Epigenetic Inheritance Research Paper

1. Definitions And Historical Background

‘Epigenetics,’ ‘epigenetic,’ and ‘epigenetic inheritance’ are relatively new terms, derived from the much older term ‘epigenesis.’ According to the ancient and influential theory of epigenesis, development involves qualitative changes in organization, with the parts of the adult animal forming gradually and sequentially from an ovum that is amorphous and unorganized. In the rival theory of preformation, which was popular in the late seventeenth and eighteenth centuries, development was assumed to entail the growth or unfolding of parts that already exist in miniature in the egg (Pinto-Correia 1997). Since the beginning of the nineteenth century, it has been accepted generally that development is through epigenesis, although a subtle form of preformation was introduced towards the end of the nineteenth century, when it was recognized that although developmental changes are qualitative, they are controlled by preformed determinants whose transmission and effects ensure hereditary continuity. For several decades after the rediscovery of Mendel’s laws in 1900, the new science of genetics was concerned with the way these determinants, the genes, are transmitted from one generation to the next; their role in development received little attention until the second half of the twentieth century.

The introduction of the term ‘epigenetics’ by the British embryologist Conrad Waddington in 1947 (see Waddington 1975), reflected a growing interest in the relationship between genes and development, an interest which increased as the molecular nature of the gene was unraveled. Waddington coined the term epigenetics for the study of the causal mechanisms of development; the adjective ‘epigenetic’ is applied to the processes through which the genetic information in a fertilized egg is expressed and used in the production of the adult form, the visible phenotype. As the study of genetics and development progressed, it became clear that different cell types usually have identical genotypes, but express different sets of genes. (One important exception proved to be the cells of the immune system, where epigenetic changes involve alterations in DNA sequences.) Finding out which genes are expressed and what controls when and where they are expressed became the key to understanding the functional and structural specialization of cells and tissues during development. It also became clear that once a cell is committed to a particular form or function, that state is often transmitted to daughter cells, even though the stimulus that originally induced its development is no longer present. Thus, once a cell is committed to becoming a liver cell, it breeds true and by division gives rise to a lineage of liver cells; similarly, skin cells will give rise to skin cells, and kidney cells to kidney cells. This stable transmission of the alternative phenotypes of cells with the same genotype became known as ‘cellular heredity,’ ‘cell heredity,’ or ‘epigenetic inheritance.’

Interest in the transmission of cellular states began to grow during the mid-1970s, as the molecular mechanisms and systems that underlie the control of gene expression started to be unraveled (Holliday 1990). Gradually, it was recognized that epigenetic information is transmitted not only between generations of cells in the cell lineages within an individual, but also between generations of individuals. The concept of epigenetic inheritance was therefore extended and now has both a narrow and a broad meaning. The narrow meaning limits it to cell memory in lineages within an organism, whereas the broad meaning includes the transmission of epigenetic information between any reproducing entities—cells, individuals, and even groups of individuals. This research paper focuses first on epigenetic inheritance in cell lines, and then discusses the consequences of the transmission of epigenetic variations between generations of individuals.

2. Mechanisms Of Transmission

The systems that underlie epigenetic inheritance and enable the phenotypic expression of the genetic information in a cell to be transmitted to the next generation have been called epigenetic inheritance systems (EISs). Three broad types have been characterized (Jablonka and Lamb 1995): steady-state systems, structural systems, and chromatin-marking systems.

2.1 Steady-State Systems

These systems lead to patterns of gene activity persisting in cell lineages through the operation of regulatory feedback loops. The simplest example is that of a gene that controls its own transcription through positive feedback. When the activity of such a gene is induced by an external stimulus, some of the gene’s product bind to its own control region. This binding leads to the continued activity of the gene. In this way, gene activity that initially depended on the presence of an external inducer is maintained by self-regulation—by the continuous induction of the gene by its own product. If the concentration of the gene-product is high enough and cell division is more or less equal, the gene’s active state will be inherited, because the regulatory gene-product will be transmitted to daughter cells as an automatic consequence of cell division. This type of self-regulation means that cells with the same DNA sequence can have different but stable patterns of cell-heritable activities, which reflect their developmental history. Many examples of such self-perpetuating regulatory loops have been found in a variety of animals and plants. In most cases the systems are more complicated than the one described, with several genes and gene products involved in the feedback loop, but the principle is the same.

2.2 Structural Inheritance Systems

Cells contain many complex three-dimensional structures whose assembly seems to depend on the presence of existing similar structures. In ways that are not understood, old structures are used as templates for the production of the new structures that are required for cell growth and multiplication. The best-known examples of this type of inheritance come from the study of single-celled organisms, such as the ciliated protozoan Paramecium. Genetically identical paramecia can show heritable differences in the patterns of ciliary rows on their cell surface, and experimentally altered patterns can be transmitted to daughter cells for hundreds of cell generations (Grimes and Aufderheide 1991). Although this type of inheritance is particularly conspicuous and stable in ciliated protozoa, structural inheritance is probably universal, since all cells rely on pre-existing structures when they produce new ones. The self-templating properties of some three-dimensional protein complexes is believed to underlie the transmission of diseases such as mad cow disease (BSE—bovine spongiform encephalopathy), where aberrant prion proteins seem to induce function-affecting changes in the conformation of normal prion proteins (Prusiner 1998).

2.3 Chromatin-Marking Systems

Chromatin-marking systems are currently the bestunderstood EISs. Chromatin is the complex of DNA, proteins, and other macromolecules that make up chromosomes, and chromatin marks are the binding proteins or chemical groups that influence the activity of the DNA to which they are attached (Jablonka and Lamb 1995). The epigenetic information contained in chromatin marks is carried from one cell generation to the next with DNA. A good example of an inherited chromatin mark is a gene’s methylation pattern. In many plants and animals, some of the cytosines in DNA are methylated. Although cytosine (C) is one of the four bases whose sequence encodes genetic information, the presence of a methyl group (Cm) does not affect its coding properties. However, cytosine methylation within or around a gene often determines whether or not the gene is active, and how easy it is to activate: usually low levels of methylation are associated with potential activity, while high levels are associated with inactivity.

Changes in methylation patterns occur during growth and development, so the same DNA sequence can have several different methylation patterns, each reflecting a different functional state, and each inherited stably through many cell divisions. The mechanism of transmission in this case is well understood, and depends on the way a cytosine in one strand of the DNA double helix is always paired with a guanine base (G) in the other. Methylation occurs symmetrically on the two strands, usually in CG doublets in which CmG is paired with GCm. Following DNA replication, in which the two parental DNA strands separate and are used as templates for building complementary daughter strands, the previously methylated sites remain methylated on the parental strand, but are unmethylated on the newly synthesized daughter strand. However, special enzymes recognize the asymmetrical, half-methylated sites, and preferentially methylate the cytosines of the new strand (Holliday 1990, Jablonka and Lamb 1995). Thus, because of the mirror symmetry of CG sites and the semiconservative nature of DNA replication, the specific pattern of methylation of a region of DNA is reproduced at every cell division.

Methylation patterns are not the only type of heritable chromatin marks. Chromatin marks involving DNA-associated proteins that affect the maintenance of gene activity can also be transmitted in cell lineages. The way these protein marks are replicated is beginning to be understood, and plausible models for the reproduction of nucleoprotein complexes which ensure that daughter cells inherit the state of activity of parental cells have been proposed (Lyko and Paro 1999).

3. Genetic And Epigenetic Inheritance Compared

The properties of the genetic and epigenetic inheritance systems overlap, but certain features are more characteristic of one than the other. Most stem from the fact that epigenetic systems are concurrently inheritance systems and response systems, whereas, with a few exceptions, information transmitted by the genetic system is not altered in response to external factors. The response function of the epigenetic system means that, unlike genetic variations, the origin of heritable epigenetic variations is not random—they are often induced by specific developmental or environmental changes. Frequently induced epigenetic variations are adaptive, although they need not be so. Whereas changes in the DNA sequence of a gene are rare, and reversion to the original sequence is even rarer, the response function of EISs means that, under some circumstances, the rate of change between epigenetic variants is very high and there may be coordinated changes in the epigenetic marks of several genes. However, although some inherited epigenetic changes differ from typical genetic changes in being nonrandom, frequent, reversible and adaptive, others resemble genetic mutations in that they are rare, random, nonadaptive, and unlikely to revert. No single criterion or set of criteria can be used to distinguish between the properties of the genetic and epigenetic systems.

4. Transgenerational Epigenetic Inheritance

Studies of the mechanisms of epigenetic inheritance were initially focused on cells in the cell lineages of multicellular organisms, but subsequently it was found that single-celled organisms such as bacteria and yeasts also transmit epigenetic variations to their descendants (Grandjean et al. 1998, Klar 1998). It was also realized that multicellular organisms sometimes transmit epigenetic variations between generations. Transgenerational transmission was recognized in two ways: either as genomic imprinting, in which a gene’s expression is influenced by the sex of the parent that transmitted it, or as the long-term inheritance of acquired variations over several generations.

4.1 Genomic Imprinting

During the formation of sperm and eggs, chromatin is modified. The way that it is modified in the male and female germ lines differs, so, at the beginning of embryonic development, the genes transmitted by the two parents are in different epigenetic states. If these differences persist during development and have phenotypic effects, the genes are said to be ‘imprinted.’ Imprints may involve differences in methylation patterns or in other types of chromatin marks. The effect of genomic imprinting is that the expression of some genes depends on the sex of the parent from which they were inherited. Normally imprints are erased and replaced in the germ line, so when a gene that was inherited from one sex is transmitted to the next generation through the opposite sex, the imprints are reversed. Imprinting seems to be widespread in both plants and animals, but currently it is being studied most intensively in mammals. It is known to be necessary for normal development and to affect the severity of expression of some genetic diseases, such as Prader-Willi and Angelman syndromes (Reik and Surani 1997).

4.2 Long-Term Transmission

Most cases of the long-term transmission of epigenetic variations have been found in plants, which often have vegetative as well as sexual reproduction, but it has also been found in a variety of animals (Jablonka and Lamb 1995, 1998). Remarkably, the first morphological flower-mutant ever to be characterized, a peloric form of toadflax described by Linnaeus over 250 years ago, has turned out to be an epimutation, not a mutation; the difference between the normal and peloric forms is due to a difference in the gene’s state of methylation, not in its DNA sequence (Cubas et al. 1999). Similarly, a well-studied case of variation in the coat color of the mouse has been shown to be the result of heritable epigenetic modifications, rather than of genetic or environmental effects (Morgan et al. 1999). Findings like these suggest that the long-term transmission of epigenetic variations may be far more common than was at one time thought likely.

5. Implications

Recognizing the ubiquity and importance of epigenetic inheritance has major implications for medicine and agriculture, as well as for the way that we think about heredity and evolution. Since the practical implications were the first to be generally recognized, they will be considered first.

5.1 Practical Implications

In recent years it has become clear that the variations transmitted through EISs can affect health and disease. First, many cancers involve cell-heritable epigenetic modifications, such as alterations in methylation patterns and other aspects of chromatin organization (Zingg and Jones 1997). Second, some hereditary diseases are caused by mutated imprinted genes, which show peculiar but characteristic patterns of inheritance (Reik and Surani 1997). In some cases the inherited conditions may not be caused by mutations, but by epimutations. Third, prionic diseases such as BSE and kuru seem to be the consequence of transmissible infectious protein complexes and the mechanism of reproduction and reconstruction of the infectious agents seems to involve structural, threedimensional templating (Prusiner 1998). Fourth, some environmentally induced diseases, such as those caused by starvation or by taking thalidomide, seem to have long-term transgenerational effects (Holliday 1998). Epidemiological research programs and medical practice will have to accommodate information like this, and develop ways of recognizing, avoiding, and curing the diseases caused by heritable epigenetic changes.

In agriculture, the importance of epigenetic inheritance is already acknowledged widely, because it has caused many problems in genetic engineering aimed at crop improvement. Commonly, newly inserted foreign genes are heritably silenced through extensive DNA methylation, so ways of circumventing this problem have had to be developed. On the positive side, since some epigenetic variations can be induced by environmental changes, it may be possible to develop agricultural practices that exploit these inducing effects and thus develop epigenetically ‘engineered’ improved crops.

5.2 A Broader Concept Of Inheritance And Evolution

Including EISs and other non-DNA inheritance systems (such as the transmission of information through behavior or language) produces a much richer and more general concept of heredity. Heredity does not depend solely on genes, and not only genotypes are inherited. Even at the strictly cellular level, the production and transmission of inherited variations involves several different mechanisms. With some of these, such as those underlying structural inheritance and steady-state systems, there is no real equivalent of the phenotype–genotype distinction, because the reconstruction of the phenotype is an integral part of the transmission mechanism.

With all EISs, the inheritance of acquired (induced) variation is common. Consequently, there is a ‘Lamarckian’ component in evolution, with the environment being both an inducer and a selector of epigenetic variations. The gradual broadening of the concept of heredity, and recognition that natural selection acts on several different types of heritable variation, which began in the last decades of the twentieth century, has challenged the widely accepted gene-centered neo-Darwinian version of Darwinism. A more comprehensive and more powerful Darwinian evolutionary theory is now being constructed, one that incorporates multiple and interacting inheritance systems.

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