Genetica

, Volume 130, Issue 3, pp 227–239 | Cite as

A statistical model for dissecting genomic imprinting through genetic mapping

Original Paper

Abstract

As a result of nonequivalent genetic contribution of maternal and paternal genomes to offsprings, genomic imprinting or called parent-of-origin effect, has been broadly identified in plants, animals and humans. Its role in shaping organism’s development has been unanimously recognized. However, statistical methods for identifying imprinted quantitative trait loci (iQTL) and estimating the imprinted effect have not been well developed. In this article, we propose an efficient statistical procedure for genomewide estimating and testing the effects of significant iQTL underlying the quantitative variation of interested traits. The developed model can be applied to two different genetic cross designs, backcross and F2 families derived from inbred lines. The proposed procedure is built within the maximum likelihood framework and implemented with the EM algorithm. Extensive simulation studies show that the proposed model is well performed in a variety of situations. To demonstrate the usefulness of the proposed approach, we apply the model to a published data in an F2 family derived from LG/S and SM/S mouse stains. Two partially maternal imprinting iQTL are identified which regulate the growth of body weight. Our approach provides a testable framework for identifying and estimating iQTL involved in the genetic control of complex traits.

Keywords

EM algorithm Genomic Imprinting Inbred Lines Maximum likelihood Quantitative trait loci 

References

  1. Agrawal AF, Brodie ED III, Brown J (2001) Parent–offspring coadaptation and the dual genetic control of maternal care. Science 292:1710–1712PubMedCrossRefGoogle Scholar
  2. Alleman M, Doctor J (2000) Genomic imprinting in plants: observations and evolutionary implications. Plant Mol Biol 43:147–161PubMedCrossRefGoogle Scholar
  3. Bartolomei MS, Tilghman SM (1997) Genomic imprinting in mammals. Annu Rev Genet 31:493–525PubMedCrossRefGoogle Scholar
  4. Bennett ST, Todd JA, Waterworth DM, Franks S, McCarthy MI (1997) Association of insulin gene VNTR polymorphism with polycystic ovary syndrome. Lancet 349:1771–1772CrossRefGoogle Scholar
  5. Cattanach BM, Beechey CV, Peters J (2004) Interactions between imprinting effects in the mouse. Genetics 168:397–413PubMedCrossRefGoogle Scholar
  6. Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138:963–971PubMedGoogle Scholar
  7. Clapcott SJ, Teale AJ, Kemp SJ (2000) Evidence for genomic imprinting of the major QTL controlling susceptibility to trypanosomiasis in mice. Parasite Immunol (Oxf) 22:259–264CrossRefGoogle Scholar
  8. Cui YH, Casella G, Wu RL (2004) Mapping quantitative trait locus interactions from the maternal and offspring genomes. Genetics 167:1017–1026PubMedCrossRefGoogle Scholar
  9. Cui YH, Lu Q, Cheverud JM, Littell RC, Wu RL (2006) Model for mapping imprinted quantitative trait loci in an inbred F2 design. Genomics 87:543–551PubMedCrossRefGoogle Scholar
  10. de Koning D-J, Rattink AP, Harlizius B, van Arendonk JAM, Brascamp EW et al (2000) Genome-wide scan for body composition in pigs reveals important role of imprinting. Proc Natl Acad Sci USA 97:7947–7950PubMedCrossRefGoogle Scholar
  11. de Koning D-J, Bovenhuis H, van Arendonk JAM (2002) On the detection of imprinted quantitative trait loci in experimental crosses of outbred species. Genetics 161:931–938PubMedGoogle Scholar
  12. DeChiara TM, Robertson EJ, Efstratiadis A (1991) Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64:849–859PubMedCrossRefGoogle Scholar
  13. Dempster AP, Laird NM, Rubin DB (1977) Maximum likelihood from incomplet data via the EM algorithm. J R Statist Soc B 39(1):1–38Google Scholar
  14. Dietrich WF, Miller J, Steen R, Merchant MA, Damron-Boles D et al (1996) A comprehensive genetic map of the mouse genome. Nature 380:149–152PubMedCrossRefGoogle Scholar
  15. Falls JG, Pulford DJ, Wylie AA, Jirtle RL (1999) Genomic imprinting: implications for human disease. Am J Pathol 154:635–647PubMedGoogle Scholar
  16. Feinberg AP (2001) Genomic imprinting and cancer. In: Scriver CR, Beaudet al, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 525–537Google Scholar
  17. Haldane JBS (1922) The part played by recurrent mutation in evolution. Am Nat 67:5–9CrossRefGoogle Scholar
  18. Hanson RL, Kobes S, Lindsay RS, Kmowler WC (2001) Assessment of parent-of-origin effects in titative traits. Am J Hum Genet 68:951–962PubMedCrossRefGoogle Scholar
  19. Horike S, Cai S, Miyano M, Cheng J-F, Kohwi-Shigematsu T (2005) Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat Genet 37:31–40PubMedCrossRefGoogle Scholar
  20. Jeon J-T, Carlborg O, Tornsten A, Giuffra E, Amarger V et al (1999) A paternally expressed nd cardiac muscle mass in pigs maps to the IGF2 locus. Nat Genet 21:157–158PubMedCrossRefGoogle Scholar
  21. Knapp M, Strauch K (2004) Affected-sib-pair test for linkage based on constraints for identical-by-descent distributions corresponding to disease models with imprinting. Genet Epidemiol 26:273–285PubMedCrossRefGoogle Scholar
  22. Lander ES, Botstein D (1989) Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121:185–199PubMedGoogle Scholar
  23. Lin M, Lou X-Y, Chang M, Wu RL (2003) A general statistical framework for mapping quantitative trait loci in nonmodel systems: issue for characterizing linkage phases. Genetics 165:901–913PubMedGoogle Scholar
  24. Louis TA (1982) Finding the observed information matrix when using the EM algorithm. J Roy Stat Soc Ser B 44:226–233Google Scholar
  25. Luedi PJ, Hartemink AJ, Jirtle RL (2005) Genome-wide prediction of imprinted murine genes. Genome Res 15:875–884PubMedCrossRefGoogle Scholar
  26. McInnis MG, Lan TH, Willour VL, Mcmahon FJ, Simpson SG et al (2003) Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12. Mol Psychiatry 8:288–298PubMedCrossRefGoogle Scholar
  27. Morison IM, Ramsay JP, Spencer HG (2005) A census of mammalian imprinting. Trends Genet 21:457–465PubMedCrossRefGoogle Scholar
  28. Naumova AK, Croteau S (2004) Mechanisms of epigenetic variation: polymorphic imprinting. Curr Genomics 5:417–429CrossRefGoogle Scholar
  29. Nezer C, Moreau L, Brouwers B, Coppieters W, Detilleux J et al (1999) An imprinted QTL with major effect on muscle mass and fat deposition maps to the IGF2 locus in pigs. Nat Genet 21:155–156PubMedCrossRefGoogle Scholar
  30. Ono R, Shiura H, Aburatani H, Kohda T, Kaneko-Ishino T, Ishino F (2003) Identification of a large novel imprinted gene cluster on mouse proximal chromosome 6. Genome Res 13:1696–1705PubMedCrossRefGoogle Scholar
  31. Paterson AD, Naimark DMJ, Petronis A (1999) The analysis of parental origin of alleles may detect susceptibility loci for complex disorders. Hum Hered 49:197–204PubMedCrossRefGoogle Scholar
  32. Pfeifer K (2000) Mechanisms of genomic imprinting. Am J Hum Genet 67:777–787PubMedCrossRefGoogle Scholar
  33. Sandovici I, Leppert M, Hawk PR, Suarez A, Linares Y, Sapienza C (2003) Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. Hum Mol Genet 12:1569–1578PubMedCrossRefGoogle Scholar
  34. Sandovici I, Kassovska-Bratinova S, Loredo-Osti JC, Leppert M, Suazez A et al (2005) Interindividual variability and parent of origin DNA methylation differences at specific human Alu elements. Hum Mol Genet 14:2135–2143PubMedCrossRefGoogle Scholar
  35. Sapienza C (1990) Sex-linked dosage-sensitive modifiers as imprinting genes. Dev Suppl 107–113Google Scholar
  36. Shete S, Zhou X, Amos CI (2003) Genomic imprinting and linkage test for quantitative trait loci in extended pedigrees. Am J Hum Genet 73:933–938PubMedCrossRefGoogle Scholar
  37. Spencer HG (2002) The correlation between relatives on the supposition of genomic imprinting. Genetics 161:411–417PubMedGoogle Scholar
  38. Strauch K, Fimmers R, Kurz T, Deichmann KA, Wienker TF, Baur MP (2000) Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: application to mite sensitization. Am J Hum Genet 66:1945–1957PubMedCrossRefGoogle Scholar
  39. Tuiskula-Haavisto M, de Koning DJ, Honkatukia M, Schulman NF, Maki-Tanila A, Vilkki J (2004) Quantitative trait loci with parent-of-origin effects in chicken. Genet Res 84:57–66PubMedCrossRefGoogle Scholar
  40. Van Laere AS, Nguyen M, Braunschweig M, Nezer C, Collette C et al (2003) A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature 425:832–836PubMedCrossRefGoogle Scholar
  41. Vaughn TT, Pletscher LS, Peripato A, King-Ellison K, Adams E, Erikson C, Cheverud JM (1999) Mapping quantitative trait loci for murine growth. A closer look at genetic architecture. Genet Res 74:313–322PubMedCrossRefGoogle Scholar
  42. Wade MJ (1998) The evolutionary genetics of maternal effects. In: Mousseau TA, Fox CW (eds) Maternal effects as adaptations. Oxford University Press, New York, pp 5–21Google Scholar
  43. Wolf JB (2000) Gene interactions from maternal effects. Evolution 54:1882–1898PubMedGoogle Scholar
  44. Wolf JB, Vaughn TT, Pletscher LS, Cheverud JM (2002) Contribution of maternal effect QTL to genetic architecture of early growth in mice. Heredity 89:300–310PubMedCrossRefGoogle Scholar
  45. Xu S (1998) Mapping quantitative trait loci using multiple families of line crosses. Genetics 148:517–524PubMedGoogle Scholar
  46. Zou F, Yandell BS, Fine JP (2001) Statistical issues in the analysis of quantitative traits in combined crosses. Genetics 158:1339–1346PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  1. 1.Department of Statistics and ProbabilityMichigan State UniversityEast LansingUSA
  2. 2.Department of Anatomy and NeurobiologyWashington University Medical SchoolSt. LouisUSA
  3. 3.Department of StatisticsUniversity of FloridaGainesvilleUSA

Personalised recommendations