Progress and prospects in rat genetics: a community view

Abstract

The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research.

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References

  1. 1

    Jacob, H. Functional genomics and rat models. Genome Res. 9, 1013–1016 (1999).

    CAS  Article  Google Scholar 

  2. 2

    Lindsey, J.R. Historical foundations in the laboratory rat. in The Laboratory Rat (eds. Baker, H.J., Lindsey, J.R. & Weisbroth, S.H.) 1–36 (Academic, New York, 1979).

    Google Scholar 

  3. 3

    Pravenec, M., Klir, P., Kren, V., Zicha, J. & Kunes, J. An analysis of spontaneous hypertension in spontaneously hypertensive rats by means of new recombinant inbred strains. J. Hypertens. 7, 217–221 (1989).

    CAS  Article  Google Scholar 

  4. 4

    Pravenec, M. et al. Genetic analysis of “metabolic syndrome” in the spontaneously hypertensive rat. Physiol. Res. 53 (suppl. 1), S15–S22 (2004).

    CAS  PubMed  Google Scholar 

  5. 5

    Cowley, A.W., Jr, Roman, R.J. & Jacob, H.J. Application of chromosomal substitution techniques in gene-function discovery. J. Physiol. (Lond.) 554, 46–55 (2004).

    CAS  Article  Google Scholar 

  6. 6

    Gibbs, R.A. et al. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428, 493–521 (2004).

    CAS  Article  Google Scholar 

  7. 7

    Dewey, C. et al. Accurate identification of novel human genes through simultaneous gene prediction in human, mouse, and rat. Genome Res. 14, 661–664 (2004).

    CAS  Article  Google Scholar 

  8. 8

    Gibbs, R.A. et al. Evolutionary and biomedical insights from the rhesus macaque genome. Science 316, 222–234 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Samad, A.H. et al. Mapping the genome one molecule at a time—optical mapping. Nature 378, 516–517 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Serikawa, T. et al. Rat gene mapping using PCR-analyzed microsatellites. Genetics 131, 701–721 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Jacob, H.J. et al. A genetic linkage map of the laboratory rat, Rattus norvegicus. Nat. Genet. 9, 63–69 (1995).

    CAS  Google Scholar 

  12. 12

    Watanabe, T.K. et al. A radiation hybrid map of the rat genome containing 5,255 markers. Nat. Genet. 22, 27–36 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Kwitek, A.E. et al. High-density rat radiation hybrid maps containing over 24,000 SSLPs, genes, and ESTs provide a direct link to the rat genome sequence. Genome Res. 14, 750–757 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Wilder, S.P. et al. Integration of the rat recombination and EST maps in the rat genomic sequence and comparative mapping analysis with the mouse genome. Genome Res. 14, 758–765 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Zimdahl, H. et al. A SNP map of the rat genome generated from cDNA sequences. Science 303, 807 (2004).

    CAS  Article  Google Scholar 

  16. 16

    STAR Consortium. SNP and haplotype mapping for genetic analysis in the rat. Nat. Genet. 40, 560–566 (2008).

  17. 17

    Hamta, A. et al. Chromosome ideograms of the laboratory rat (Rattus norvegicus) based on high-resolution banding, and anchoring of the cytogenetic map to the DNA sequence by FISH in sample chromosomes. Cytogenet. Genome Res. 115, 158–168 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Twigger, S.N. et al. What everybody should know about the rat genome and its online resources. Nat. Genet. 40, 523–527 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Twigger, S.N., Shimoyama, M., Bromberg, S., Kwitek, A.E. & Jacob, H.J. The Rat Genome Database, update 2007—easing the path from disease to data and back again. Nucleic Acids Res. 35, D658–D662 (2007).

    CAS  Article  Google Scholar 

  20. 20

    Kashiwazaki, N. et al. Generation of rat offspring derived from cryopreserved spermatozoa in Japanese National Bioresources. Reprod. Fertil. Dev. 19, 124–125 (2007).

    Article  Google Scholar 

  21. 21

    Mashimo, T. et al. An ENU-induced mutant archive for gene targeting in rats. Nat. Genet. 40, 514–515 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Belknap, J.K. Effect of within-strain sample size on QTL detection and mapping using recombinant inbred mouse strains. Behav. Genet. 28, 29–38 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Voigt, B. et al. Evaluation of LEXF/FXLE rat recombinant inbred strains for genetic dissection of complex traits. Physiol. Genomics 32, 335–342 (2008).

    CAS  Article  Google Scholar 

  24. 24

    Kemlink, D., Jerabkova, V., Janku, M., Krenova, D. & Kren, V. PXO set of recombinant inbred strains of the rat: a new strain distribution pattern containing 448 markers. Folia Biol. (Praha) 49, 165–176 (2003).

    CAS  Google Scholar 

  25. 25

    Hedrich, H.J. Recombinant inbred strains, 487–494 (Gustav Fisher, Stuttgart, 1990).

    Google Scholar 

  26. 26

    Petretto, E. et al. Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass. Nat. Genet. 40, 546–552 (2008).

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

    Aitman, T.J. et al. Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive rats. Nat. Genet. 16, 197–201 (1997).

    CAS  Article  Google Scholar 

  29. 29

    Hansen, C. & Spuhler, K. Development of the National Institutes of Health genetically heterogeneous rat stock. Alcohol. Clin. Exp. Res. 8, 477–479 (1984).

    CAS  Article  Google Scholar 

  30. 30

    Mott, R., Talbot, C.J., Turri, M.G., Collins, A.C. & Flint, J. A method for fine mapping quantitative trait loci in outbred animal stocks. Proc. Natl. Acad. Sci. USA 97, 12649–12654 (2000).

    Article  Google Scholar 

  31. 31

    Valdar, W. et al. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nat. Genet. 38, 879–887 (2006).

    CAS  Article  Google Scholar 

  32. 32

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

    CAS  Article  Google Scholar 

  33. 33

    Yokoi, N. et al. Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat. Genet. 31, 391–394 (2002).

    CAS  Article  Google Scholar 

  34. 34

    MacMurray, A.J. et al. Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene. Genome Res. 12, 1029–1039 (2002).

    CAS  Article  Google Scholar 

  35. 35

    Hornum, L., Romer, J. & Markholst, H. The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1. Diabetes 51, 1972–1979 (2002).

    CAS  Article  Google Scholar 

  36. 36

    Olofsson, P. et al. Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat. Genet. 33, 25–32 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Swanberg, M. et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat. Genet. 37, 486–494 (2005).

    CAS  Article  Google Scholar 

  38. 38

    Aitman, T.J. et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439, 851–855 (2006).

    CAS  Article  Google Scholar 

  39. 39

    Behmoaras, J. et al. Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility. Nat. Genet. 40, 553–559 (2008).

    CAS  Article  Google Scholar 

  40. 40

    Samuelson, D.J. et al. Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk. Proc. Natl. Acad. Sci. USA 104, 6299–6304 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Monti, J. et al. Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. Nat. Genet. 40, 560–566 (2008).

    Article  Google Scholar 

  42. 42

    Guryev, V. et al. Distribution and functional impact of DNA copy number variation in the rat. Nat. Genet. 40, 538–545 (2008).

    CAS  Article  Google Scholar 

  43. 43

    Ward, C.J. et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat. Genet. 30, 259–269 (2002).

    Article  Google Scholar 

  44. 44

    Masyuk, T.V. et al. Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat. Gastroenterology 125, 1303–1310 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Fischer, E. et al. Defective planar cell polarity in polycystic kidney disease. Nat. Genet. 38, 21–23 (2006).

    CAS  Article  Google Scholar 

  46. 46

    Gattone, V.H., II, Wang, X., Harris, P.C. & Torres, V.E. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat. Med. 9, 1323–1326 (2003).

    CAS  Article  Google Scholar 

  47. 47

    Wang, X., Gattone, V.H., II, Harris, P.C. & Torres, V.E. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061. J. Am. Soc. Nephrol. 16, 846–851 (2005).

    CAS  Article  Google Scholar 

  48. 48

    Nagao, S. et al. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J. Am. Soc. Nephrol. 17, 2220–2227 (2006).

    CAS  Article  Google Scholar 

  49. 49

    Wang, X., Wu, Y., Ward, C.J., Harris, P.C. & Torres, V.E. Vasopressin directly regulates cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 19, 102–108 (2007).

    Article  Google Scholar 

  50. 50

    Masyuk, T.V., Masyuk, A.I., Torres, V.E., Harris, P.C. & Larusso, N.F. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3′,5′-cyclic monophosphate. Gastroenterology 132, 1104–1116 (2007).

    CAS  Article  Google Scholar 

  51. 51

    Tesson, L. et al. Transgenic modifications of the rat genome. Transgenic Res. 14, 531–546 (2005).

    CAS  Article  Google Scholar 

  52. 52

    van den Brandt, J., Wang, D., Kwon, S.H., Heinkelein, M. & Reichardt, H.M. Lentivirally generated eGFP-transgenic rats allow efficient cell tracking in vivo. Genesis 39, 94–99 (2004).

    CAS  Article  Google Scholar 

  53. 53

    Broser, P., Grinevich, V., Osten, P., Sakmann, B. & Wallace, D.J. Critical period plasticity of axonal arbors of layer 2/3 pyramidal neurons in rat somatosensory cortex: layer-specific reduction of projections into deprived cortical columns. Cereb. Cortex, published online 12 November 2007 (doi: 10.1093/cercor/bhm189).

    Google Scholar 

  54. 54

    Dozortsev, D., Wakaiama, T., Ermilov, A. & Yanagimachi, R. Intracytoplasmic sperm injection in the rat. Zygote 6, 143–147 (1998).

    CAS  Article  Google Scholar 

  55. 55

    Hirabayashi, M. et al. Factors affecting production of transgenic rats by ICSI-mediated DNA transfer: effects of sonication and freeze-thawing of spermatozoa, rat strains for sperm and oocyte donors, and different constructs of exogenous DNA. Mol. Reprod. Dev. 70, 422–428 (2005).

    CAS  Article  Google Scholar 

  56. 56

    Kato, M. et al. Production of transgenic rats by ooplasmic injection of spermatogenic cells exposed to exogenous DNA: a preliminary study. Mol. Reprod. Dev. 69, 153–158 (2004).

    CAS  Article  Google Scholar 

  57. 57

    Hirabayashi, M. et al. Offspring derived from intracytoplasmic injection of transgenic rat sperm. Transgenic Res. 11, 221–228 (2002).

    CAS  Article  Google Scholar 

  58. 58

    Young-Pearse, T.L. et al. A critical function for β-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J. Neurosci. 27, 14459–14469 (2007).

    CAS  Article  Google Scholar 

  59. 59

    Dann, C.T. New technology for an old favorite: lentiviral transgenesis and RNAi in rats. Transgenic Res. 16, 571–580 (2007).

    CAS  Article  Google Scholar 

  60. 60

    Buehr, M. et al. Rapid loss of Oct-4 and pluripotency in cultured rodent blastocysts and derivative cell lines. Biol. Reprod. 68, 222–229 (2003).

    CAS  Article  Google Scholar 

  61. 61

    Vassilieva, S., Guan, K., Pich, U. & Wobus, A.M. Establishment of SSEA-1- and Oct-4-expressing rat embryonic stem-like cell lines and effects of cytokines of the IL-6 family on clonal growth. Exp. Cell Res. 258, 361–373 (2000).

    CAS  Article  Google Scholar 

  62. 62

    Demers, S.P., Yoo, J.G., Lian, L., Therrien, J. & Smith, L.C. Rat embryonic stem-like (ES-like) cells can contribute to extraembryonic tissues in vivo. Cloning Stem Cells 9, 512–522 (2007).

    CAS  Article  Google Scholar 

  63. 63

    Popova, E., Bader, M. & Krivokharchenko, A. Full-term development of rat after transfer of nuclei from two-cell stage embryos. Biol. Reprod. 75, 524–530 (2006).

    CAS  Article  Google Scholar 

  64. 64

    Roh, S. et al. Birth of rats following nuclear exchange at the 2-cell stage. Zygote 11, 317–321 (2003).

    Article  Google Scholar 

  65. 65

    Zhou, Q. et al. Generation of fertile cloned rats by regulating oocyte activation. Science 302, 1179 (2003).

    CAS  Article  Google Scholar 

  66. 66

    Flood, D.G. et al. A transgenic rat model of Alzheimer's disease with extracellular Aβ deposition. Neurobiol. Aging, published online 28 November 2007 (doi:10.1016/j.neurobiolaging.2007.10.006).

    Google Scholar 

  67. 67

    Howland, D.S. et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc. Natl. Acad. Sci. USA 99, 1604–1609 (2002).

    CAS  Article  Google Scholar 

  68. 68

    Zilka, N. et al. Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 580, 3582–3588 (2006).

    CAS  Article  Google Scholar 

  69. 69

    Zan, Y. et al. Production of knockout rats using ENU mutagenesis and a yeast-based screening assay. Nat. Biotechnol. 21, 645–651 (2003).

    CAS  Article  Google Scholar 

  70. 70

    Amos-Landgraf, J.M. et al. A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc. Natl. Acad. Sci. USA 104, 4036–4041 (2007).

    CAS  Article  Google Scholar 

  71. 71

    Smits, B.M. et al. Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis. Pharmacogenet. Genomics 16, 159–169 (2006).

    CAS  PubMed  Google Scholar 

  72. 72

    Wienholds, E. et al. Efficient target-selected mutagenesis in zebrafish. Genome Res. 13, 2700–2707 (2003).

    CAS  Article  Google Scholar 

  73. 73

    Kitada, K. et al. Transposon-tagged mutagenesis in the rat. Nat. Methods 4, 131–133 (2007).

    CAS  Article  Google Scholar 

  74. 74

    Lu, B. et al. Generation of rat mutants using a coat color-tagged Sleeping Beauty transposon system. Mamm. Genome 18, 338–346 (2007).

    CAS  Article  Google Scholar 

  75. 75

    Hamra, F.K. et al. Self renewal, expansion, and transfection of rat spermatogonial stem cells in culture. Proc. Natl. Acad. Sci. USA 102, 17430–17435 (2005).

    CAS  Article  Google Scholar 

  76. 76

    Shinohara, T. et al. Rats produced by interspecies spermatogonial transplantation in mice and in vitro microinsemination. Proc. Natl. Acad. Sci. USA 103, 13624–13628 (2006).

    CAS  Article  Google Scholar 

  77. 77

    Mashimo, T., Voigt, B., Kuramoto, T. & Serikawa, T. Rat Phenome Project: the untapped potential of existing rat strains. J. Appl. Physiol. 98, 371–379 (2005).

    Article  Google Scholar 

  78. 78

    Rogers, D.C. et al. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Genome 8, 711–713 (1997).

    CAS  Article  Google Scholar 

  79. 79

    Smith, C.L., Goldsmith, C.A. & Eppig, J.T. The Mammalian Phenotype Ontology as a tool for annotating, analyzing and comparing phenotypic information. Genome Biol. 6, R7 (2005).

    Article  Google Scholar 

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Acknowledgements

This Perspective is supported by 257 members of the rat genetics and genomics community, who are listed in Supplementary Table 1 online. The authors thank them for their support in the drafting of the manuscript.

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Correspondence to Timothy J Aitman or Howard J Jacob.

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The consomic rats are distributed through Physiogenix, for which H.J.J. is a founder and significant shareholder. The Program for Genomic Application grant required a commercial distributor. When Charles River reneged on distribution, Physiogenix stepped in to fill this need. Physiogenix is formally a contract research organization and contracts with Hilltop Farms to distribute the rats.

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Aitman, T., Critser, J., Cuppen, E. et al. Progress and prospects in rat genetics: a community view. Nat Genet 40, 516–522 (2008). https://doi.org/10.1038/ng.147

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