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Epigenetic inheritance at the agouti locus in the mouse

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.

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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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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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