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.

SNP and haplotype mapping for genetic analysis in the rat

Abstract

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

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

Relevant articles

Open Access articles citing this article.

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

Figure 1: Phylogenetic neighbor-net network constructed from 20,283 polymorphic positions genotyped in 167 laboratory rats.
Figure 2: Identified discrepancies between rat genome assembly and genetic maps.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Jacob, H.J. & Kwitek, A.E. Rat genetics: attaching physiology and pharmacology to the genome. Nat. Rev. Genet. 3, 33–42 (2002).

    Article  CAS  Google Scholar 

  2. Bihoreau, M.T. et al. A linkage map of the rat genome derived from three F2 crosses. Genome Res. 7, 434–440 (1997).

    Article  CAS  Google Scholar 

  3. Guryev, V., Berezikov, E., Malik, R., Plasterk, R.H. & Cuppen, E. Single nucleotide polymorphisms associated with rat expressed sequences. Genome Res. 14, 1438–1443 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Thomas, M.A., Chen, C.F., Jensen-Seaman, M.I., Tonellato, P.J. & Twigger, S.N. Phylogenetics of rat inbred strains. Mamm. Genome 14, 61–64 (2003).

    Article  Google Scholar 

  6. Kurtz, T.W. & Morris, R.C. Jr. Biological variability in Wistar-Kyoto rats. Implications for research with the spontaneously hypertensive rat. Hypertension 10, 127–131 (1987).

    Article  CAS  Google Scholar 

  7. Kurtz, T.W., Montano, M., Chan, L. & Kabra, P. Molecular evidence of genetic heterogeneity in Wistar-Kyoto rats: implications for research with the spontaneously hypertensive rat. Hypertension 13, 188–192 (1989).

    Article  CAS  Google Scholar 

  8. Gauguier, D. The rat as a model physiological system. In Encyclopedia of Genetics vol. 3 (eds. Jorde, L.B., Little, P., Dunn, M. & Subramaniam, S.) 1154–1171 (Wiley, London, 2006).

    Google Scholar 

  9. Arbiza, L. et al. Selective pressures at a codon-level predict deleterious mutations in human disease genes. J. Mol. Biol. 358, 1390–1404 (2006).

    Article  CAS  Google Scholar 

  10. Goñi, J.R., de la Cruz, X. & Orozco, M. Triplex-forming oligonucleotide target sequences in the human genome. Nucleic Acids Res. 32, 354–360 (2004).

    Article  Google Scholar 

  11. Hedrich, H.J. (ed.) Genetic Monitoring of Inbred Strains of Rat (Gustav Fischer, Stuttgart, New York, 1990).

    Google Scholar 

  12. Huson, D.H. & Bryant, D. Application of phylogenetic networks in evolutionary studies. Mol. Biol. Evol. 23, 254–267 (2006).

    Article  CAS  Google Scholar 

  13. Mashimo, T. et al. A set of highly informative rat simple sequence length polymorphism (SSLP) markers and genetically defined rat strains. BMC Genet. 7, 19 (2006).

    Article  Google Scholar 

  14. Smits, B.M. et al. Efficient single nucleotide polymorphism discovery in laboratory rat strains using wild rat-derived SNP candidates. BMC Genomics 6, 170 (2005).

    Article  Google Scholar 

  15. Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).

    Article  CAS  Google Scholar 

  16. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  17. Wade, C.M. et al. The mosaic structure of variation in the laboratory mouse genome. Nature 420, 574–578 (2002).

    Article  CAS  Google Scholar 

  18. Frazer, K.A. et al. A sequence-based variation map of 8.27 million SNPs in inbred mouse strains. Nature 448, 1050–1053 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005).

    Article  CAS  Google Scholar 

  21. Guryev, V. et al. Haplotype block structure is conserved across mammals. PLoS Genet. 2, e121 (2006).

    Article  Google Scholar 

  22. Jensen-Seaman, M.I. et al. Comparative recombination rates in the rat, mouse, and human genomes. Genome Res. 14, 528–538 (2004).

    Article  CAS  Google Scholar 

  23. Grupe, A. et al. In silico mapping of complex disease-related traits in mice. Science 292, 1915–1918 (2001).

    Article  CAS  Google Scholar 

  24. Payseur, B.A. & Place, M. Prospects for association mapping in classical inbred mouse strains. Genetics 175, 1999–2008 (2007).

    Article  CAS  Google Scholar 

  25. Gauguier, D. et al. Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat. Genet. 12, 38–43 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Dumas, M.E. et al. Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models. Nat. Genet. 39, 666–672 (2007).

    Article  CAS  Google Scholar 

  28. 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 

  29. Ihaka, R. & Gentleman, R.R. A language for data analysis and graphics. J. Comput. Graph. Statist. 5, 299–314 (1996).

    Google Scholar 

  30. Broman, K.W. The genomes of recombinant inbred lines. Genetics 169, 1133–1146 (2005).

    Article  CAS  Google Scholar 

  31. Shisa, H. et al. The LEXF: a new set of rat recombinant inbred strains between LE/Stm and F344. Mamm. Genome 8, 324–327 (1997).

    Article  CAS  Google Scholar 

  32. Fujiyama, A. et al. Construction and analysis of a human-chimpanzee comparative clone map. Science 295, 131–134 (2002).

    Article  Google Scholar 

  33. Ning, Z., Cox, A.J. & Mullikin, J.C. SSAHA: a fast search method for large DNA databases. Genome Res. 11, 1725–1729 (2001).

    Article  CAS  Google Scholar 

  34. Oliphant, A., Barker, D.L., Stuelpnagel, J.R. & Chee, M.S. BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. Biotechniques 32 (suppl.), 56–58, 60–61 (2002).

    Google Scholar 

  35. Hardenbol, P. et al. Multiplexed genotyping with sequence-tagged molecular inversion probes. Nat. Biotechnol. 21, 673–678 (2003).

    Article  CAS  Google Scholar 

  36. Hardenbol, P. et al. Highly multiplexed molecular inversion probe genotyping: over 10,000 targeted SNPs genotyped in a single tube assay. Genome Res. 15, 269–275 (2005).

    Article  CAS  Google Scholar 

  37. Vlieghe, D. et al. A new generation of JASPAR, the open-access repository for transcription factor binding site profiles. Nucleic Acids Res. 34, D95–D97 (2006).

    Article  CAS  Google Scholar 

  38. Blanco, E., Messeguer, X., Smith, T.F. & Guigo, R. Transcription factor map alignment of promoter regions. PLOS Comput. Biol. 2, e49 (2006).

    Article  Google Scholar 

  39. Tamura, K., Dudley, J., Nei, M. & Kumar, S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol. Biol. Evol. 24, 1596–1599 (2007).

    Article  CAS  Google Scholar 

  40. Reimand, J., Kull, M., Peterson, H., Hansen, J. & Vilo, J. g:Profiler–a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res. 35, W193–W200 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by European Union grants LSGH-2004-005235 and LSHG-CT-2005-019015. We acknowledge funding from the National Genome Research Network of the German Ministry of Science and Education. We thank all of the technical staff of the Sequencing Technology Team at the RIKEN Genomic Sciences Center for their assistance. Part of this work was supported by the National BioResource Project of the Ministry of Education, Culture, Sports, Science and Technology of Japan. D.G. is supported by a Wellcome Trust Senior Fellowship in Basic Biomedical Science (057733/Z/99/A). M.-T.B. and D.G. acknowledge support from the Wellcome Cardiovascular Functional Genomics Initiative (066780/Z/01/Z). M. Pravenec is supported by the Howard Hughes Medical Institute and by the Grant Agency of the Czech Republic. M. Pravenec and V.K. are supported by grants from the Ministry of Education of the Czech Republic.

Author information

Authors and Affiliations

Consortia

Corresponding author

Correspondence to Norbert Hubner.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 1–6, Supplementary Methods, Supplementary Note (PDF 3127 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

The STAR Consortium. SNP and haplotype mapping for genetic analysis in the rat. Nat Genet 40, 560–566 (2008). https://doi.org/10.1038/ng.124

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.124

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