KEYNOTE ADDRESS: Metastable Epialleles in Mice and Humans

Emma Whitelaw
School of Molecular and Microbial Biosciences; University of Sydney

My lab has spent many years studying a particular group of genes in the mouse, called metastable epialleles, which are particularly sensitive to epigenetic state and where the phenotype of the adult is determined by that state [1, 2, 3]. Studying epigenetics is best done using genetically identical organisms to control for genetic modifiers. In humans, this can be accomplished by studying monozygotic twins. Particularly interesting are those twins who differ in phenotype for a particular trait. This discordance may turn out to correlate with differences in the epigenetic status at a given locus. Using bisulphite sequencing and DNA from monozygotic twins, we have studied a number of sites in an attempt to discover variable methylation patterns which might indicate variable expression of genes within the twin pairs. One of the loci studied is AXIN 1, the human homologue of axin, a gene required for the prevention of caudal duplication in the mouse. We have found that the CpG island at human AXIN 1 is quite variable, with most people displaying low or moderate methylation levels (up to ~40% methylation). A pair of twins, discordant for a number of birth defects (collectively known as caudal duplication syndrome) have higher methylation levels than all controls, and the affected twin is more methylated than the unaffected twin.


  1. Morgan H., Sutherland H., Martin D.I.K. and Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 23: 314-317, 1999.

  2. Rakyan V K, Blewitt M, Druker R, Preis J, and Whitelaw E. Metastable epialleles in mammals. Trends Genet.18: 348-351, 2002.

  3. Rakyan V , Chong S, Luu K, Cuthbert. P, and Whitelaw E. Meiotic inheritance of epigenetic states at the murine AxinFU allele occurs following both maternal and paternal transmission. Proc. Nat. Acad. Sci. (USA) 100: 2538-2543, 2003.