Genomic Mismatch Scanning for the Mapping of Genetic Traits

  • Farideh Mirzayans
  • Michael A. Walter
Part of the Methods in Molecular Biology™ book series (MIMB, volume 175)


Genome mismatch scanning (GMS) is a rapid method of isolating regions of identity by descent (IBD) between two related individuals (1, 2, 3, 4, 5). With the availability of simple PCR techniques, vast numbers of highly informative genomewide polymorphic markers, and more recently, radiation hybrid mapping, DNA microarrays, and gene chip technology (Research Genetics, AL), GMS is a very practical shortcut to conventional genetic linkage methods. The basic procedure (Fig. 1) involves the restriction enzyme digestion of each of the genomic DNA samples from two related individuals, yielding fragment sizes up to 20 kb, followed by the methylation of one genome. Hybridization of the two genomes (one fully methylated and one fully unmethylated) results in four possible DNA hybrid fragments. Through specific restriction enzyme digestions, the fully methylated and the fully unmethylated homohybrids (both strands from the same individual) are removed. The E. coli mismatch repair enzyme selection facilitates the removal of most of the mismatch-containing heterohybrids (6,7), therefore, DNA fragments from all IBD regions are isolated on the basis of their ability to form extended mismatch-free heterohybrids (double-stranded DNA [dsDNA] molecules consisting of one strand from each of the individuals). These GMS-enriched mismatch-free heterohybrids are likely to include a disease gene locus inherited through a common ancestor.
Fig. 1.

A schematic outline of the GMS process.


Radiation Hybrid Mapping Adenine Residue Sodium Thiocyanate Gene Chip Technology Mismatch Repair Enzyme 
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.


  1. 1.
    Nelson, S. F., McCusker, J. H., Sander, M. A., Kee, Y., and Modrich, P. (1993) Genomic mismatch scanning: a new approach to genetic linkage mapping. Nature Genet. 4, 11–18.PubMedCrossRefGoogle Scholar
  2. 2.
    Brown, P. O. (1994) Genome scanning methods. Curr. Opin. Genet. Dev. 4, 366–373.PubMedCrossRefGoogle Scholar
  3. 3.
    Mirzayans, F., Mears, A. J., Guo, S.-W., Pearce, W. G., and Walter, M. A. (1997) Identification of the human chromosomal region containing the iridogoniodysgenesis anomaly locus by genomic-mismatch scanning. Am. J. Hum. Genet. 61, 111–119.PubMedCrossRefGoogle Scholar
  4. 4.
    Cheung, V. G. and Nelson, S. F. (1998) Genomic mismatch scanning identifies human genomic DNA shared identical by descent. Genomics 47, 1–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Cheung, V. G., Gregg, J. P., Goglin-Ewens, K. J., Bandong, J., Stanley, C. A. Baker, L., Higgins, M. J., Nowak, N. J., Shows, T. B., Ewens, W. J., Nelson, S. F., and Spielman, R. S. (1998) Linkage-disequilibrium mapping without genotyping. Nature Genet. 18, 225–230.PubMedCrossRefGoogle Scholar
  6. 6.
    Lahue, R. S., Au, K. G., and Modrich, P. (1989) DNA mismatch correction in a defined system. Science 245, 160–164.PubMedCrossRefGoogle Scholar
  7. 7.
    Learn, B. A. and Graistrom, R. H. (1989) Methyl-directed repair of frameshift heteroduplexes in cell extracts from Escherichia coli. J. Bact. 171, 6473–6481.PubMedGoogle Scholar
  8. 8.
    Shalon, D., Smith, S. J., and Brown, P. O. (1996) A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridisation. Genome Res. 6, 639–645.PubMedCrossRefGoogle Scholar
  9. 9.
    DeRisi, J., Penland, L., Brown, P. O., Bittner, M. L., Meltzer, P. S., Ray, M., Chen, Y., Su, Y. A., and Trent, J. M. (1996) Use of a cDNA microarray to analyze gene expression patterns in human cancer. Nature Genet. 14, 457–460.PubMedCrossRefGoogle Scholar
  10. 10.
    McAllister, L., Penland, L., and Brown, P. O. (1998) Enrichment for loci identical-by-descent between pairs of mouse or human genomes by genomic mismatch scanning. Genomics 47, 7–11.PubMedCrossRefGoogle Scholar
  11. 11.
    Mears, A. J., Mirzayans, F., Gould, D. B., Pearce, W. G., Walter, M. A. (1996) Autosomal dominant iridogoniodysgenesis maps to 6p25. Am. J. Hum. Genet. 59, 1321–1327.PubMedGoogle Scholar
  12. 12.
    Guo, S.-W. (1995) Proportion of genome shared identical by descent by relatives: concept, computation, and applications. Am. J. Hum. Genet., 56, 1468–1476.PubMedGoogle Scholar
  13. 13.
    Kunkel, L., Smith, K., Boyer, S., Borgaorkar, D., Wachtel, S., Miller, O., Berg, W., Jones, H., and Rary, J. (1977) Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. PNAS 74, 1245–1249.PubMedCrossRefGoogle Scholar
  14. 14.
    Madisen, L., Hoar, D. I., Holroyd, C. D., Crisp, M., and Hodes, M. E. (1987) The effect of storage of blood and isolated DNA on the integrity of DNA. Am. J. Med. Genet. 27, 379–390.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2001

Authors and Affiliations

  • Farideh Mirzayans
    • 1
  • Michael A. Walter
    • 1
  1. 1.Department of Ophthalmology, Ocular Genetics LaboratoryUniversity of AlbertaEdmontonCanada

Personalised recommendations