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Epigenetic inheritance at the agouti locus in the mouse

Nature Genetics volume 23, pages 314–318 (1999)Cite this article

Abstract

Epigenetic modifications have effects on phenotype, but they are generally considered to be cleared on passage through the germ line in mammals, so that only genetic traits are inherited. Here we describe the inheritance of an epigenetic modification at the agouti locus in mice. In viable yellow ( Avy/a) mice, transcription originating in an intra-cisternal A particle (IAP) retrotransposon inserted upstream of the agouti gene ( A) causes ectopic expression of agouti protein, resulting in yellow fur, obesity, diabetes and increased susceptibility to tumours1. The pleiotropic effects of ectopic agouti expression are presumably due to effects of the paracrine signal on other tissues. Avy mice display variable expressivity because they are epigenetic mosaics for activity of the retrotransposon: isogenic Avy mice have coats that vary in a continuous spectrum from full yellow, through variegated yellow/agouti, to full agouti (pseudoagouti). The distribution of phenotypes among offspring is related to the phenotype of the dam; when an Avy dam has the agouti phenotype, her offspring are more likely to be agouti2,3. We demonstrate here that this maternal epigenetic effect is not the result of a maternally contributed environment. Rather, our data show that it results from incomplete erasure of an epigenetic modification when a silenced Avy allele is passed through the female germ line, with consequent inheritance of the epigenetic modification. Because retrotransposons are abundant in mammalian genomes, this type of inheritance may be common.

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Figure 1: The Avy allele: map of the A locus and range of phenotypes in isogenic Avy mice.
Figure 2: Increased methylation of Avy in pseudoagouti mice.
Figure 3: Inheritance of maternal phenotype.
Figure 4: Oocyte transfer between different intrauterine environments does not affect the phenotypes of offspring.
Figure 5: Breeding schemes used to produce pseudoagouti offspring from yellow dams.

References

  1. Duhl, D.M.J., Vrieling, H., Miller, K.A., Wolff, G.L. & Barsh, G.S. Neomorphic agouti mutations in obese yellow mice. Nature Genet. 8, 59 –64 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Wolff, G.L. Influence of maternal phenotype on metabolic differentiation of agouti locus mutants in the mouse. Genetics 88, 529–539 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Wolff, G.L., Kodell, R.L., Moore, S.R. & Cooney, C.A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 12, 949–957 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Bultman, S.J., Michaud, E.J. & Woychik, R.P. Molecular characterization of the mouse agouti locus. Cell 71, 1195– 1204 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Perry, W.L., Copeland, N.G. & Jenkins, N.A. The molecular basis for dominant yellow agouti coat colour mutations. Bioessays 16, 705–707 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Argeson, A.C., Nelson, K.K. & Siracusa, L.D. Molecular basis of the pleiotropic phenotype of mice carrying the hypervariable yellow (Ahvy) mutation at the agouti locus. Genetics 142, 557 –567 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Michaud, E.J. et al. Differential expression of a new dominant agouti allele ( Aiapy) is correlated with methylation state and is influenced by parental lineage. Genes Dev. 8, 1463– 1472 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Brink, R.A. A genetic change associated with the R locus in maize which is directed and potentially reversible. Genetics 41, 872–889 (1956).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hollick, J.B., Patterson, G.I., Coe, E.H. Jr, Cone, K.C. & Chandler, V.L. Allelic interactions heritably alter the activity of a metastable maize pl allele. Genetics 141, 709–719 ( 1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Grewal, S.I.S. & Klar, A.J.S. Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. Cell 86, 95–101 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  11. Cavalli, G. & Paro, R. The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis. Cell 93, 505–518 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  12. Jensen, S., Gassama, M.-P. & Heidman, T. Taming of transposable elements by homology-dependent gene silencing. Nature Genet. 21, 209– 212 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Federoff, N.Y. & Banks, J.A. Is the suppressor-mutator controlled by a basic developmental regulatory mechanism? Genetics 120, 559–557 ( 1988).

    Google Scholar 

  14. Martienssen, R. & Baron, A. Coordinate suppression of mutation caused by Robertson's mutator transposons in maize. Genetics 136, 1157–1170 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Barkan, A. & Martienssen, R.A. Inactivation of maize transposon Mu suppresses a mutant phenotype by activating an outward-reading promoter near the end of Mu1. Proc. Natl Acad. Sci. USA 88, 3502–3506 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Allen, N.D., Norris, M.L. & Surani, M.A. Epigenetic control of transgene expression and imprinting by genotype-specific modifiers. Cell 61, 853–861 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Hadchouel, M., Farza, H., Simon, D., Tollias, P. & Pourcel, C. Maternal inhibition of hepatitus B surface antigen gene expression in transgenic mice correlates with de novo methylation. Nature 329, 454–456 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Roemer, I., Reik, W., Dean, W. & Klose, J. Epigenetic inheritance in the mouse. Curr. Biol. 7, 277– 280 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Silva, A.J. & White, R. Inheritance of allelic blueprints for methylation patterns. Cell 54, 145– 152 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Jablonka, E., Lachmann, M. & Lamb, M.J. Evidence, mechanisms and models for the inheritance of acquired characters. J. Theor. Biol. 158, 245–268 (1992).

    Article  Google Scholar 

  21. Monk, M. Epigenetic programming of differential gene expression in development and evolution. Dev. Genet. 17, 188– 197 (1992).

    Article  Google Scholar 

  22. Belayev, D.K., Ruvinsky, A.O. & Trut, L.N. Inherited activation-inactivation of the star gene in foxes. J. Hered. 72, 267– 274 (1981).

    Article  Google Scholar 

  23. Smit, A. The origin of interspersed repeats in the human genome. Curr. Opin. Genet. Dev. 6, 743–748 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  24. Walsh, C.P., Chaillet, J.R. & Bestor, T.H. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nature Genet. 20, 116–117 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, Y., Duhl, D.M.J. & Barsh, G.S. Opposite orientations of an inverted duplication and alleleic variation at the mouse agouti locus. Genetics 144, 265–277 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank E. Michaud for A vy /a mice and G. Barsh for a clone of the A locus. H.D.M. and H.G.E.S. were supported by Australian Postgraduate Awards. This work was supported by a grant from the National Health and Medical Research Council of Australia to E.W. and an NIH grant to D.I.K.M., a Scholar of the Leukemia Society of America.

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Authors and Affiliations

  1. Department of Biochemistry, University of Sydney, 2006, NSW, Australia

    Hugh D. Morgan & Emma Whitelaw

  2. MRC Human Genetics Unit, Edinburgh, Scotland, UK

    Heidi G.E. Sutherland

  3. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    David I.K. Martin

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  1. Hugh D. Morgan
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Correspondence to Emma Whitelaw.

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Morgan, H., Sutherland, H., Martin, D. et al. Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23, 314–318 (1999). https://doi.org/10.1038/15490

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