Nature Genetics
23, 314 - 318 (1999)
doi:10.1038/15490
Epigenetic inheritance at the agouti locus in the mouseHugh D. Morgan1, Heidi G.E. Sutherland2, David I.K. Martin3
& Emma Whitelaw11
Department of Biochemistry, University of Sydney,
NSW, 2006, Australia. 2
MRC Human Genetics Unit, Edinburgh,
Scotland, UK. 3
Fred Hutchinson Cancer Research Center,
Seattle, Washington, USA.
Correspondence should be addressed to Emma Whitelaw e.whitelaw@biochem.usyd.edu.auEpigenetic 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 A
vy 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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