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Modern Genetic Analysis Chapter 14. Regulation of Gene Transcription
Epigenetic Inheritance

We now have a general view of transcriptional regulation that can account for most observations that geneticists have made in the past century. However, there are still some phenomena that beg for explanation. An important set of phenomena, termed epigenetic inheritance, seem to be due to heritable alterations in which the DNA sequence itself is unchanged. Indeed, it is likely that these phenomena constitute another, poorly understood level of gene control. Examples of epigenetic inheritance in which the activity state of a gene depends on its genealogical history are paramutation and parental imprinting.

Paramutation

The phenomenon of paramutation has been described in several plant species, most notably in corn (see Figure 14-36 on the next page). Paramutation was observed at only a few genes in corn. In this phenomenon, certain special but seemingly normal alleles, called paramutable alleles, suffer irreversible changes after having been present in the same genome as another class of special alleles, called paramutagenic alleles. The B-I gene in corn encodes an enzyme in the pathway of anthocyanin pigments in various tissues in corn. Ordinary null b alleles lack these pigments, and these b alleles are completely recessive to B-I. There is a special paramutagenic allele, called B, that confers the ability to make only a small amount of anthocyanin pigment. In crosses of B-I with B homozygotes, the resulting heterozygotes are weakly pigmented, thus appearing indistinguishable from the B homozygous plants. This result would seemingly suggest that B-I is recessive to B. If this simple explanation were true, self-crosses of these heterozygous plants would generate homozygous B-I plants. However, instead, only B alleles appear in the next (and subsequent) generations, indicating that the B-I allele has been paramutated. Somehow, by virtue of having been exposed to the paramutagenic B allele by being in the same genotype for but a single generation, the B-I allele has been permanently crippled in its activity.

Parental Imprinting

Another example of epigenetic inheritance, discovered about 10 years ago in mammals, is parental imprinting. In parental imprinting, certain autosomal genes have seemingly unusual inheritance patterns. For example, the mouse Igf2 gene is expressed in a mouse only if it was inherited from the mouse's father. It is said to be maternally imprinted, inasmuch as a copy of the gene derived from the mother is inactive. Conversely, the mouse H19 gene is expressed only if it was inherited from the mother; H19 is paternally imprinted. The consequence of parental imprinting is that imprinted genes are expressed as if they were hemizygous, even though there are two copies of each of these autosomal genes in each cell. Furthermore, when these genes are examined at the molecular level, no changes in their DNA sequences are observed. Rather, the only changes that are seen are extra methyl (CH3) groups present on certain bases of the DNA of the imprinted genes. Occasional bases of the DNA of most higher organisms are methylated (an exception being Drosophila). These methyl groups are enzymatically added and removed, through the action of special methylases and demethylases. The level of methylation generally correlates with the transcriptional state of a gene: active genes are less methylated than inactive genes. However, whether altered levels of DNA methyl-ation cause epigenetic changes in gene activity or whether altered methylation levels arise as a consequence of such changes is unknown.

What do these examples of epigenetic inheritance have in common? The main thread is that, somehow, a piece of a chromosome can be labeled as different on the basis of its ancestry or on which other genes were in the same genome. For many of these examples, differences in DNA methylation have been associated with differences in gene activity. Nonetheless, the underlying mechanisms and rationales for why such systems evolved still seem rather mysterious.

© 1999 by W. H. Freeman and Company. All rights reserved.