- Kent Suyenaga*,‡,
- Jennifer Reichert§,
- Andrew Boudreau*,‡,
- James Eberle*,‡,
- Carsten Bruckner*,‡,
- Maneesh Jain*,‡,
- George Karlin-Neumann*,‡,
- Hywel B. Jones*,‡,
- Thomas D. Willis*,‡,
- Joseph D. Buxbaum§, and
- Ronald W. Davis¶,†
- *ParAllele BioScience, 7300 Shoreline Court, South San Francisco, CA 94080; ¶Stanford Genome Technology Center, 855 California Avenue, Palo Alto, CA 94304; and §Laboratory of Molecular Neuropsychiatry, Departments of Psychiatry and Neurobiology, and Seaver Autism Research Center, Greater New York Autism Research Center of Excellence, Mount Sinai School of Medicine, New York, NY 10029
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Contributed by Ronald W. Davis, August 4, 2005
Abstract
Identification of the genetic basis of common disease may require comprehensive sequence analysis of coding regions and regulatory elements in patients and controls to find genetic effects caused by rare or heterogeneous mutations. In this study, we demonstrate how mismatch repair detection on tag arrays can be applied in a case-control study. Mismatch repair detection allows >1,000 amplicons to be screened for variations in a single laboratory reaction. Variation scanning in 939 amplicons, mostly in coding regions within a linkage peak, was done for 372 patients and 404 controls. In total, >180 Mb of DNA was scanned. Several variants more prevalent in patients than in controls were identified. This study demonstrates an approach to the discovery of susceptibility genes for common disease: large-scale direct sequence comparison between patients and controls. We believe this approach can be scaled up to allow sequence comparison in the whole-genome coding regions among large sets of cases and controls at a reasonable cost in the near future.
Footnotes
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↵ † To whom correspondence may be addressed. E-mail: malek{at}p-gene.com or dbowe{at}stanford.edu.
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↵ ‡ In the interest of full disclosure, M.F. would like to point out that many of the authors (M.F., J.Z., M.M., H.F.-R., E.N., K.W., Z.W., S.G.C., L.L., K.S., A.B., J.E., C.B., M.J., G.K.-N., H.B.J., and T.D.W.) are employees of ParAllele BioScience, the licensee of the mismatch repair detection technology.
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Abbreviations: MRD, mismatch repair detection; AGRE, Autism Genetic Resource Exchange.
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↵ ∥ We have a proof of principle showing that a 3,000-plex reaction is feasible (M.F. and R.W.D., unpublished work)
- Copyright © 2005, The National Academy of Sciences
