In Vitro Mutagenesis Protocols pp 203-213

Part of the Methods in Molecular Biology book series (MIMB, volume 634)

Approaches for Using Animal Models to Identify Loci That Genetically Interact with Human Disease-Causing Point Mutations



The complexity of human illnesses often extends beyond a single mutation in one gene. Mutations at other loci may act synergistically to affect the penetrance and severity of the associated clinical manifestations. Discovering the additional loci that contribute to an illness is a challenging problem. Animal models for disease, based on engineered point mutations in a homologous gene, have proven invaluable to better understand the mechanism(s) which give(s) rise to the observed physiological effects. Importantly, these animals can also function as the basis for genetic modifier screens to discover other loci which contribute to an illness. This chapter discusses the theory, considerations, and methodology for performing genetic modifier screens in animal models for human disease.

Key words

Modifier screen Genetic interaction Model organism MYH9-related disorders 


  1. 1.
    Kunishima S, Kojima T, Matsushita T, Tanaka T, Tsurusawa M, Furukawa Y, Nakamura Y, Okamura T, Amemiya N, Nakayama T, Kamiya T, Saito H (2001) Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly/Sebastian syndrome). Blood 97(4):1147–1149PubMedCrossRefGoogle Scholar
  2. 2.
    Kelley MJ, Jawien W, Ortel TL, Korczak JF (2000) Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly. Nat Genet 26(1):106–108PubMedCrossRefGoogle Scholar
  3. 3.
    Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, Nigro A, Noris P, Gangarossa S, Rocca B, Gresele P, Bizzaro N, Malatesta P, Koivisto PA, Longo I, Musso R, Pecoraro C, Iolascon A, Magrini U, Rodriguez Soriano J, Renieri A, Ghiggeri GM, Ravazzolo R, Balduini CL, Savoia A (2003) MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore) 82(3):203–215Google Scholar
  4. 4.
    Balduini CL, Iolascon A, Savoia A (2002) Inherited thrombocytopenias: from genes to therapy. Haematologica 87(8):860–880PubMedGoogle Scholar
  5. 5.
    Young PE, Richman AM, Ketchum AS, Kiehart DP (1993) Morphogenesis in Drosophila requires nonmuscle myosin heavy chain function. Genes Dev 7:29–41PubMedCrossRefGoogle Scholar
  6. 6.
    Franke JD, Montague RA, Rickoll WL, Kiehart DP (2007) An MYH9 human disease model in flies: site-directed mutagenesis of the Drosophila non-muscle myosin II results in hypomorphic alleles with dominant character. Hum Mol Genet 16(24):3160–3173PubMedCrossRefGoogle Scholar
  7. 7.
    Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401–415PubMedGoogle Scholar
  8. 8.
    Sauer B (1998) Inducible gene targeting in mice using the Cre/lox system. Methods 14(4):381–392PubMedCrossRefGoogle Scholar
  9. 9.
    Deiters A, Yoder JA (2006) Conditional transgene and gene targeting methodologies in zebrafish. Zebrafish 3(4):415–429PubMedCrossRefGoogle Scholar
  10. 10.
    Halsell SR, Kiehart DP (1998) Second-site noncomplementation identifies genomic regions required for Drosophila nonmuscle myosin function during morphogenesis. Genetics 148(4):1845–1863PubMedGoogle Scholar
  11. 11.
    Halsell SR, Chu B, Kiehart DP (2000) Genetic analysis demonstrates a direct link between Rho signaling and nonmuscle myosin function during Drosophila morphogenesis. Genetics 155:1253–1265PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Biological SciencesCarnegie Mellon UniversityPittsburghUSA

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