Home LiteratureArticle Details
PMID: 12871915 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Genetics ·Vol. 164 ·No. 3 ·2003-07-00 ·Pages 1055-70

Kohn MH, Pelz HJ, Wayne RK

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.

MeSH Terms
Animals Drug Resistance/genetics Gene Frequency Genetic Variation Genetics, Population Geography Germany Microsatellite Repeats/genetics Mixed Function Oxygenases Rats/genetics Rodenticides/poisoning Selection, Genetic Vitamin K Epoxide Reductases Warfarin/poisoning
Chemicals
Rodenticides Warfarin Mixed Function Oxygenases Vitamin K Epoxide Reductases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Kohn Michael H
Department of Organismic Biology, Ecology, and Evolution (OBEE), University of California, Los Angeles, California 90095-1606, USA. [email protected]
Pelz Hans-Joachim
Wayne Robert K
References (42)
42 references, click to expand
  1. 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):1996-8 PMID: 10961907
  2. 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):272-83 PMID: 9679322
  3. Testing the heterogeneity of F values: a suggestion and a correction.
    Genetics. 1976 Oct;84(2):399-401 PMID: 793925
  4. How strong is natural selection?
    Trends Ecol Evol. 2001 May 1;16(5):215-217 PMID: 11301137
  5. The detection of disease clustering and a generalized regression approach.
    Cancer Res. 1967 Feb;27(2):209-20 PMID: 6018555
  6. 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):10769-74 PMID: 11553812
  7. Inference of population structure using multilocus genotype data.
    Genetics. 2000 Jun;155(2):945-59 PMID: 10835412
  8. Relative fitness of genotypes in a population of Rattus norvegicus polymorphic for warfarin resistance.
    Heredity (Edinb). 1979 Oct;43(2):239-46 PMID: 295047
  9. Hitchhiking mapping: a population-based fine-mapping strategy for adaptive mutations in Drosophilamelanogaster.
    Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12949-54 PMID: 12351680
  10. Genomic assignment of the warfarin resistance locus, Rw, in the rat.
    Mamm Genome. 1999 Jul;10(7):696-8 PMID: 10384042
  11. Mechanism of coumarin action: sensitivity of vitamin K metabolizing enzymes of normal and warfarin-resistant rat liver.
    Biochemistry. 1982 May 11;21(10):2406-11 PMID: 6807339
  12. Evaluating gene flow using selected markers: a case study.
    Genetics. 1998 Jul;149(3):1383-92 PMID: 9649528
  13. 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 PMID: 11531004
  14. The nucleotide changes governing cuticular hydrocarbon variation and their evolution in Drosophila melanogaster.
    Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3920-5 PMID: 11259658
  15. Patterns of multiallelic polymorphism maintained by migration and selection.
    Theor Popul Biol. 2001 Jun;59(4):297-313 PMID: 11560450
  16. Distribution of gene frequency as a test of the theory of the selective neutrality of polymorphisms.
    Genetics. 1973 May;74(1):175-95 PMID: 4711903
  17. Towards a molecular characterization of adaptation in local populations.
    Curr Opin Genet Dev. 2002 Dec;12(6):683-7 PMID: 12433582
  18. Natural selection mapping of the warfarin-resistance gene.
    Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7911-5 PMID: 10884423
  19. Genetic hitch-hiking in a subdivided population.
    Genet Res. 1998 Apr;71(2):155-60 PMID: 9717437
  20. A major gene controlling warfarin-resistance in the house mouse.
    J Hyg (Lond). 1976 Apr;76(2):173-81 PMID: 1063212
  21. Warfarin-resistance genotype determination in the Norway rat, Rattus norvegicus.
    Lab Anim. 1979 Jul;13(3):209-14 PMID: 553191
  22. 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):307-16 PMID: 10336090
  23. Balancing selection at allozyme loci in oysters: implications from nuclear RFLPs.
    Science. 1992 Apr 3;256(5053):100-2 PMID: 1348870
  24. Hitchhiking and associative overdominance at a microsatellite locus.
    Mol Biol Evol. 1995 May;12(3):473-80 PMID: 7739389
  25. Genetic hitchhiking.
    Philos Trans R Soc Lond B Biol Sci. 2000 Nov 29;355(1403):1553-62 PMID: 11127900
  26. Drift variances of FST and GST statistics obtained from a finite number of isolated populations.
    Theor Popul Biol. 1977 Jun;11(3):307-25 PMID: 877909
  27. Linkages between genes for coat colour and resistance to warfarin in Rattus norvegicus.
    Nature. 1969 Oct 18;224(5216):284-5 PMID: 5344614
  28. A population genetic test of selection at the molecular level.
    Science. 1995 Dec 1;270(5241):1497-9 PMID: 7491497
  29. Multiple allelism at the locus controlling warfarin resistance in the Norway rat.
    Genet Res. 1982 Aug;40(1):59-64 PMID: 7141222
  30. Adaptive maintenance of genetic polymorphism in an intertidal barnacle: habitat- and life-stage-specific survivorship of Mpi genotypes.
    Evolution. 2001 Jul;55(7):1336-44 PMID: 11525458
  31. Use of unlinked genetic markers to detect population stratification in association studies.
    Am J Hum Genet. 1999 Jul;65(1):220-8 PMID: 10364535
  32. 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):128-33 PMID: 9684798
  33. Rat genetics: attaching physiology and pharmacology to the genome.
    Nat Rev Genet. 2002 Jan;3(1):33-42 PMID: 11823789
  34. 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):375-85 PMID: 7705638
  35. Novel PKD1 deletions and missense variants in a cohort of Hellenic polycystic kidney disease families.
    Eur J Hum Genet. 2001 Sep;9(9):677-84 PMID: 11571556
  36. Genetic mechanisms for hypersensitivity and resistance to the anticoagulant Warfarin.
    Clin Chim Acta. 2001 Jun;308(1-2):9-15 PMID: 11412812
  37. Maintenance of genetic heterogeneity.
    Cold Spring Harb Symp Quant Biol. 1955;20:25-31; discussion, 31-2 PMID: 13433552
  38. An update on hypercoagulable disorders.
    Arch Intern Med. 2001 Apr 23;161(8):1051-6 PMID: 11322838
  39. 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):155-74 PMID: 9449192
  40. Gene frequency distributions as a test of selective neutrality.
    Genetics. 1975 Dec;81(4):775-85 PMID: 1213275
  41. Polymorphism and locus-specific effects on polymorphism at microsatellite loci in natural Drosophila melanogaster populations.
    Genetics. 1997 May;146(1):309-20 PMID: 9136020
  42. Case-control studies of association in structured or admixed populations.
    Theor Popul Biol. 2001 Nov;60(3):227-37 PMID: 11855957
Article Info
Journal
Genetics
Abbr.
Genetics
ISSN
0016-6731
DOI
10.1093/genetics/164.3.1055
Email
[email protected]
Published
2003-07-00
Pages
1055-70
Language
English
Region
United States
NLM ID
0374636
PMCID
PMC1462631
Subset
IM
External Links
PubMed source DOI: 10.1093/genetics/164.3.1055 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2