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.

  • Viewpoint
  • Published:

The future of model organisms in human disease research

Abstract

Model organisms have played a huge part in the history of studies of human genetic disease, both in identifying disease genes and characterizing their normal and abnormal functions. But is the importance of model organisms diminishing? The direct discovery of disease genes and variants in humans has been revolutionized, first by genome-wide association studies and now by whole-genome sequencing. Not only is it now much easier to directly identify potential disease genes in humans, but the genetic architecture that is being revealed in many cases is hard to replicate in model organisms. Furthermore, disease modelling can be done with increasing effectiveness using human cells. Where does this leave non-human models of disease?

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Aitman, T. J. et al. Progress and prospects in rat genetics: a community view. Nature Genet. 40, 516–522 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Shao, H. et al. Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proc. Natl Acad. Sci. USA 105, 19910–19914 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rapp, J. P. Genetic analysis of inherited hypertension in the rat. Physiol. Rev. 80, 135–172 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Aitman, T. J. et al. Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nature Genet. 21, 76–83 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Hubner, N. et al. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nature Genet. 37, 243–253 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Petretto, E. et al. Heritability and tissue specificity of expression quantitative trait loci. PLoS Genet. 2, e172 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pravenec, M. et al. Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension. Nature Genet. 40, 952–954 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Snyder, M. & Gallagher, J. E. Systems biology from a yeast omics perspective. FEBS Lett. 583, 3895–3899 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chuang, H. Y., Hofree, M. & Ideker, T. A decade of systems biology. Ann. Rev. Cell Dev. Biol. 26, 721–744 (2010).

    Article  CAS  Google Scholar 

  10. Engel, S. R. et al. Saccharomyces Genome Database provides mutant phenotype data. Nucleic Acids Res. 38, D433–D436 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Menne, T. F. et al. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genet. 39, 486–495 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. McGary, K. L. et al. Systematic discovery of nonobvious human disease models through orthologous phenotypes. Proc. Natl Acad. Sci. USA 107, 6544–6549 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Visscher, P. M, & Montgomery, G.W. Genome-wide association studies and human disease: from trickle to flood. JAMA 302, 2028–2029 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Paigen, K. One hundred years of mouse genetics: an intellectual history. II. The molecular revolution (1981–2002). Genetics 163, 1227–1235 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M. & Horvitz, H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 β-converting enzyme. Cell 75, 641–652 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Savage, C. et al. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor β pathway components. Proc. Natl Acad. Sci. USA 93, 790–794 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    Article  CAS  PubMed  Google Scholar 

  19. Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Chalfie, M., Tu, Y., Euskirchen, G., Ward, W. W. & Prasher, D. C. Green fluorescent protein as a marker for gene expression. Science 263, 802–805 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Abbott, A. Basel Declaration defends animal research. Nature 468, 742 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Flint, J. & Mackay, T. F. C. Genetic architecture of quantitative traits in mice, flies, and humans. Genome Res. 19, 723–733 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mackay, T. F. C., Stone, E. A. & Ayroles, J. F. The genetics of quantitative traits: challenges and prospects. Nature Rev. Genet. 10, 565–577 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ober, C., Loisel, D. A. & Gilad, Y. Sex-specific genetic architecture of human disease. Nature Rev. Genet. 9, 911–922 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Caspi, A. et al. Role of genotype in the cycle of violence in maltreated children. Science 297, 851–854 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Ober, C. & Vercelli, D. Gene-environment interactions in human disease: nuisance or opportunity? Trends Genet. 27, 107–115 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hill, W. G., Goddard, M. E. & Visscher, P. M. Data and theory point to mainly additive genetic variance for complex traits. PLoS Genet. 4, e1000008 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shulman, J. M. & Feany, M. B. Genetic modifiers of tauopathy in Drosophila. Genetics 165, 1233–1242 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lessing, D. & Bonini, N. M. Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants. Nature Rev. Genet. 10, 359–370 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Rockman, M. V. Reverse engineering the genotype-phenotype map with natural genetic variation. Nature 456, 738–744 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Ayroles, J. F. et al. Systems genetics of complex traits in Drosophila melanogaster. Nature Genet. 41, 299–307 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. 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 

  36. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Livet, J., et al. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450, 56–62 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Kamei, M. et al. Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442, 453–456 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Nusslein-Volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 (1980).

    Article  CAS  PubMed  Google Scholar 

  40. Chalfie, M., Horvitz, H. R. & Sulston, J. E. Mutations that lead to reiterations in the cell lineages of C. elegans. Cell 24, 59–69 (1981).

    Article  CAS  PubMed  Google Scholar 

  41. Driever, W. et al. A genetic screen for mutations affecting embryogenesis in zebrafish. Development 123, 37–46 (1996).

    CAS  PubMed  Google Scholar 

  42. Haffter, P. et al. The identification of genes with unique and essential functions in the development of the zebrafish, Danio rerio. Development 123, 1–36 (1996).

    CAS  PubMed  Google Scholar 

  43. Atanur, S. S. et al., The genome sequence of the spontaneously hypertensive rat: analysis and functional significance. Genome Res. 20, 791–803 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Johannesson, M. et al. A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock. Genome Res. 19, 150–158 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tong, C., Li, P., Wu, N. L., Yan, Y. & Ying, Q.L. Production of p53 gene knockout rats by homologous recombination in embryonic stem cells. Nature 467, 211–213 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Geurts, A. M. et al. Knockout rats via embryo microinjection of zinc-finger nucleases. Science 325, 433 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jacob, H. J., Lazar, J., Dwinell, M. R., Moreno, C. & Geurts, A. M. Gene targeting in the rat: advances and opportunities. Trends Genet. 26, 510–518 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Heinig, M. et al. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467, 460–464 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fields, S. & Johnston, M. Cell biology. Whither model organism research? Science 307, 1885–1886 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Perocchi, F. et al. Assessing systems properties of yeast mitochondria through an interaction map of the organelle. PLoS Genet. 2, e170 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Hao, H. X. et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325, 1139–1142 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Khurana, V. & Lindquist, S. Modelling neurodegeneration in Saccharomyces cerevisiae: why cook with baker's yeast? Nature Rev. Neurosci. 11, 436–449 (2010).

    Article  CAS  Google Scholar 

  53. Marini, N. J., Thomas, P. D. & Rine, J. The use of orthologous sequences to predict the impact of amino acid substitutions on protein function. PLoS Genet. 6, e1000968 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ehrenreich, I. M. et al. Dissection of genetically complex traits with extremely large pools of yeast segregants. Nature 464, 1039–1042 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Costanzo, M. et al. The genetic landscape of a cell. Science 327, 425–431 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hartman, J. L, Garvik, B. & Hartwell, L. Principles for the buffering of genetic variation. Science 291, 1001–1004 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Dowell, R. D. et al. Genotype to phenotype: a complex problem. Science 328, 469 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yang, H. et al. A customized and versatile high-density genotyping array for the mouse. Nature Methods 6, 663–666 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  60. Boone, C., Bussey, H. & Andrews, B. J. Exploring genetic interactions and networks with yeast. Nature Rev. Genet. 8, 437–449 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Hunter, K. W. & Crawford, N. P. S. The future of mouse QTL mapping to diagnose disease in mice in the age of whole-genome association studies. Ann. Rev. Genet. 42, 131–141 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Yang, H., Bell, T. A., Churchill, G. A. & Pardo-Manuel de Villena, F. On the subspecific origin of the laboratory mouse. Nature Genet. 39, 1100–1107 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Yang, H. et al. Subspecific origin and haplotye diversity in the laboratory mouse. Nature Genet. 43, 648–655 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Threadgill, D. W., Hunter, K. W. & Williams, R. W. Genetic dissection of complex and quantitative traits: from fantasy to reality via a community effort. Mamm. Genome 13, 175–178 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. 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 

  66. Aylor, D. L. et al. Genetic analysis of complex traits in the emerging collaborative cross. Genome Res. 15 Mar 2011 (doi:10.1101/gr.111310.110).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rose, M. R., Mueller, L. D. & Burke, M. K. New experiments for an undivided genetics. Genetics 188, 1–10 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  68. McClellan, J. & King M.-C. Genetic heterogeneity in human disease. Cell 141, 210–217 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Dickson, S. P., Wang, K., Krantz, I., Hakonarson, H. & Goldstein, D. B. Rare variants create synthetic genome-wide associations. PLoS Biol. 8, e1000294 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Milloz, J., Duveau, F., Nuez, I. & Felix, M. A. Intraspecific evolution of the intercellular signaling network underlying a robust developmental system. Genes Dev. 22, 3064–3075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Li, Y. et al. Global genetic robustness of the alternative splicing machinery in Caenorhabditis elegans. Genetics 186, 405–410 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chandler, C. H. Cryptic intraspecific variation in sex determination in Caenorhabditis elegans revealed by mutations. Heredity 105, 473–482 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Gerstein, M. B. et al. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330, 1775–1787 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Roy, S. et al. Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science 330, 1787–1797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Fox Keller, E. A Feeling for the Organism: The Life and Work of Barbara McClintock (W. H. Freeman and Company, New York, 1983).

    Google Scholar 

  76. Threadgill, D. W., Pardo-Manuel de Villena, F., Miller, D. R., Miller, D. R. & Churchill, G. A. The collaborative cross: a recombinant inbred mouse population for the systems genetic era. ILAR J. 52, 24–31 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Teer, J. K. & Mullikin, J. C. Exome sequencing: the sweet spot before whole genomes. Hum. Mol. Genet. 19, R145–R151 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nasevicius, A. & Ekker, S. C. Effective targeted gene 'knockdown' in zebrafish. Nature Genet. 26, 216–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Khanna, H. et al. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nature Genet. 41, 739–745 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Anderson, C. A., Soranzo, N., Zeggini, E. & Barrett, J. C. Synthetic associations are unlikely to account for many common disease genome-wide association signals. PLoS Biol. 9, e1000580 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Liston, A., Lesage, S., Gray, D. H., Boyd, R. L. & Goodnow, C. C. Genetic lesions in T-cell tolerance and thresholds for autoimmunity. Immunol. Rev. 204, 87–101 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Cheung, C. & Gonzalez, F. J. Humanized mouse lines and their application for prediction of human drug metabolism and toxicological risk assessment. J. Pharmacol. Exp. Ther. 327, 288–299 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

T.J.A. acknowledges funding from the Medical Research Council (MRC) Clinical Sciences Centre, the Imperial British Heart Foundation Centre of Excellence, the European Union EURATRANS consortium and the Leducq Cardianet Transatlantic Network of Excellence. C.B. is grateful for comments provided by B. Andrews. G.A.C. and T.F.C.M. both acknowledge funding from the US National Institutes of Health (NIH), grant numbers GM076468 and GM45146, respectively.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Timothy J. Aitman, Charles Boone, Gary A. Churchill, Michael O. Hengartner, Trudy F. C. Mackay or Derek L. Stemple.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Timothy J. Aitman's homepage

Charles Boone's homepage

Gary A. Churchill's homepage

Michael O. Hengartner's homepage

Trudy F. C. Mackay's homepage

Center for Genome Dynamics

House of Lords Science and Technology Committee 2009 'Genomic Medicine' report

Saccharomyces Genome Database (SGD)

Schizosaccharomyces pombe GeneDB

Zebrafish (Danio rerio) Sequencing Project

Zebrafish Mutation Project

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aitman, T., Boone, C., Churchill, G. et al. The future of model organisms in human disease research. Nat Rev Genet 12, 575–582 (2011). https://doi.org/10.1038/nrg3047

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3047

This article is cited by

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