The pattern of methylation of germ cells is established in each sex during gametogenesis. This takes place in two steps.
- First, the existing pattern of methylation is erased in primordial germ cells.
- The pattern that is specific for each sex is imposed during meiosis.
In males, the methylation pattern develops in two stages: first, the methylation pattern that is characteristic of mature sperm is established in the spermatocyte. Further changes in the pattern are made during fertilization. In females, the maternal pattern is imposed during oogenesis.
Systematic changes occur during early embryogenesis. Some sites will continue to be methylated, while some sites will be specifically unmethylated in cells in which a gene is expressed. As specific genes are activated, individual sequence-specific demethylation occurs during somatic cell development.
The specific pattern of methyl groups in germ cells is responsible for the phenomenon of imprinting. The difference in the behaviour between the alleles inherited from each parent is because of imprinting. For example, the allele coding for insulin-like growth factor II (IGF-II) that is inherited from the father is expressed, but the allele inherited from mother is not expressed. This is because the IGF-II gene of oocytes is methylated in its promoter whereas the IGF-II gene of sperm is not methylated so. Thus, the two alleles behave differently in the zygote. This sex-dependent pattern is reversed for some gene.
The consequence of imprinting is that an embryo is hemizygous for any imprinted gene. Thus, in the case of heterozygous cross over where the allele of one parent has an inactivating mutation, the embryo will survive if the wild-type allele comes from the parent in which this allele is active, but will die if the wild-type allele is the imprinted allele. This type of dependence on the directionality of the cross is an example of epigenetic inheritance. In this type of inheritance, the factors other than the sequence of genes themselves influence their effects. Although the paternal and maternal alleles have identical sequences, they have different properties, depending on which parent provided them. These properties are inherited through meiosis and subsequent mitosis. About 1–2 per cent of the mammalian transcriptosome comprise of imprinted genes and these are sometimes clustered.
Prader-Willi syndrome is caused by the deletion of a 20-kb sequence that silences distant genes on either side of the deletion. This prevents the Male from resetting the paternal mode to a chromosome inherited from the mother. Consequently, both genes remain in maternal mode, so that the paternal and maternal alleles are silent in the offspring.