Chromatin marking refers to the enzyme-mediated addition of methyl groups (CH3) to the C (cytosine) bases in regions of DNA where C is followed by G (guanine), i.e., CpG dinucleotides. While (following Jablonka & Lamb 1995) I have grouped chromatin marking as one of three general classes of epigenetic inheritance systems, DNA methylation is generally what is meant in current biomedical literature when the terms epigenetic programming or epigenetic mechanisms are invoked. This is perhaps because the direct chemical modication of DNA would appear to correspond most closely to an etymologically literal interpretation of the word epigenetic. (The semantic link between epigenetic and epigenesis is lost to most researchers and clinicians, who are woefully unschooled in the history of biology.)

The addition of the above methyl groups to the CpG dincleotides within DNA decreases the likelihood of transcriptional activation, probably by inhibiting the association of DNA with proteins that promote transcriptional activity. Recent literature has also indicated an association between the methylation of DNA and the chemical modication of histone proteins which form the structural matrix of chromatin particles. The full signicance of this with respect to epigenetic stability, heritability, and transcriptional repression is yet to be fully revealed. In addition to inuencing transcriptional activation, the methylation state is also found to affect the susceptibility of DNA toward mutation, translocation, and meiotic recombination. Chromatin marking results in context-dependent modulation of genome activity in two distinct ways. During the gametogenesis of mammalian eggs and sperm chromosomes are methylated according to 111 112 Chapter 3

The genes of the mammalian zygote are thus differentially predisposed to activation or inactivation depending on the parent of origin. This phenomenon has been referred to as imprinting and is understood to be responsible for the inability of mammals to reproduce parthenogenically. Imprinting seems to ensure that the availability of both maleand female-derived chromosomes are necessary for successful development. Because the same allele (gene) at the same locus on differentially marked chromosomes can have different phenotypic consequences, the term epialleles has been introduced. Two epialleles can be associated with different phenotypesnot because of differences in their nucleic acid sequence but rather because of differences in their pattern of CpG methylation. For example, Prader-Willi syndrome and Angelman syndrome represent two phenotypically different human genetic diseases, which, as it turns out, are due to the same chromosome 15 deletion. In the cas

· of the former it is associated with the paternal chromosome and in the case of the latter the maternal chromosome. Recent studies on Turners syndrome individuals, females who have only one X chromosome (instead of two), have shown that it makes a differ ence whether the one X was derived from the mother or from the father. Those who derived their X chromosome paternally were reported to have a tendency toward better social skills acquisition. The phenotypic dif ferences between Prader -Willi individuals and Angelman individuals and between different subclasses of patients with Turners are correlated with the possession of different epialleles. Huntingtons disease, which is routinely touted as a paradigm example of the utility of classical genet ics owing to its high rate of penetrance, is in fact notably non Mendelian in a number of ways, including epigenetic based parent of origin affects.