Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Towards better mouse models: enhanced genotypes, systemic phenotyping and envirotype modelling

Nature Reviews Genetics volume 10, pages 371–380 (2009)Cite this article

Key Points

  • The mouse is the leading mammalian model organism for basic genetic research and to study human diseases. The current mouse mutant resources already contain mutations for essentially all genes and markers, but many of these mutations still need to be established in mouse lines as a free resource for the scientific community.

  • To maximize the potential of the mouse as a model organism, we now face challenges that go beyond simply establishing a mutant line for every gene. The focus of genetic research for the next generation of mouse models can be considered at three main levels: the genotype, the phenotype and what we term the envirotype.

  • At the genotype level, mutations are required that are more closely related to human mutations and genetic variants.

  • At the phenotype level, systematic (each mutant mouse line) and systemic (examining all organ systems) analysis of mutant mouse lines is required.

  • Several mouse clinics have provided essential phenotype data that is fundamental for the analysis of primary and secondary effects of mutations. The capacities of these mouse clinics will need to be increased to make significant progress at a faster pace.

  • The analysis of envirotypes (which are sets of exogenous factors that affect the phenotype) will be essential for accurately modelling human diseases in the mouse, but this research is just beginning.

  • A map of exogenous factors and their effects on the mammalian genome will be required. The extent to which the effects of particular envirotypes are the same in mice and humans remains to be determined.

Abstract

The mouse is the leading mammalian model organism for basic genetic research and for studying human diseases. Coordinated international projects are currently in progress to generate a comprehensive map of mouse gene functions — the first for any mammalian genome. There are still many challenges ahead to maximize the value of the mouse as a model, particularly for human disease. These involve generating mice that are better models of human diseases at the genotypic level, systemic (assessing all organ systems) and systematic (analysing all mouse lines) phenotyping of existing and new mouse mutant resources, and assessing the effects of the environment on phenotypes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Maximizing the potential of the mouse as a model organism.
Figure 2: Scheme of the primary phenotyping protocol of the German Mouse Clinic (GMC).
Figure 3: Frequency of new mutant phenotypes detected in mutant mouse lines analysed in the German Mouse Clinic (GMC).
Figure 4: Schematic representation of the five environmental platforms currently being established at the German Mouse Clinic.

Similar content being viewed by others

References

  1. Nadeau, J. H. et al. Sequence interpretation. Functional annotation of mouse genome sequences. Science 291, 1251–1255 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Austin, C. P. et al. The knockout mouse project. Nature Genet. 36, 921–924 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Auwerx, J. et al. The European dimension for the mouse genome mutagenesis program. Nature Genet. 36, 925–927 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Patten, B. C. in Eco Targets, Goal Functions, and Orientors (eds Muller, F. & Leupelt, M.) 137–160 (Springer, Berlin, 1998). We believe that this publication introduced the term 'envirotype'. In particular, it is mentioned that “the genotype–phenotype pair of classical genetics is an incomplete specification of determinate reproduction; an external envirotype is needed to complete the mechanism.”

    Book  Google Scholar 

  5. Bult, C. J., Eppig, J. T., Kadin, J. A., Richardson, J. E. & Blake, J. A. The Mouse Genome Database (MGD): mouse biology and model systems. Nucleic Acids Res. 36, D724–D728 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Paigen, K. One hundred years of mouse genetics: an intellectual history. II. The molecular revolution (1981–2002). Genetics 163, 1227–1235 (2003). References 6 and 7 give an excellent historical overview of 100 years of mouse genetics, from its beginning to the genomic era.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Paigen, K. One hundred years of mouse genetics: an intellectual history. I. The classical period (1902–1980). Genetics 163, 1–7 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Qiu, J. Animal research: mighty mouse. Nature 444, 814–816 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Collins, F. S., Finnell, R. H., Rossant, J. & Wurst, W. A new partner for the international knockout mouse consortium. Cell 129, 235 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Collins, F. S., Rossant, J. & Wurst, W. A mouse for all reasons. Cell 128, 9–13 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Hansen, G. M. et al. Large-scale gene trapping in C57BL/6N mouse embryonic stem cells. Genome Res. 18, 1670–1679 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gondo, Y. Trends in large-scale mouse mutagenesis: from genetics to functional genomics. Nature Rev. Genet. 9, 803–810 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Carlson, C. M. et al. Transposon mutagenesis of the mouse germline. Genetics 165, 243–256 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ding, S. et al. Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell 122, 473–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Dupuy, A. J., Akagi, K., Largaespada, D. A., Copeland, N. G. & Jenkins, N. A. Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436, 221–226 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Keng, V. W. et al. A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma. Nature Biotechnol. 27, 264–274 (2009).

    Article  CAS  Google Scholar 

  17. Rosenthal, N. & Brown, S. The mouse ascending: perspectives for human-disease models. Nature Cell Biol. 9, 993–999 (2007). A comprehensive and insightful recent review of the genetic tools available for the mouse and the challenges that mouse models of human diseases are facing.

    Article  CAS  PubMed  Google Scholar 

  18. Gieger, C. et al. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet. 4, e1000282 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. McCarroll, S. A. & Altshuler, D. M. Copy-number variation and association studies of human disease. Nature Genet. 39, S37–S42 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. McCarroll, S. A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genet. 40, 1166–1174 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Justice, M. J., Noveroske, J. K., Weber, J. S., Zheng, B. & Bradley, A. Mouse ENU mutagenesis. Hum. Mol. Genet. 8, 1955–1963 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Soewarto, D., Klaften, M. & Rubio-Aliaga, I. Features and strategies of ENU mouse mutagenesis. Curr. Pharm. Biotechnol. 10, 198–213 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Nolan, P. M. et al. Implementation of a large-scale ENU mutagenesis program: towards increasing the mouse mutant resource. Mamm. Genome 11, 500–506 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Nolan, P. M. et al. A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nature Genet. 25, 440–443 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Hrabe de Angelis, M. H. et al. Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nature Genet. 25, 444–447 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Balling, R. ENU mutagenesis: analyzing gene function in mice. Annu. Rev. Genomics Hum. Genet. 2, 463–492 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Vreugde, S. et al. Beethoven, a mouse model for dominant, progressive hearing loss DFNA36. Nature Genet. 30, 257–258 (2002). This paper of an ENU-induced mouse model was published along with an article that describes patients with the same progressive deafness phenotype caused by a mutation in the homologous human gene.

    Article  PubMed  Google Scholar 

  28. Lisse, T. S. et al. ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. PLoS Genet. 4, e7 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Klaften, M. & Hrabe de Angelis, M. ARTS: a web-based tool for the set-up of high-throughput genome-wide mapping panels for the SNP genotyping of mouse mutants. Nucleic Acids Res. 33, W496–W500 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Augustin, M. et al. Efficient and fast targeted production of murine models based on ENU mutagenesis. Mamm. Genome 16, 405–413 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Coghill, E. L. et al. A gene-driven approach to the identification of ENU mutants in the mouse. Nature Genet. 30, 255–256 (2002).

    Article  PubMed  Google Scholar 

  32. Michaud, E. J. et al. Efficient gene-driven germ-line point mutagenesis of C57BL/6J mice. BMC Genomics 6, 164 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Quwailid, M. M. et al. A gene-driven ENU-based approach to generating an allelic series in any gene. Mamm. Genome 15, 585–591 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Sakuraba, Y. et al. Molecular characterization of ENU mouse mutagenesis and archives. Biochem. Biophys. Res. Commun. 336, 609–616 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Sakuraba, Y. et al. Identification and characterization of new long conserved noncoding sequences in vertebrates. Mamm. Genome 19, 703–712 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Takahasi, K. R., Sakuraba, Y. & Gondo, Y. Mutational pattern and frequency of induced nucleotide changes in mouse ENU mutagenesis. BMC Mol. Biol. 8, 52 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Herault, Y., Rassoulzadegan, M., Cuzin, F. & Duboule, D. Engineering chromosomes in mice through targeted meiotic recombination (TAMERE). Nature Genet. 20, 381–384 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Olson, L. E., Richtsmeier, J. T., Leszl, J. & Reeves, R. H. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306, 687–690 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kmita, M., Fraudeau, N., Herault, Y. & Duboule, D. Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs. Nature 420, 145–150 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Couzin, J. RNA interference. Mini RNA molecules shield mouse liver from hepatitis. Science 299, 995 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Kunath, T. Transgenic RNA interference to investigate gene function in the mouse. Methods Mol. Biol. 461, 165–186 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Raoul, C. et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nature Med. 11, 423–428 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Bibikova, M., Golic, M., Golic, K. G. & Carroll, D. Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics 161, 1169–1175 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Lloyd, A., Plaisier, C. L., Carroll, D. & Drews, G. N. Targeted mutagenesis using zinc-finger nucleases in Arabidopsis. Proc. Natl Acad. Sci. USA 102, 2232–2237 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zeevi, V., Tovkach, A. & Tzfira, T. Increasing cloning possibilities using artificial zinc finger nucleases. Proc. Natl Acad. Sci. USA 105, 12785–12790 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mani, M., Kandavelou, K., Dy, F. J., Durai, S. & Chandrasegaran, S. Design, engineering, and characterization of zinc finger nucleases. Biochem. Biophys. Res. Commun. 335, 447–457 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Steuber-Buchberger, P., Wurst, W. & Kuhn, R. Simultaneous Cre-mediated conditional knockdown of two genes in mice. Genesis 46, 144–151 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Zender, L. et al. An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer. Cell 135, 852–864 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hitz, C., Steuber-Buchberger, P., Delic, S., Wurst, W. & Kuhn, R. Generation of shRNA transgenic mice. Methods Mol. Biol. 530, 1–29 (2009).

    Article  CAS  Google Scholar 

  50. Echeverri, C. J. et al. Minimizing the risk of reporting false positives in large-scale RNAi screens. Nature Methods 3, 777–779 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Meng, X., Noyes, M. B., Zhu, L. J., Lawson, N. D. & Wolfe, S. A. Targeted gene inactivation in zebrafish using engineered zinc-finger nucleases. Nature Biotechnol. 26, 695–701 (2008).

    Article  CAS  Google Scholar 

  52. Yan, Z., Sun, X. & Engelhardt, J. F. Progress and prospects: techniques for site-directed mutagenesis in animal models. Gene Ther. 19 Feb 2009 (doi:10.1038/gt.2009.16).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Matera, I. et al. A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Hum. Mol. Genet. 17, 2118–2131 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mohan, S., Baylink, D. J. & Srivastava, A. K. A chemical mutagenesis screen to identify modifier genes that interact with growth hormone and TGF-beta signaling pathways. Bone 42, 388–395 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Rubio-Aliaga, I. et al. A genetic screen for modifiers of the delta1-dependent Notch signaling function in the mouse. Genetics 175, 1451–1463 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dietrich, W. F. et al. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75, 631–639 (1993). A hallmark article on the genetic mapping of the first quantitative trait gene or modifier affecting a mouse model for human disease.

    Article  CAS  PubMed  Google Scholar 

  57. Erickson, R. P. Mouse models of human genetic disease: which mouse is more like a man? Bioessays 18, 993–998 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Gregorova, S. et al. Mouse consomic strains: exploiting genetic divergence between Mus m. musculus and Mus m. domesticus subspecies. Genome Res. 18, 509–515 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rogner, U. C. & Avner, P. Congenic mice: cutting tools for complex immune disorders. Nature Rev. Immunol. 3, 243–252 (2003).

    Article  CAS  Google Scholar 

  60. Matin, A., Collin, G. B., Asada, Y., Varnum, D. & Nadeau, J. H. Susceptibility to testicular germ-cell tumours in a 129.MOLF-Chr 19 chromosome substitution strain. Nature Genet. 23, 237–240 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Nadeau, J. H., Singer, J. B., Matin, A. & Lander, E. S. Analysing complex genetic traits with chromosome substitution strains. Nature Genet. 24, 221–225 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Singer, J. B. et al. Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304, 445–448 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Singer, J. B., Hill, A. E., Nadeau, J. H. & Lander, E. S. Mapping quantitative trait loci for anxiety in chromosome substitution strains of mice. Genetics 169, 855–862 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Grattan, M., Mi, Q. S., Meagher, C. & Delovitch, T. L. Congenic mapping of the diabetogenic locus Idd4 to a 5.2-cM region of chromosome 11 in NOD mice: identification of two potential candidate subloci. Diabetes 51, 215–223 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Hill, N. J. et al. NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans. Diabetes 49, 1744–1747 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Lamhamedi-Cherradi, S. E. et al. Further mapping of the Idd5.1 locus for autoimmune diabetes in NOD mice. Diabetes 50, 2874–2878 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Shao, H. et al. Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proc. Natl Acad. Sci. USA 105, 19910–19914 (2008). An insightful article on the frequent occurrence of QTLs in the rodent genome and how the interaction of QTLs is neither simple nor additive.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Churchill, G. A. et al. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nature Genet. 36, 1133–1137 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Iraqi, F. A., Churchill, G. & Mott, R. The Collaborative Cross, developing a resource for mammalian systems genetics: a status report of the Wellcome Trust cohort. Mamm. Genome 19, 379–381 (2008).

    Article  PubMed  Google Scholar 

  71. Chesler, E. J. et al. The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics. Mamm. Genome 19, 382–389 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Davisson, M. FIMRe: Federation of International Mouse Resources: global networking of resource centers. Mamm. Genome 17, 363–364 (2006).

    Article  PubMed  Google Scholar 

  73. Davis, M. M. A Prescription for human immunology. Immunity 29, 835–838 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. von Herrath, M. G. & Nepom, G. T. Lost in translation: barriers to implementing clinical immunotherapeutics for autoimmunity. J. Exp. Med. 202, 1159–1162 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nishie, W. et al. Humanization of autoantigen. Nature Med. 13, 378–383 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Traggiai, E. et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304, 104–107 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Cocco, M. et al. CD34+ cord blood cell-transplanted Rag2−/−γc−/− mice as a model for Epstein–Barr virus infection. Am. J. Pathol. 173, 1369–1378 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Gorantla, S. et al. Human immunodeficiency virus type 1 pathobiology studied in humanized BALB/c-Rag2−/−γc−/− mice. J. Virol. 81, 2700–2712 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Proia, D. A. & Kuperwasser, C. Reconstruction of human mammary tissues in a mouse model. Nature Protoc. 1, 206–214 (2006).

    Article  CAS  Google Scholar 

  80. Gailus-Durner, V. et al. Introducing the German Mouse Clinic: open access platform for standardized phenotyping. Nature Methods 2, 403–404 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Brown, S. D., Chambon, P. & de Angelis, M. H. EMPReSS: standardized phenotype screens for functional annotation of the mouse genome. Nature Genet. 37, 1155 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Green, E. C. et al. EMPReSS: European mouse phenotyping resource for standardized screens. Bioinformatics 21, 2930–2931 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Mallon, A. M., Blake, A. & Hancock, J. M. EuroPhenome and EMPReSS: online mouse phenotyping resource. Nucleic Acids Res. 36, D715–D718 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Woychik, R. P., Klebig, M. L., Justice, M. J., Magnuson, T. R. & Avner, E. D. Functional genomics in the post-genome era. Mutat. Res. 400, 3–14 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Horsch, M. et al. Systematic gene expression profiling of mouse model series reveals coexpressed genes. Proteomics 8, 1248–1256 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Frey, I. M. et al. Profiling at mRNA, protein, and metabolite levels reveals alterations in renal amino acid handling and glutathione metabolism in kidney tissue of Pept2−/− mice. Physiol. Genomics 28, 301–310 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Ntziachristos, V., Culver, J. P. & Rice, B. W. Small-animal optical imaging. J. Biomed. Opt. 13, 011001 (2008).

    Article  PubMed  Google Scholar 

  88. Niedre, M. J. et al. Early photon tomography allows fluorescence detection of lung carcinomas and disease progression in mice in vivo. Proc. Natl Acad. Sci. USA 105, 19126–19131 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ahting, U. et al. Neurological phenotype and reduced lifespan in heterozygous Tim23 knockout mice, the first mouse model of defective mitochondrial import. Biochim. Biophys. Acta 9 Dec 2008 (doi:10.1016/j.bbabio.2008.12.001).

    Article  CAS  Google Scholar 

  90. Soker, T. et al. Pleiotropic effects in Eya3 knockout mice. BMC Dev. Biol. 8, 118 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hoelter, S. M. et al. “Sighted C3H” mice — a tool for analysing the influence of vision on mouse behaviour? Front. Biosci. 13, 5810–5823 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Schmidt, S. et al. Deletion of glucose transporter GLUT8 in mice increases locomotor activity. Behav. Genet. 38, 396–406 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fuchs, H. et al. Phenotypic characterization of mouse models for bone-related diseases in the German Mouse Clinic. J. Musculoskelet. Neuronal Interact. 8, 13–14 (2008).

    CAS  PubMed  Google Scholar 

  94. Bender, A. et al. Creatine improves health and survival of mice. Neurobiol. Aging 29, 1404–1411 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Vauti, F. et al. The mouse Trm1-like gene is expressed in neural tissues and plays a role in motor coordination and exploratory behaviour. Gene 389, 174–185 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Barrantes Idel, B. et al. Generation and characterization of dickkopf3 mutant mice. Mol. Cell Biol. 26, 2317–2326 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Colucci-Guyon, E., Gimenez, Y. R. M., Maurice, T., Babinet, C. & Privat, A. Cerebellar defect and impaired motor coordination in mice lacking vimentin. Glia 25, 33–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Colucci-Guyon, E. et al. Mice lacking vimentin develop and reproduce without an obvious phenotype. Cell 79, 679–694 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. Eckes, B. et al. Impaired wound healing in embryonic and adult mice lacking vimentin. J. Cell Sci. 113, 2455–2462 (2000).

    CAS  PubMed  Google Scholar 

  100. Henrion, D. et al. Impaired flow-induced dilation in mesenteric resistance arteries from mice lacking vimentin. J. Clin. Invest. 100, 2909–2914 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Schiffers, P. M. et al. Altered flow-induced arterial remodeling in vimentin-deficient mice. Arterioscler. Thromb. Vasc. Biol. 20, 611–616 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Terzi, F. et al. Reduction of renal mass is lethal in mice lacking vimentin. Role of endothelin-nitric oxide imbalance. J. Clin. Invest. 100, 1520–1528 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Welsh, E., Jirotka, M. & Gavaghan, D. Post-genomic science: cross-disciplinary and large-scale collaborative research and its organizational and technological challenges for the scientific research process. Philos. Transact. A Math. Phys. Eng. Sci. 364, 1533–1549 (2006). A sociological study on the far-reaching impact that the advent of 'big science' in life science research is beginning to have, for example, in the areas of organizational cultures, working practice, rewarding systems, education and communication technology.

    Article  CAS  Google Scholar 

  104. Paigen, K. & Eppig, J. T. A mouse phenome project. Mamm. Genome 11, 715–717 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Bogue, M. Mouse Phenome Project: understanding human biology through mouse genetics and genomics. J. Appl. Physiol. 95, 1335–1337 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Bogue, M. A. & Grubb, S. C. The Mouse Phenome Project. Genetica 122, 71–74 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Bogue, M. A., Grubb, S. C., Maddatu, T. P. & Bult, C. J. Mouse Phenome Database (MPD). Nucleic Acids Res. 35, D643–D649 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Hancock, J. M. & Mouse Phenotype Database Integration Consortium. Integration of mouse phenome data resources. Mamm. Genome 18, 157–163 (2007).

    Article  PubMed  Google Scholar 

  109. Brown, S. D., Hancock, J. M. & Gates, H. Understanding mammalian genetic systems: the challenge of phenotyping in the mouse. PLoS Genet. 2, e118 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Richter, S. H., Garner, J. P. & Wurbel, H. Environmental standardization: cure or cause of poor reproducibility in animal experiments? Nature Methods 6, 257–261 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Valérie Gailus-Durner et al. in Gene Knockout Protocols 2nd edn Vol. 530 (eds Wurst, W. & Kühn, R.) 436–509 (Humana Press, New Jersey, 2009).

Download references

Acknowledgements

The authors are funded through the German Ministry of Science and Education and the European Commission (grant numbers: 01GS0850, LSHG-2006-037188, 211414, LSHG-CT-2006-518240, MRTN-CT-2006-035468).

Author information

Authors and Affiliations

  1. Institute of Experimental Genetics, Helmholtz Zentrum München, GmbH, Ingolstädter Landstrasse 1, Neuherberg, 85764, Germany

    Johannes Beckers & Martin Hrabé de Angelis

  2. Technical University Munich, Center of Life and Food Sciences, Weihenstephan, Alte Akademie 8, Freising, 85354, Germany

    Johannes Beckers & Wolfgang Wurst

  3. Institute of Developmental Genetics, Helmholtz Zentrum München, GmbH, Ingolstädter Landstrasse 1, Neuherberg, 85764, Germany

    Wolfgang Wurst & Martin Hrabé de Angelis

Authors
  1. Johannes Beckers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wolfgang Wurst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Hrabé de Angelis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Johannes Beckers or Martin Hrabé de Angelis.

Related links

Related links

FURTHER INFORMATION

Australian Phenomics Facility (APF)

CASIMIR

Charles River's phenotyping screens, Massachusetts

Comparative Pathology Laboratory (CPL)

EMPReSS

EUCOMM

EUMODIC

EUMORPHIA

EuroPhenome

FIMRe

Frimorfo, Switzerland

German Mouse Clinic (GMC)

Helmholtz Centre Munich

IMGS

Infrafrontier

Institut Clinique de la Souris (ICS)

InterPhenome

Jackson Laboratory Phenotyping Services

KOMP

Laboratory Animal Sciences Program (LASP)

Mammalian Genetics Phenotyping

Mary Lyon Centre

MGD

Mouse Genetics Programme — Phenotyping

Mouse Phenome Database

Mouse Phenotyping Shared Resource (MPSR)

NorCOMM

Phenotyping Core

Research Animal Diagnostic Laboratory (RADIL)

RIKEN BioResource Center

Taconic Farms, Inc.

TIGM

Toronto Centre for Phenogenomics (TCP)

Unit for Laboratory Animal Medicine

Yale University Mouse Research Pathology (YMRP)

Glossary

Genotype

A description of the endogenous genetic information carried by an organism, as distinguished from its physical appearance (its phenotype) and external environmental factors (its envirotype).>

Phenotype

A description of any observable (macroscopic, microscopic or molecular) trait of an individual with respect to some inherited characteristic.

Envirotype

A description of factors that are exogenous to the organism. The environmental code and the genetic code together affect the phenotype.

Pleiotropic

A situation in which a single gene has an effect on two or more distinct phenotypic characters.

Transposon

A type of mobile genetic element that consists of DNA that can move to new genomic locations conservatively (without replicating itself) or replicatively (by moving a copy of itself).

QTL

Genetic locus or chromosomal region that contributes to the variability in complex quantitative traits (such as body weight), as identified by statistical analysis. Quantitative traits are typically affected by several genes and by the environment.

Genotype-driven mutagenesis

A reverse genetic approach that starts with the targeted mutagenesis of a known gene or marker sequence. The gene targeting is followed by the analysis of the mutant phenotype. This approach is generally based on a hypothesis about a potential function of the mutated gene.

Phenotype-driven mutagenesis

A forward genetic approach that starts with the identification of a mutant phenotype caused by a random mutation in the genome. The identification of the mutated gene or marker is subsequent to the identification of the mutant mouse line. This approach makes no assumption of which genes may underlie a disease.

SNP

A type of polymorphism in which genomic segments differ by a single base pair.

Copy number variant

A type of polymorphism in which a segment of genomic DNA is present at a different copy number with respect to a reference genome.

N-ethyl-N-nitrosourea

A chemical mutagen that introduces point mutations in spermatogonia of male mice with high efficiency. It can be used as a mutagen in gene-driven and phenotype-driven mutagenesis.

Zinc-finger nuclease

Synthetic protein composed of a nonspecific DNA-cleaving domain and a highly specific DNA-binding domain, which comprises a string of zinc-finger motifs. Zinc-finger nucleases and subsequent DNA repair by homologous recombination can be used to mutagenize genes.

Off-target effect

These effects may compromise the specificity of RNAi and can occur if there is sequence identity between the small interfering RNA and random mRNA transcripts, causing knockdown of the expression of non-targeted genes.

Redundancy

When two genes can fulfil an equivalent function. Because gene functions are frequently pleiotropic, redundancy is often partial, with two genes having overlapping rather than equivalent functions.

Epistasis

The interaction between different genes that affect the same trait. Epistasis takes place when the phenotype of one genetic allele (mutant or natural variant) is modified by one or several other genes (also called modifier genes), such that the joint phenotype differs from the one that would be produced if the two genes were acting independently.

Sensitized mutagenesis screen

A phenotype-driven mutagenesis screen in which mice carrying a targeted mutation are bred with N-ethyl-N-nitrosourea-treated males in order to provide a sensitized system for detecting dominant modifier mutations.

Consomic

Describes a mouse strain that is produced by a breeding strategy in which recombinants between two inbred strains are backcrossed to produce a strain that carries a single chromosome from one strain on the genetic background of the other.

Congenic

Describes a mouse strain that is produced by a breeding strategy in which recombinants between two inbred strains are backcrossed to produce a strain that carries a single genomic segment from one strain on the genetic background of the other.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beckers, J., Wurst, W. & de Angelis, M. Towards better mouse models: enhanced genotypes, systemic phenotyping and envirotype modelling. Nat Rev Genet 10, 371–380 (2009). https://doi.org/10.1038/nrg2578

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2578

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing