Figure 7–46 The CG islands surrounding the promoter in three mammalian housekeeping genes. the yellow boxes show the extent of each island. As for most genes in mammals, the exons (dark red) are very short relative to the introns (light red). (Adapted from A.p. Bird, Trends Genet. 3:342–347, 1987. with permission from elsevier.) methylation of most CG sequences in germ line many millions of years of evolution mRNA mRNA BOTH PARENTS EXPRESS THE SAME ALLELE OF GENE Aimprinted allele of gene Aexpressed allele of gene Asomatic cell somatic cell REMOVAL OF IMPRINTING IN GERM CELLS, FOLLOWED BY MEIOSIS FEMALE IMPRINT ESTABLISHED MALE IMPRINT ESTABLISHED EGGS SPERM OFFSPRING DIFFER IN THE ALLELE OF GENE ATHAT IS EXPRESSED mRNA mRNA chromosome inherited from father
Figure 7–48 Imprinting in the mouse. the top portion of the figure shows a pair of homologous chromosomes in the somatic cells of two adult mice, one male and one female. in this example, both mice have inherited the top homolog from their father and the bottom homolog from their mother, and the paternal copy of a gene subject to imprinting (indicated in orange) is methylated, preventing its expression. the maternally derived copy of the same gene (yellow) is expressed. the remainder of the figure shows the outcome of a cross between these two mice. During germ-cell formation, but before meiosis, the imprints are erased and then, much later in germ-cell development, they are reimposed in a sex-specific pattern (middle portion of figure). in eggs produced from the female, neither allele of the A gene is methylated. in sperm from the male, both alleles of gene A are methylated. Shown at the bottom of the figure are two of the possible imprinting patterns inherited by the progeny mice; the mouse on the left has the same imprinting pattern as each of the parents, whereas the mouse on the right has the opposite pattern. if the two alleles of gene A are distinct, these different imprinting patterns can cause phenotypic differences in the progeny mice, even though they carry exactly the same DnA sequences of the two A gene alleles. imprinting provides an important exception to classical genetic behavior, and several hundred mouse genes are thought to be affected in this way. however, the majority of mouse genes are not imprinted, and therefore the rules of Mendelian inheritance apply to most of the mouse genome.
In the early embryo, genes subject to imprinting are marked by methylation according to whether they were derived from a sperm or an egg chromosome. In this way, DNA methylation is used as a mark to distinguish two copies of a gene that may be otherwise identical (Figure 7–48). Because imprinted genes are somehow protected from the wave of demethylation that takes place shortly after fertilization (see pp. 404–405), this mark enables somatic cells to “remember” the parental origin of each of the two copies of the gene and to regulate their expression accordingly. In most cases, the methyl imprint silences nearby gene expression. In some cases, however, it can activate expression of a gene. In the case of Igf 2, for example, methylation of an insulator element on the paternally derived chromosome blocks its function and allows distant cis-regulatory sequences to activate transcription of the Igf 2 gene. On the maternally derived chromosome, the insulator is not methylated and the Igf 2 gene is therefore not transcribed (Figure 7–49A).