Designing Optimally Multiplexed SNP Genotyping Assays

  • Yonatan Aumann
  • Efrat Manisterski
  • Zohar Yakhini
Part of the Lecture Notes in Computer Science book series (LNCS, volume 2812)


We consider the task of SNP (Single Nucleotide Polymorphism) genotyping. In many studies, genotyping of a large number of SNP must be performed. Multiple SNPs can be genotyped together in the same assay (a process called multiplexed genotyping), provided they adhere to some constraints. We address the optimization problem of designing assays that maximize the number of SNPs genotyped, subject to the multiplexing constraints. We focus on the SNP genotyping method based on primer extension and mass-spectrometry (PEA/MS). We translate the optimization problem to a graph coloring problem, and provide an essentially optimal heuristics for solving the corresponding coloring problem. In addition, we present a method that enables a dramatic increase in the multiplexing rate by modifying primer masses. In this case, the multiplexing design problem can be modelled as a matching problem in hypergraphs. We analyze the problem from both theoretical and practical aspects, providing theoretical hardness results and practical heuristics. The heuristics are tested using simulation methods, and prove to be close to optimal in practice.


Greedy Algorithm Edge Coloring Single Nucleotide Polymorphism Locus Graph Coloring Problem Single Nucleotide Polymorphism Site 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., Watson, J.D.: Molecular Biology of the Cell, 3rd edn. Garland Publishing, New York (1994)Google Scholar
  2. 2.
    Berge, C.: Hypergraphes. Gauthier-Villars (1987)Google Scholar
  3. 3.
    Cardon, L., Bell, J.: Association study design for complex diseases. Nat. Rev. Genet. 2, 91–99 (2001)CrossRefGoogle Scholar
  4. 4.
    Garey, M.R., Johnson, D.S.: Computers and Intractability: A Guide to the Theory of NP-Completeness. W. H. Freeman and Co., San Francisco (1979)zbMATHGoogle Scholar
  5. 5.
    Gibbons, A.: Algorithmic Graph Theory. ch. 5. Cambridge University Press, Cambridge (1985)zbMATHGoogle Scholar
  6. 6.
    Gut, G.: Automation of genotyping of single nucleotide polymorphisms. Human Mutation 17, 475–492 (2001)CrossRefGoogle Scholar
  7. 7.
    Holyer, I.: The np-completeness of edge colorings. SIAM J. Comput. 10, 718–720 (1981)zbMATHCrossRefMathSciNetGoogle Scholar
  8. 8.
    Kivioja, T., Arvas, M., Kataja, K., Penttila, M., Soberlund, H., Ukkonen, E.: Assigning probes into a small number of pools separable by electrophoresis. Bioinformatics 1(1), 1–8 (2002)Google Scholar
  9. 9.
    Manisterski, E.: Optimal multiplexing schemes for snp genotyping massspectrometry. Master’s thesis, Bar Ilan University, Department of Computer Science (2001)Google Scholar
  10. 10.
    Matula, D.W., Beck, L.L.: Smallest-last ordering and clustering and graph coloring algorithms. J. ACM 30, 417–427 (1983)zbMATHCrossRefMathSciNetGoogle Scholar
  11. 11.
    Ott, J.: Analysis of Human Genetic Linkage. Johns Hopkins University Press, Baltimore (1991)Google Scholar
  12. 12.
    Pritchard, J., Przeworski, M.: Linkage disequilibrium in humans: Models and data. Am. J. Hum. Genet. (69), 1–14 (2001)Google Scholar
  13. 13.
    Ross, P., Hall, L., Smirnov, I., Haff, L.: High level multiplex genotyping by maldi-tof mass spectrometry. Nature Biotechnolgy 16, 1347–1351 (1998)CrossRefGoogle Scholar
  14. 14.
    Wang, D.G., Fan, J.B., Siao, C.J., Berno, A., Young, P.P., et al.: Large-scale identification, mapping, and genotyping of single- nucleotide polymorphisms in the human genome. Science 280(5366), 1077–1082 (1998)CrossRefGoogle Scholar
  15. 15.
    Yakhini, Z., Webb, P., Roth, R.: Partitioning of Polymorphic DNAs. US Patent 6,074,831 (2000)Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • Yonatan Aumann
    • 1
  • Efrat Manisterski
    • 1
  • Zohar Yakhini
    • 2
  1. 1.Dept. of Computer ScienceBar-Ilan UniversityRamat GanIsrael
  2. 2.Agilent Laboratories and Departmemt of Computer Sciencethe TechnionHaifaIsrael

Personalised recommendations