Natural Polymorphisms in Influence Negative Selection and CD4∶CD8 Lineage Commitment in the Rat

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Genetic variation in the major histocompatibility complex (MHC) affects CD4∶CD8 lineage commitment and MHC expression. However, the contribution of specific genes in this gene-dense region has not yet been resolved. Nor has it been established whether the same genes regulate MHC expression and T cell selection. Here, we assessed the impact of natural genetic variation on MHC expression and CD4∶CD8 lineage commitment using two genetic models in the rat. First, we mapped Quantitative Trait Loci (QTLs) associated with variation in MHC class I and II protein expression and the CD4∶CD8 T cell ratio in outbred Heterogeneous Stock rats. We identified 10 QTLs across the genome and found that QTLs for the individual traits colocalized within a region spanning the MHC. To identify the genes underlying these overlapping QTLs, we generated a large panel of MHC-recombinant congenic strains, and refined the QTLs to two adjacent intervals of ∼0.25 Mb in the MHC-I and II regions, respectively. An interaction between these intervals affected MHC class I expression as well as negative selection and lineage commitment of CD8 single-positive (SP) thymocytes. We mapped this effect to the transporter associated with antigen processing 2 (Tap2) in the MHC-II region and the classical MHC class I gene(s) (RT1-A) in the MHC-I region. This interaction was revealed by a recombination between RT1-A and Tap2, which occurred in 0.2% of the rats. Variants of Tap2 have previously been shown to influence the antigenicity of MHC class I molecules by altering the MHC class I ligandome. Our results show that a restricted peptide repertoire on MHC class I molecules leads to reduced negative selection of CD8SP cells. To our knowledge, this is the first study showing how a recombination between natural alleles of genes in the MHC influences lineage commitment of T cells.

Vyšlo v časopise: Natural Polymorphisms in Influence Negative Selection and CD4∶CD8 Lineage Commitment in the Rat. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004151
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004151

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Zdroje

1. FlajnikMF, KasaharaM (2001) Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 15: 351–362.

2. Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing (1999) Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. Nature 401: 921–923 doi:10.1038/44853

3. TrowsdaleJ, KnightJC (2013) Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet 14: 301–323 doi:10.1146/annurev-genom-091212-153455

4. FernandoMMA, StevensCR, WalshEC, De JagerPL, GoyetteP, et al. (2008) Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet 4: e1000024 doi:10.1371/journal.pgen.1000024

5. GabrielSB, SchaffnerSF, NguyenH, MooreJM, RoyJ, et al. (2002) The structure of haplotype blocks in the human genome. Science 296: 2225–2229 doi:10.1126/science.1069424

6. CullenM, PerfettoSP, KlitzW, NelsonG, CarringtonM (2002) High-resolution patterns of meiotic recombination across the human major histocompatibility complex. Am J Hum Genet 71: 759–776 doi:10.1086/342973

7. JeffreysAJ, NeumannR (2002) Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot. Nat Genet 31: 267–271 doi:10.1038/ng910

8. TraherneJA, HortonR, RobertsAN, MirettiMM, HurlesME, et al. (2006) Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history. PLoS Genet 2: e9 doi:10.1371/journal.pgen.0020009

9. HurtP (2004) The Genomic Sequence and Comparative Analysis of the Rat Major Histocompatibility Complex. Genome Research 14: 631–639 doi:10.1101/gr.1987704

10. GibbsRA, WeinstockGM, MetzkerML, MuznyDM, SodergrenEJ, et al. (2004) Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428: 493–521 doi:10.1038/nature02426

11. AtanurSS, BirolI, GuryevV, HirstM, HummelO, et al. (2010) The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance. Genome Research 20: 791–803 doi:10.1101/gr.103499.109

12. GuoX, BrennerM, ZhangX, LaragioneT, TaiS, et al. (2013) Whole-genome sequences of DA and F344 rats with different susceptibilities to arthritis, autoimmunity, inflammation and cancer. Genetics 194: 1017–1028 doi:10.1534/genetics.113.153049

13. AtanurSS, DiazAG, MaratouK, SarkisA, RotivalM, et al. (2013) Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat. Cell 154: 691–703 doi:10.1016/j.cell.2013.06.040

14. WalterL, GüntherE (2000) Physical mapping and evolution of the centromeric class I gene-containing region of the rat MHC. Immunogenetics 51: 829–837.

15. IoanniduS, WalterL, DresselR, GüntherE (2001) Physical map and expression profile of genes of the telomeric class I gene region of the rat MHC. J Immunol 166: 3957–3965.

16. StrongRK, HolmesMA, LiP, BraunL, LeeN, et al. (2003) HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities. J Biol Chem 278: 5082–5090 doi:10.1074/jbc.M208268200

17. HowcroftTK, SingerDS (2003) Expression of nonclassical MHC class Ib genes: comparison of regulatory elements. Immunol Res 27: 1–30 doi:10.1385/IR:27:1:1

18. González-MuñozAL, Le RolleA-F, BrunH, HedrichHJ, WedekindD, et al. (2003) A novel instance of class I modification (cim) affecting two of three rat class I RT1-A molecules within one MHC haplotype. J Immunol 171: 274–284.

19. JolyE, Le RolleAF, GonzélezAL, MehlingB, StevensJ, et al. (1998) Co-evolution of rat TAP transporters and MHC class I RT1-A molecules. Current Biology 8: 169–180 Available: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=9443915&retmode=ref&cmd=prlinks.

20. BahramS, ArnoldD, BresnahanM, StromingerJL, SpiesT (1991) Two putative subunits of a peptide pump encoded in the human major histocompatibility complex class II region. Proc Natl Acad Sci USA 88: 10094–10098.

21. PowisSH, MockridgeI, KellyA, KerrLA, GlynneR, et al. (1992) Polymorphism in a second ABC transporter gene located within the class II region of the human major histocompatibility complex. Proc Natl Acad Sci USA 89: 1463–1467.

22. PowisSJ, DeversonEV, CoadwellWJ, CiruelaA, HuskissonNS, et al. (1992) Effect of polymorphism of an MHC-linked transporter on the peptides assembled in a class I molecule. Nature 357: 211–215 doi:10.1038/357211a0

23. The distribution of Tap2 alleles among laboratory rat RT1 haplotypes (1994) The distribution of Tap2 alleles among laboratory rat RT1 haplotypes. 40: 45–53 Available: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=8206525&retmode=ref&cmd=prlinks.

24. JolyE, ButcherGW (1998) Why are there two rat TAPs? Immunol Today 19: 580–585 doi:10.1016/S0167-5699(98)01348-6

25. LivingstoneAM, PowisSJ, DiamondAG, ButcherGW, HowardJC (1989) A trans-acting major histocompatibility complex-linked gene whose alleles determine gain and loss changes in the antigenic structure of a classical class I molecule. J Exp Med 170: 777–795.

26. MomburgF, RoelseJ, HowardJC, ButcherGW, HammerlingGJ, et al. (1994) Selectivity of MHC-encoded peptide transporters from human, mouse and rat. Nature 367: 648–651 doi:10.1038/367648a0

27. HeemelsMT, SchumacherTN, WonigeitK, PloeghHL (1993) Peptide translocation by variants of the transporter associated with antigen processing. Science 262: 2059–2063.

28. PowisSJ, YoungLL, JolyE, BarkerPJ, RichardsonL, et al. (1996) The rat cim effect: TAP allele-dependent changes in a class I MHC anchor motif and evidence against C-terminal trimming of peptides in the ER. Immunity 4: 159–165.

29. PowisSJ, HowardJC, ButcherGW (1991) The major histocompatibility complex class II-linked cim locus controls the kinetics of intracellular transport of a classical class I molecule. J Exp Med 173: 913–921.

30. CosgroveD, GrayD, DierichA, KaufmanJ, LemeurM, et al. (1991) Mice lacking MHC class II molecules. Cell 66: 1051–1066.

31. ZijlstraM, BixM, SimisterNE, LoringJM, RauletDH, et al. (1990) Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature 344: 742–746 doi:10.1038/344742a0

32. ViretC, WongFS, JanewayCA (1999) Designing and maintaining the mature TCR repertoire: the continuum of self-peptide∶self-MHC complex recognition. Immunity 10: 559–568.

33. KirbergJ, BernsA, Boehmer vonH (1997) Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules. J Exp Med 186: 1269–1275.

34. FerreiraMAR, ManginoM, BrummeCJ, ZhaoZZ, MedlandSE, et al. (2010) Quantitative trait loci for CD4∶CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control. Am J Hum Genet 86: 88–92 doi:10.1016/j.ajhg.2009.12.008

35. YalcinB, NicodJ, BhomraA, DavidsonS, CleakJ, et al. (2010) Commercially available outbred mice for genome-wide association studies. PLoS Genet 6 doi:10.1371/journal.pgen.1001085

36. DamoiseauxJG, CautainB, BernardI, MasM, van Breda VriesmanPJ, et al. (1999) A dominant role for the thymus and MHC genes in determining the peripheral CD4/CD8 T cell ratio in the rat. J Immunol 163: 2983–2989.

37. HansenC, SpuhlerK (1984) Development of the National Institutes of Health genetically heterogeneous rat stock. Alcohol Clin Exp Res 8: 477–479.

38. TalbotCJ, NicodA, ChernySS, FulkerDW, CollinsAC, et al. (1999) High-resolution mapping of quantitative trait loci in outbred mice. Nat Genet 21: 305–308 doi:10.1038/6825

39. YazbekSN, BuchnerDA, GeisingerJM, BurrageLC, SpiezioSH, et al. (2011) Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis. Genome Research 21: 1065–1073 doi:10.1101/gr.120741.111

40. TanIKL, MackinL, WangN, PapenfussAT, ElsoCM, et al. (2010) A recombination hotspot leads to sequence variability within a novel gene (AK005651) and contributes to type 1 diabetes susceptibility. Genome Research 20: 1629–1638 doi:10.1101/gr.101881.109

41. Rat Genome Sequencing and Mapping Consortium (2013) BaudA, HermsenR, GuryevV, StridhP, et al. (2013) Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Nat Genet 45: 767–775 doi:10.1038/ng.2644

42. JohannessonM, Lopez-AumatellR, StridhP, DiezM, TuncelJ, et al. (2009) A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock. Genome Research 19: 150–158 doi:10.1101/gr.081497.108

43. JeffreysAJ, KauppiL, NeumannR (2001) Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 29: 217–222 doi:10.1038/ng1001-217

44. MyersS, BottoloL, FreemanC, McVeanG, DonnellyP (2005) A fine-scale map of recombination rates and hotspots across the human genome. Science 310: 321–324 doi:10.1126/science.1117196

45. AgarwalAK, XingC, DeMartinoGN, MizrachiD, HernandezMD, et al. (2010) PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet 87: 866–872 doi:10.1016/j.ajhg.2010.10.031

46. DeversonEV, LeongL, SeeligA, CoadwellWJ, TredgettEM, et al. (1998) Functional analysis by site-directed mutagenesis of the complex polymorphism in rat transporter associated with antigen processing. J Immunol 160: 2767–2779.

47. MomburgF, ArmandolaEA, PostM, HammerlingGJ (1996) Residues in TAP2 peptide transporters controlling substrate specificity. J Immunol 156: 1756–1763.

48. JonssonAK, RaskL (1989) Human class II DNA and DOB genes display low sequence variability. Immunogenetics 29: 411–413.

49. ButcherGW (1987) A list of monoclonal antibodies specific for alloantigens of the rat. J Immunogenet 14: 163–176.

50. DiamondAG, LarkinsAP, WrightB, EllisST, ButcherGW, et al. (1984) The alloantigenic organization of RT1Aa, a class I major histocompatibility complex molecule of the rat. Eur J Immunol 14: 405–412 doi:10.1002/eji.1830140505

51. HowardJC, ButcherGW, GalfreG, MilsteinC, MilsteinCP (1979) Monoclonal Antibodies as Tools to Analyze the Serological and Genetic Complexities of Major Transplantation Antigens. Immunol Rev 47: 139–174 doi:10.1111/j.1600-065X.1979.tb00292.x

52. JolyE, LeongL, CoadwellWJ, ClarksonC, ButcherGW (1996) The rat MHC haplotype RT1c expresses two classical class I molecules. J Immunol 157: 1551–1558.

53. RadaC, LorenziR, PowisSJ, van den BogaerdeJ, ParhamP, et al. (1990) Concerted evolution of class I genes in the major histocompatibility complex of murine rodents. Proc Natl Acad Sci USA 87: 2167–2171.

54. CosmanD, KressM, KhouryG, JayG (1982) Tissue-specific expression of an unusual H-2 (class I)-related gene. Proc Natl Acad Sci USA 79: 4947–4951.

55. JolyE, ClarksonC, HowardJC, ButcherGW (1995) Isolation of a functional cDNA encoding the RT1.Au MHC class I heavy chain by a novel PCR-based method. Immunogenetics 41: 326–328.

56. HedrichHJ, AdamsM, ScienceICFLA (1990) Genetic monitoring of inbred strains of rats. Gustav Fischer 1.

57. FukumotoT, Robert McMasterW, WilliamsAF (1982) Mouse monoclonal antibodies against rat major histocompatibility antigens. Two Ia antigens and expression of Ia and class I antigens in rat thymus. Eur J Immunol 12: 237–243 doi:10.1002/eji.1830120313

58. SpencerSC, FabreJW (1987) Identification in rat liver and serum of water-soluble class I MHC molecules possibly homologous to the murine Q10 gene product. Journal of Experimental Medicine 165: 1595–1608 Available: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=3585249&retmode=ref&cmd=prlinks.

59. SpencerSC, FabreJW (1987) Water-soluble form of RT1.A class I MHC molecules in the kidney and liver of the rat. Immunogenetics 25: 91–98.

60. DijkstraCD, DöppEA, JolingP, KraalG (1985) The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 54: 589–599.

61. LivingstoneAM, PowisSJ, GüntherE, CramerDV, HowardJC, et al. (1991) Cim: an MHC class II-linked allelism affecting the antigenicity of a classical class I molecule for T lymphocytes. Immunogenetics 34: 157–163.

62. SpeiserDE, LeesRK, HengartnerH, ZinkernagelRM, MacDonaldHR (1989) Positive and negative selection of T cell receptor V beta domains controlled by distinct cell populations in the thymus. J Exp Med 170: 2165–2170.

63. BommhardtU, BeyerM, HünigT, ReichardtHM (2004) Molecular and cellular mechanisms of T cell development. Cell Mol Life Sci 61: 263–280 doi:10.1007/s00018-003-3224-3

64. HünigT, Torres-NagelN, MehlingB, ParkHJ, HerrmannT (2001) Thymic development and repertoire selection: the rat perspective. Immunol Rev 184: 7–19.

65. LawDA, SpruytLL, PatersonDJ, WilliamsAF (1989) Subsets of thymopoietic rat thymocytes defined by expression of the CD2 antigen and the MRC OX-22 determinant of the leukocyte-common antigen CD45. Eur J Immunol 19: 2289–2295 doi:10.1002/eji.1830191217

66. MitnachtR, BischofA, Torres-NagelN, HünigT (1998) Opposite CD4/CD8 lineage decisions of CD4+8+ mouse and rat thymocytes to equivalent triggering signals: correlation with thymic expression of a truncated CD8 alpha chain in mice but not rats. J Immunol 160: 700–707.

67. HünigT, MitnachtR (1991) T cell receptor-mediated selection of functional rat CD8 T cells from defined immature thymocyte precursors in short-term suspension culture. J Exp Med 173: 561–568.

68. HogquistKA, GavinMA, BevanMJ (1993) Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture. J Exp Med 177: 1469–1473.

69. YangCP, BellEB (1992) Functional maturation of recent thymic emigrants in the periphery: development of alloreactivity correlates with the cyclic expression of CD45RC isoforms. Eur J Immunol 22: 2261–2269 doi:10.1002/eji.1830220913

70. HosseinzadehH, GoldschneiderI (1993) Recent thymic emigrants in the rat express a unique antigenic phenotype and undergo post-thymic maturation in peripheral lymphoid tissues. J Immunol 150: 1670–1679.

71. VolkmannA, ZalT, StockingerB (1997) Antigen-presenting cells in the thymus that can negatively select MHC class II-restricted T cells recognizing a circulating self antigen. J Immunol 158: 693–706.

72. KleinL, HinterbergerM, Rohrscheidt vonJ, AichingerM (2011) Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance. Trends Immunol 32: 188–193 doi:10.1016/j.it.2011.03.002

73. Ashton-RickardtPG, Van KaerL, SchumacherTN, PloeghHL, TonegawaS (1993) Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus. Cell 73: 1041–1049.

74. DelaneyJR, SykulevY, EisenHN, TonegawaS (1998) Differences in the level of expression of class I major histocompatibility complex proteins on thymic epithelial and dendritic cells influence the decision of immature thymocytes between positive and negative selection. Proc Natl Acad Sci USA 95: 5235–5240.

75. MurataS, SasakiK, KishimotoT, NiwaS-I, HayashiH, et al. (2007) Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316: 1349–1353 doi:10.1126/science.1141915

76. XingY, JamesonSC, HogquistKA (2013) Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection. Proc Natl Acad Sci USA 110: 6979–6984 doi:10.1073/pnas.1222244110

77. KanetaM, OsawaM, SudoK, NakauchiH, FarrAG, et al. (2000) A role for pref-1 and HES-1 in thymocyte development. J Immunol 164: 256–264.

78. VercauterenSM, SutherlandHJ (2004) Constitutively active Notch4 promotes early human hematopoietic progenitor cell maintenance while inhibiting differentiation and causes lymphoid abnormalities in vivo. Blood 104: 2315–2322 doi:10.1182/blood-2004-01-0204

79. PuiJC, AllmanD, XuL, DeRoccoS, KarnellFG, et al. (1999) Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11: 299–308.

80. DickinsonLA, JohT, KohwiY, Kohwi-ShigematsuT (1992) A tissue-specific MAR/SAR DNA-binding protein with unusual binding site recognition. Cell 70: 631–645.

81. NieH, MaikaSD, TuckerPW, GottliebPD (2005) A role for SATB1, a nuclear matrix association region-binding protein, in the development of CD8SP thymocytes and peripheral T lymphocytes. J Immunol 174: 4745–4752.

82. DouekDC, AltmannDM (1997) HLA-DO is an intracellular class II molecule with distinctive thymic expression. Int Immunol 9: 355–364.

83. GuceAI, MortimerSE, YoonT, PainterCA, JiangW, et al. (2013) HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism. Nat Struct Mol Biol 20: 90–98 doi:10.1038/nsmb.2460

84. YoonT, MacmillanH, MortimerSE, JiangW, RinderknechtCH, et al. (2012) Mapping the HLA-DO/HLA-DM complex by FRET and mutagenesis. Proc Natl Acad Sci USA 109: 11276–11281 doi:10.1073/pnas.1113966109

85. BraunsteinNS, GermainRN (1986) The mouse E beta 2 gene: a class II MHC beta gene with limited intraspecies polymorphism and an unusual pattern of transcription. EMBO J 5: 2469–2476.

86. GreeneJM, WisemanRW, LankSM, BimberBN, KarlJA, et al. (2011) Differential MHC class I expression in distinct leukocyte subsets. BMC Immunol 12: 39 doi:10.1186/1471-2172-12-39

87. WalkerBA, HuntLG, SowaAK, SkjødtK, GöbelTW, et al. (2011) The dominantly expressed class I molecule of the chicken MHC is explained by coevolution with the polymorphic peptide transporter (TAP) genes. Proc Natl Acad Sci USA 108: 8396–8401 doi:10.1073/pnas.1019496108

88. KaufmanJ, MilneS, GöbelTW, WalkerBA, JacobJP, et al. (1999) The chicken B locus is a minimal essential major histocompatibility complex. Nature 401: 923–925 doi:10.1038/44856

89. BaudatF, de MassyB (2007) Cis- and trans-acting elements regulate the mouse Psmb9 meiotic recombination hotspot. PLoS Genet 3: e100 doi:10.1371/journal.pgen.0030100

90. GuillonH, de MassyB (2002) An initiation site for meiotic crossing-over and gene conversion in the mouse. Nat Genet 32: 296–299 doi:10.1038/ng990

91. QinJ, RichardsonLL, JasinM, HandelMA, ArnheimN (2004) Mouse strains with an active H2-Ea meiotic recombination hot spot exhibit increased levels of H2-Ea-specific DNA breaks in testicular germ cells. Mol Cell Biol 24: 1655–1666.

92. CullenM, NobleJ, ErlichH, ThorpeK, BeckS, et al. (1997) Characterization of recombination in the HLA class II region. Am J Hum Genet 60: 397–407.

93. LobelSA, CramerDV (1981) Demonstration of a new genetic locus in the major histocompatibility system of the rat. Immunogenetics 13: 465–473.

94. TuncelJ, HaagS, CarlsenS, YauACY, LuS, et al. (2012) Class II major histocompatibility complex-associated response to type XI collagen regulates the development of chronic arthritis in rats. Arthritis Rheum 64: 2537–2547 doi:10.1002/art.34461

95. GillTJ, KunzHW (1979) Gene complex controlling growth and fertility linked to the major histocompatibility complex in the rat. The American Journal of Pathology 96: 185–206.

96. GillettA, MaratouK, FewingsC, HarrisRA, JagodicM, et al. (2009) Alternative splicing and transcriptome profiling of experimental autoimmune encephalomyelitis using genome-wide exon arrays. PLoS ONE 4: e7773 doi:10.1371/journal.pone.0007773

97. YtterbergAJ, PeltierJ-B, van WijkKJ (2006) Protein profiling of plastoglobules in chloroplasts and chromoplasts. A surprising site for differential accumulation of metabolic enzymes. Plant Physiol 140: 984–997 doi:10.1104/pp.105.076083

98. MottR, TalbotCJ, TurriMG, CollinsAC, FlintJ (2000) A method for fine mapping quantitative trait loci in outbred animal stocks. Proc Natl Acad Sci USA 97: 12649–12654 doi:10.1073/pnas.230304397

99. ValdarW, HolmesCC, MottR, FlintJ (2009) Mapping in structured populations by resample model averaging. Genetics 182: 1263–1277 doi:10.1534/genetics.109.100727