Towards better mouse models: enhanced genotypes, systemic phenotyping and envirotype modelling | Nature Reviews Genetics

Towards better mouse models: enhanced genotypes, systemic phenotyping and envirotype modelling | Nature Reviews Genetics
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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.
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Figure 1: Maximizing the potential of the mouse as a model organism.
The alternative text for this image may have been generated using AI.
Figure 2: Scheme of the primary phenotyping protocol of the German Mouse Clinic (GMC).
The alternative text for this image may have been generated using AI.
Figure 3: Frequency of new mutant phenotypes detected in mutant mouse lines analysed in the German Mouse Clinic (GMC).
The alternative text for this image may have been generated using AI.
Figure 4: Schematic representation of the five environmental platforms currently being established at the German Mouse Clinic.
The alternative text for this image may have been generated using AI.
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References
Nadeau, J. H. et al. Sequence interpretation. Functional annotation of mouse genome sequences.
Science
291
, 1251–1255 (2001).
Article
CAS
PubMed
Google Scholar
Austin, C. P. et al. The knockout mouse project.
Nature Genet.
36
, 921–924 (2004).
Article
CAS
PubMed
Google Scholar
Auwerx, J. et al. The European dimension for the mouse genome mutagenesis program.
Nature Genet.
36
, 925–927 (2004).
Article
CAS
PubMed
Google Scholar
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
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
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
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
Qiu, J. Animal research: mighty mouse.
Nature
444
, 814–816 (2006).
Article
CAS
PubMed
Google Scholar
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
Collins, F. S., Rossant, J. & Wurst, W. A mouse for all reasons.
Cell
128
, 9–13 (2007).
Article
CAS
PubMed
Google Scholar
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
Gondo, Y. Trends in large-scale mouse mutagenesis: from genetics to functional genomics.
Nature Rev. Genet.
, 803–810 (2008).
Article
CAS
PubMed
Google Scholar
Carlson, C. M. et al. Transposon mutagenesis of the mouse germline.
Genetics
165
, 243–256 (2003).
CAS
PubMed
PubMed Central
Google Scholar
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
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
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
Rosenthal, N. & Brown, S. The mouse ascending: perspectives for human-disease models.
Nature Cell Biol.
, 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
Gieger, C. et al. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.
PLoS Genet.
, e1000282 (2008).
Article
CAS
PubMed
PubMed Central
Google Scholar
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
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
Justice, M. J., Noveroske, J. K., Weber, J. S., Zheng, B. & Bradley, A. Mouse ENU mutagenesis.
Hum. Mol. Genet.
, 1955–1963 (1999).
Article
CAS
PubMed
Google Scholar
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
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
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
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
Balling, R. ENU mutagenesis: analyzing gene function in mice.
Annu. Rev. Genomics Hum. Genet.
, 463–492 (2001).
Article
CAS
PubMed
Google Scholar
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
Lisse, T. S. et al. ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta.
PLoS Genet.
, e7 (2008).
Article
CAS
PubMed
PubMed Central
Google Scholar
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
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
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
Michaud, E. J. et al. Efficient gene-driven germ-line point mutagenesis of C57BL/6J mice.
BMC Genomics
, 164 (2005).
Article
CAS
PubMed
PubMed Central
Google Scholar
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
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
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
Takahasi, K. R., Sakuraba, Y. & Gondo, Y. Mutational pattern and frequency of induced nucleotide changes in mouse ENU mutagenesis.
BMC Mol. Biol.
, 52 (2007).
Article
CAS
PubMed
PubMed Central
Google Scholar
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
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
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
Couzin, J. RNA interference. Mini RNA molecules shield mouse liver from hepatitis.
Science
299
, 995 (2003).
Article
CAS
PubMed
Google Scholar
Kunath, T. Transgenic RNA interference to investigate gene function in the mouse.
Methods Mol. Biol.
461
, 165–186 (2008).
Article
CAS
PubMed
Google Scholar
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
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
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
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
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
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
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
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
Echeverri, C. J. et al. Minimizing the risk of reporting false positives in large-scale RNAi screens.
Nature Methods
, 777–779 (2006).
Article
CAS
PubMed
Google Scholar
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
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
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
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
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
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
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
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
Rogner, U. C. & Avner, P. Congenic mice: cutting tools for complex immune disorders.
Nature Rev. Immunol.
, 243–252 (2003).
Article
CAS
Google Scholar
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
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
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
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
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
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
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
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
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
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
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
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
Davisson, M. FIMRe: Federation of International Mouse Resources: global networking of resource centers.
Mamm. Genome
17
, 363–364 (2006).
Article
PubMed
Google Scholar
Davis, M. M. A Prescription for human immunology.
Immunity
29
, 835–838 (2008).
Article
CAS
PubMed
PubMed Central
Google Scholar
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
Nishie, W. et al. Humanization of autoantigen.
Nature Med.
13
, 378–383 (2007).
Article
CAS
PubMed
Google Scholar
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
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
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
Proia, D. A. & Kuperwasser, C. Reconstruction of human mammary tissues in a mouse model.
Nature Protoc.
, 206–214 (2006).
Article
CAS
Google Scholar
Gailus-Durner, V. et al. Introducing the German Mouse Clinic: open access platform for standardized phenotyping.
Nature Methods
, 403–404 (2005).
Article
CAS
PubMed
Google Scholar
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
Green, E. C. et al. EMPReSS: European mouse phenotyping resource for standardized screens.
Bioinformatics
21
, 2930–2931 (2005).
Article
CAS
PubMed
Google Scholar
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
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
Horsch, M. et al. Systematic gene expression profiling of mouse model series reveals coexpressed genes.
Proteomics
, 1248–1256 (2008).
Article
CAS
PubMed
Google Scholar
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
Ntziachristos, V., Culver, J. P. & Rice, B. W. Small-animal optical imaging.
J. Biomed. Opt.
13
, 011001 (2008).
Article
PubMed
Google Scholar
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
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
Soker, T. et al. Pleiotropic effects in
Eya3
knockout mice.
BMC Dev. Biol.
, 118 (2008).
Article
CAS
PubMed
PubMed Central
Google Scholar
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
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
Fuchs, H. et al. Phenotypic characterization of mouse models for bone-related diseases in the German Mouse Clinic.
J. Musculoskelet. Neuronal Interact.
, 13–14 (2008).
CAS
PubMed
Google Scholar
Bender, A. et al. Creatine improves health and survival of mice.
Neurobiol. Aging
29
, 1404–1411 (2008).
Article
CAS
PubMed
Google Scholar
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
Barrantes Idel, B. et al. Generation and characterization of
dickkopf3
mutant mice.
Mol. Cell Biol.
26
, 2317–2326 (2006).
Article
CAS
PubMed
Google Scholar
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
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
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
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
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
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
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
Paigen, K. & Eppig, J. T. A mouse phenome project.
Mamm. Genome
11
, 715–717 (2000).
Article
CAS
PubMed
Google Scholar
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
Bogue, M. A. & Grubb, S. C. The Mouse Phenome Project.
Genetica
122
, 71–74 (2004).
Article
CAS
PubMed
Google Scholar
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
Hancock, J. M. & Mouse Phenotype Database Integration Consortium. Integration of mouse phenome data resources.
Mamm. Genome
18
, 157–163 (2007).
Article
PubMed
Google Scholar
Brown, S. D., Hancock, J. M. & Gates, H. Understanding mammalian genetic systems: the challenge of phenotyping in the mouse.
PLoS Genet.
, e118 (2006).
Article
CAS
PubMed
PubMed Central
Google Scholar
Richter, S. H., Garner, J. P. & Wurbel, H. Environmental standardization: cure or cause of poor reproducibility in animal experiments?
Nature Methods
, 257–261 (2009).
Article
CAS
PubMed
Google Scholar
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).
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Institute of Experimental Genetics, Helmholtz Zentrum München, GmbH, Ingolstädter Landstrasse 1, Neuherberg, 85764, Germany
Johannes Beckers & Martin Hrabé de Angelis
Technical University Munich, Center of Life and Food Sciences, Weihenstephan, Alte Akademie 8, Freising, 85354, Germany
Johannes Beckers & Wolfgang Wurst
Institute of Developmental Genetics, Helmholtz Zentrum München, GmbH, Ingolstädter Landstrasse 1, Neuherberg, 85764, Germany
Wolfgang Wurst & Martin Hrabé de Angelis
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Johannes Beckers
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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.
-ethyl-
-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.
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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
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Issue date
June 2009
DOI
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