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.

Here we report a transgenic mouse line that exhibits significant deviations from a classic pattern of parental imprinting. When the transgene is passed through the female germline, it is completely silenced in some offspring while in others expression is reduced. This variable expressivity does not appear to be the result of differences in the presence of unlinked modifiers. Female transmission of the transgene is associated with hypermethylation. The transgene is generally reactivated on passage through the male germline. Extended pedigrees reveal complex patterns of inheritance of the phenotype. The most likely explanation for this result is that the imprint is not completely erased and reset when passed through the germline of either sex. FISH analysis reveals that the transgene has integrated into chromosome 3 band E3, a region not known to carry imprinted genes, and the integration site shows no sign of allele-specific differential methylation. These findings, in conjunction with other recent work, raise the possibility that the introduction of foreign DNA into the mammalian genome, either through retrotransposition or transgenesis, may be associated with parental imprinting that is not always erased and reset during meiosis.

AbstractDas Problem der Dissoziationsgleichgewichtskonstanten und ihr Einfluß auf die Konzentration der Ausgangssubstanzen unter nichtisothermen Bedingungen werden theoretisch behandelt.