Skip to main content
PMC home page
Genetics logoLink to Genetics
. 2003 Jul;164(3):1055–1070. doi: 10.1093/genetics/164.3.1055

Locus-specific genetic differentiation at Rw among warfarin-resistant rat (Rattus norvegicus) populations.

Michael H Kohn 1, Hans-Joachim Pelz 1, Robert K Wayne 1
PMCID: PMC1462631  PMID: 12871915

Abstract

Populations may diverge at fitness-related genes as a result of adaptation to local conditions. The ability to detect this divergence by marker-based genomic scans depends on the relative magnitudes of selection, recombination, and migration. We survey rat (Rattus norvegicus) populations to assess the effect that local selection with anticoagulant rodenticides has had on microsatellite marker variation and differentiation at the warfarin resistance gene (Rw) relative to the effect on the genomic background. Initially, using a small sample of 16 rats, we demonstrate tight linkage of microsatellite D1Rat219 to Rw by association mapping of genotypes expressing an anticoagulant-rodenticide-insensitive vitamin K 2,3-epoxide reductase (VKOR). Then, using allele frequencies at D1Rat219, we show that predicted and observed resistance levels in 27 populations correspond, suggesting intense and recent selection for resistance. A contrast of F(ST) values between D1Rat219 and the genomic background revealed that rodenticide selection has overwhelmed drift-mediated population structure only at Rw. A case-controlled design distinguished these locus-specific effects of selection at Rw from background levels of differentiation more effectively than a population-controlled approach. Our results support the notion that an analysis of locus-specific population genetic structure may assist the discovery and mapping of novel candidate loci that are the object of selection or may provide supporting evidence for previously identified loci.

Full Text

The Full Text of this article is available as a PDF (287.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barton N. H. Genetic hitchhiking. Philos Trans R Soc Lond B Biol Sci. 2000 Nov 29;355(1403):1553–1562. doi: 10.1098/rstb.2000.0716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bouba I., Koptides M., Mean R., Costi C. E., Demetriou K., Georgiou I., Pierides A., Siamopoulos K., Deltas C. C. Novel PKD1 deletions and missense variants in a cohort of Hellenic polycystic kidney disease families. Eur J Hum Genet. 2001 Sep;9(9):677–684. doi: 10.1038/sj.ejhg.5200696. [DOI] [PubMed] [Google Scholar]
  3. Cain D., Hutson S. M., Wallin R. Warfarin resistance is associated with a protein component of the vitamin K 2,3-epoxide reductase enzyme complex in rat liver. Thromb Haemost. 1998 Jul;80(1):128–133. [PubMed] [Google Scholar]
  4. Charlesworth B., Nordborg M., Charlesworth D. The effects of local selection, balanced polymorphism and background selection on equilibrium patterns of genetic diversity in subdivided populations. Genet Res. 1997 Oct;70(2):155–174. doi: 10.1017/s0016672397002954. [DOI] [PubMed] [Google Scholar]
  5. Conner J. K. How strong is natural selection? Trends Ecol Evol. 2001 May 1;16(5):215–217. doi: 10.1016/s0169-5347(01)02138-3. [DOI] [PubMed] [Google Scholar]
  6. DEMPSTER E. R. Maintenance of genetic heterogeneity. Cold Spring Harb Symp Quant Biol. 1955;20:25-31; discussion, 31-2. doi: 10.1101/sqb.1955.020.01.005. [DOI] [PubMed] [Google Scholar]
  7. Federman D. G., Kirsner R. S. An update on hypercoagulable disorders. Arch Intern Med. 2001 Apr 23;161(8):1051–1056. doi: 10.1001/archinte.161.8.1051. [DOI] [PubMed] [Google Scholar]
  8. Greaves J. H., Ayres P. B. Multiple allelism at the locus controlling warfarin resistance in the Norway rat. Genet Res. 1982 Aug;40(1):59–64. doi: 10.1017/s0016672300018905. [DOI] [PubMed] [Google Scholar]
  9. Greaves J. H., Ayres P. Linkages between genes for coat colour and resistance to warfarin in Rattus norvegicus. Nature. 1969 Oct 18;224(5216):284–285. doi: 10.1038/224284a0. [DOI] [PubMed] [Google Scholar]
  10. Harr Bettina, Kauer Max, Schlötterer Christian. Hitchhiking mapping: a population-based fine-mapping strategy for adaptive mutations in Drosophilamelanogaster. Proc Natl Acad Sci U S A. 2002 Sep 26;99(20):12949–12954. doi: 10.1073/pnas.202336899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hildebrandt E. F., Suttie J. W. Mechanism of coumarin action: sensitivity of vitamin K metabolizing enzymes of normal and warfarin-resistant rat liver. Biochemistry. 1982 May 11;21(10):2406–2411. doi: 10.1021/bi00539a020. [DOI] [PubMed] [Google Scholar]
  12. Jacob Howard J., Kwitek Anne E. Rat genetics: attaching physiology and pharmacology to the genome. Nat Rev Genet. 2002 Jan;3(1):33–42. doi: 10.1038/nrg702. [DOI] [PubMed] [Google Scholar]
  13. Karl S. A., Avise J. C. Balancing selection at allozyme loci in oysters: implications from nuclear RFLPs. Science. 1992 Apr 3;256(5053):100–102. doi: 10.1126/science.1348870. [DOI] [PubMed] [Google Scholar]
  14. Kerins G. M., MacNicoll A. D. Comparison of the half-lives and regeneration rates of blood clotting factors II, VII, and X in anticoagulant-resistant and susceptible Norway rats (Rattus norvegicus Berk.). Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1999 Mar;122(3):307–316. doi: 10.1016/s0742-8413(98)10128-7. [DOI] [PubMed] [Google Scholar]
  15. Kohn M. H., Pelz H. J. A gene-anchored map position of the rat warfarin-resistance locus, Rw, and its orthologs in mice and humans. Blood. 2000 Sep 1;96(5):1996–1998. [PubMed] [Google Scholar]
  16. Kohn M. H., Pelz H. J. A gene-anchored map position of the rat warfarin-resistance locus, Rw, and its orthologs in mice and humans. Blood. 2000 Sep 1;96(5):1996–1998. [PubMed] [Google Scholar]
  17. Kohn M. H., Pelz H. J. Genomic assignment of the warfarin resistance locus, Rw, in the rat. Mamm Genome. 1999 Jul;10(7):696–698. doi: 10.1007/s003359901073. [DOI] [PubMed] [Google Scholar]
  18. Kohn M. H., Pelz H. J., Wayne R. K. Natural selection mapping of the warfarin-resistance gene. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7911–7915. doi: 10.1073/pnas.97.14.7911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lenormand T., Guillemaud T., Bourguet D., Raymond M. Evaluating gene flow using selected markers: a case study. Genetics. 1998 Jul;149(3):1383–1392. doi: 10.1093/genetics/149.3.1383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lewontin R. C., Krakauer J. Distribution of gene frequency as a test of the theory of the selective neutrality of polymorphisms. Genetics. 1973 May;74(1):175–195. doi: 10.1093/genetics/74.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Linder M. W. Genetic mechanisms for hypersensitivity and resistance to the anticoagulant Warfarin. Clin Chim Acta. 2001 Jun;308(1-2):9–15. doi: 10.1016/s0009-8981(01)00420-x. [DOI] [PubMed] [Google Scholar]
  22. Mantel N. The detection of disease clustering and a generalized regression approach. Cancer Res. 1967 Feb;27(2):209–220. [PubMed] [Google Scholar]
  23. Martin A. D., Steed L. C., Redfern R., Gill J. E., Huson L. W. Warfarin-resistance genotype determination in the Norway rat, Rattus norvegicus. Lab Anim. 1979 Jul;13(3):209–214. doi: 10.1258/002367779780937852. [DOI] [PubMed] [Google Scholar]
  24. Nagylaki T., Lou Y. Patterns of multiallelic polymorphism maintained by migration and selection. Theor Popul Biol. 2001 Jun;59(4):297–313. doi: 10.1006/tpbi.2001.1526. [DOI] [PubMed] [Google Scholar]
  25. Nei M., Chakravarti A. Drift variances of FST and GST statistics obtained from a finite number of isolated populations. Theor Popul Biol. 1977 Jun;11(3):307–325. doi: 10.1016/0040-5809(77)90014-4. [DOI] [PubMed] [Google Scholar]
  26. Partridge G. G. Relative fitness of genotypes in a population of Rattus norvegicus polymorphic for warfarin resistance. Heredity (Edinb) 1979 Oct;43(2):239–246. doi: 10.1038/hdy.1979.79. [DOI] [PubMed] [Google Scholar]
  27. Pogson G. H., Mesa K. A., Boutilier R. G. Genetic population structure and gene flow in the Atlantic cod Gadus morhua: a comparison of allozyme and nuclear RFLP loci. Genetics. 1995 Jan;139(1):375–385. doi: 10.1093/genetics/139.1.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Pritchard J. K., Donnelly P. Case-control studies of association in structured or admixed populations. Theor Popul Biol. 2001 Nov;60(3):227–237. doi: 10.1006/tpbi.2001.1543. [DOI] [PubMed] [Google Scholar]
  29. Pritchard J. K., Rosenberg N. A. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet. 1999 Jul;65(1):220–228. doi: 10.1086/302449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pritchard J. K., Stephens M., Donnelly P. Inference of population structure using multilocus genotype data. Genetics. 2000 Jun;155(2):945–959. doi: 10.1093/genetics/155.2.945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Robertson A. Gene frequency distributions as a test of selective neutrality. Genetics. 1975 Dec;81(4):775–785. doi: 10.1093/genetics/81.4.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schlötterer C., Vogl C., Tautz D. Polymorphism and locus-specific effects on polymorphism at microsatellite loci in natural Drosophila melanogaster populations. Genetics. 1997 May;146(1):309–320. doi: 10.1093/genetics/146.1.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schlötterer Christian. Towards a molecular characterization of adaptation in local populations. Curr Opin Genet Dev. 2002 Dec;12(6):683–687. doi: 10.1016/s0959-437x(02)00349-0. [DOI] [PubMed] [Google Scholar]
  34. Schmidt P. S., Rand D. M. Adaptive maintenance of genetic polymorphism in an intertidal barnacle: habitat- and life-stage-specific survivorship of Mpi genotypes. Evolution. 2001 Jul;55(7):1336–1344. doi: 10.1111/j.0014-3820.2001.tb00656.x. [DOI] [PubMed] [Google Scholar]
  35. Slatkin M. Hitchhiking and associative overdominance at a microsatellite locus. Mol Biol Evol. 1995 May;12(3):473–480. doi: 10.1093/oxfordjournals.molbev.a040222. [DOI] [PubMed] [Google Scholar]
  36. Slatkin M., Wiehe T. Genetic hitch-hiking in a subdivided population. Genet Res. 1998 Apr;71(2):155–160. doi: 10.1017/s001667239800319x. [DOI] [PubMed] [Google Scholar]
  37. Sugano S., Kobayashi T., Tanikawa T., Kawakami Y., Kojima H., Nakamura K., Uchida A., Morishima N., Tamai Y. Suppression of CYP3A2 mRNA expression in the warfarin-resistant roof rat, Rattus rattus: possible involvement of cytochrome P450 in the warfarin resistance mechanism. Xenobiotica. 2001 Jul;31(7):399–407. doi: 10.1080/00498250110060932. [DOI] [PubMed] [Google Scholar]
  38. Takahashi A., Tsaur S. C., Coyne J. A., Wu C. I. The nucleotide changes governing cuticular hydrocarbon variation and their evolution in Drosophila melanogaster. Proc Natl Acad Sci U S A. 2001 Mar 20;98(7):3920–3925. doi: 10.1073/pnas.061465098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Taylor M. F., Shen Y., Kreitman M. E. A population genetic test of selection at the molecular level. Science. 1995 Dec 1;270(5241):1497–1499. doi: 10.1126/science.270.5241.1497. [DOI] [PubMed] [Google Scholar]
  40. Tsakas S., Krimbas C. B. Testing the heterogeneity of F values: a suggestion and a correction. Genetics. 1976 Oct;84(2):399–401. doi: 10.1093/genetics/84.2.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wallace M. E., MacSwiney F. J. A major gene controlling warfarin-resistance in the house mouse. J Hyg (Lond) 1976 Apr;76(2):173–181. doi: 10.1017/s0022172400055078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wang R., Zheng L., Touré Y. T., Dandekar T., Kafatos F. C. When genetic distance matters: measuring genetic differentiation at microsatellite loci in whole-genome scans of recent and incipient mosquito species. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10769–10774. doi: 10.1073/pnas.191003598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wiehe T. The effect of selective sweeps on the variance of the allele distribution of a linked multiallele locus: hitchhiking of microsatellites. Theor Popul Biol. 1998 Jun;53(3):272–283. doi: 10.1006/tpbi.1997.1346. [DOI] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES