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Nature Genetics
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Epigenetic inheritance at the agouti locus in the mouse

Nature Geneticsvolume 23, pages314–318 (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: isogenicAvy 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 anAvy 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 silencedAvy 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: TheAvy allele: map of theA locus and range of phenotypes in isogenicAvy mice.
Figure 2: Increased methylation ofAvy 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.

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Acknowledgements

We thank E. Michaud for Avy/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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  2. Heidi G.E. Sutherland

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  4. Emma Whitelaw

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Correspondence toEmma Whitelaw.

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Morgan, H., Sutherland, H., Martin, D.et al. Epigenetic inheritance at the agouti locus in the mouse.Nat Genet23, 314–318 (1999). https://doi.org/10.1038/15490

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