It is well recognized that there is a surprising degree of phenotypic variation among genetically identical individuals, even when the environmental influences, in the strict sense of the word, are identical. Genetic textbooks acknowledge this fact and use different terms, such as ‘intangible variation’ or ‘developmental noise’, to describe it. We believe that this intangible variation results from the stochastic establishment of epigenetic modifications to the DNA nucleotide sequence. These modifications, which may involve cytosine methylation and chromatin remodelling, result in alterations in gene expression which, in turn, affects the phenotype of the organism. Recent evidence, from our work and that of others in mice, suggests that these epigenetic modifications, which in the past were thought to be cleared and reset on passage through the germline, may sometimes be inherited to the next generation. This is termed epigenetic inheritance, and while this process has been well recognized in plants, the recent findings in mice force us to consider the implications of this type of inheritance in mammals. At this stage we do not know how extensive this phenomenon is in humans, but it may well turn out to be the explanation for some diseases which appear to be sporadic or show only weak genetic linkage.
Abbreviations used: Dnmt, DNA methyltransferase; HAT, histone acetyltransferase; HDAC, histone deacetylase; MECP2, methyl-CpG binding protein 2; MBD, methyl-CpG binding domain; Xi, inactived X chromosome; Xist, X-inactivation-specific transcript; IGF2, insulin-like growth factor 2; Avy, agouti viable yellow allele; AxinFu, axin-fused allele; IAP, intracisternal A-particle; LTR, long terminal repeat.