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Saturday, August 16, 2014

Evolution of sexual reproduction

Evolution of sexual reproduction

The evolution of sexual reproduction is described by several competing scientific hypotheses. All sexually reproducing eukaryotic organisms derive from a common ancestor which was a single celled eukaryotic species.[1][2][3] Many protists reproduce sexually, as do multicellular plants, animals, and fungi. There are a few species which have secondarily lost this feature, such as Bdelloidea and some parthenocarpic plants. The evolution of sex contains two related, yet distinct, themes: its origin and its maintenance. However, since the hypotheses for the origins of sex are difficult to test experimentally, most current work has been focused on the maintenance of sexual reproduction.

It seems that a sexual cycle is maintained because it improves the quality of progeny (fitness), despite reducing the overall number of offspring (the two-fold cost of sex). In order for sex to be evolutionarily advantageous, it must be associated with a significant increase in the fitness of offspring. One of the most widely accepted explanations for the advantage of sex lies in the creation of genetic variation. Another explanation is based on two molecular advantages. The first of these is the advantage of recombinational DNA repair (promoted during meiosis because homologous chromosomes pair at that time), while the second is the advantage of complementation (also known as hybrid vigor, heterosis or masking of mutations).

For the advantage due to genetic variation, there are three possible reasons this might happen. First, sexual reproduction can combine the effects of two beneficial mutations in the same individual (i.e. sex aids in the spread of advantageous traits). Also, the necessary mutations do not have to have occurred one after another in a single line of descendants.[4][unreliable source?] Second, sex acts to bring together currently deleterious mutations to create severely unfit individuals that are then eliminated from the population (i.e. sex aids in the removal of deleterious genes). However in organisms containing only one set of chromosomes, deleterious mutations would be eliminated immediately, and therefore removal of harmful mutations is an unlikely benefit for sexual reproduction. Lastly, sex creates new gene combinations that may be more fit than previously existing ones, or may simply lead to reduced competition among relatives.

For the advantage due to DNA repair, there is an immediate large benefit of removing DNA damage by recombinational DNA repair during meiosis, since this removal allows greater survival of progeny with undamaged DNA. The advantage of complementation to each sexual partner is avoidance of the bad effects of their deleterious recessive genes in progeny by the masking effect of normal dominant genes contributed by the other partner.

The classes of hypotheses based on the creation of variation are further broken down below. It is important to realise that any number of these hypotheses may be true in any given species (they are not mutually exclusive), and that different hypotheses may apply in different species. However, a research framework based on creation of variation has yet to be found that allows one to determine whether the reason for sex is universal for all sexual species, and, if not, which mechanisms are acting in each species.

On the other hand, the maintenance of sex based on DNA repair and complementation applies widely to all sexual species.

Historical perspective

Modern philosophical-scientific thinking on the problem can be traced back to Erasmus Darwin in the 18th century; it also features in Aristotle's writings. The thread was later picked up by August Weismann in 1889, who argued that the purpose of sex was to generate genetic variation, as is detailed in the majority of the explanations below. On the other hand, Charles Darwin concluded that the effects of hybrid vigor (complementation) "is amply sufficient to account for the ... genesis of the two sexes." This is consistent with the repair and complementation hypothesis, given below under "Other explanations."

Several explanations have been suggested by biologists including W. D. Hamilton, Alexey Kondrashov, George C. Williams, Harris Bernstein, Carol Bernstein, Michael M. Cox, Frederic A. Hopf and Richard E. Michod to explain how sexual reproduction is maintained in a vast array of different living organisms.


Some questions biologists have attempted to answer include:
  • Why sexual reproduction exists, if in many organisms it has a 50% cost (fitness disadvantage) in relation to asexual reproduction?[5]
  • Did mating types (types of gametes, according to their compatibility) arise as a result of anisogamy (gamete dimorphism), or did mating types evolve before anisogamy?[6]
  • Why do most sexual organisms use a binary mating system?[7] Why do some organisms have gamete dimorphism?

Two-fold cost of sex

This diagram illustrates the twofold cost of sex. If each individual were to contribute to the same number of offspring (two), (a) the sexual population remains the same size each generation, where the (b) asexual population doubles in size each generation.

In most multicellular sexual species, the population consists of two sexes, only one of which is capable of bearing young (with the exception of simultaneous hermaphrodites). In an asexual species, each member of the population is capable of bearing young. This implies that an asexual population has an intrinsic capacity to grow more rapidly with each generation. The cost was first described in mathematical terms by John Maynard Smith.[8] He imagined an asexual mutant arising in a sexual population, half of which comprises males that cannot themselves produce offspring. With female-only offspring, the asexual lineage doubles its representation in the population each generation, all else being equal. Technically this is not a problem of sex but a problem of some multicellular sexually reproducing organisms. There are numerous isogamous species which are sexual and do not have the problem of producing individuals which cannot directly replicate themselves.[9] The principal costs of sex is that males and females must search for each other in order to mate, and sexual selection often favours traits that reduce the survival of individuals.[8]

Evidence that the cost is not insurmountable comes from George C. Williams, who noted the existence of species which are capable of both asexual and sexual reproduction. These species time their sexual reproduction with periods of environmental uncertainty, and reproduce asexually when conditions are more favourable. The important point is that these species are observed to reproduce sexually when they could choose not to, implying that there is a selective advantage to sexual reproduction.[10]

It is widely believed that a disadvantage of sexual reproduction is that a sexually reproducing organism will only be able to pass on 50% of its genes to each offspring. This is a consequence of the fact that gametes from sexually reproducing species are haploid.[11] This, however, conflates sex and reproduction which are two separate events. The "two-fold cost of sex" may more accurately be described as the cost of anisogamy. Not all sexual organisms are anisogamous. There are numerous species which are sexual and do not have this problem because they do not produce males or females.
Yeast, for example, are isogamous sexual organisms which have two mating types which fuse and recombine their haploid genomes. Both sexes reproduce during the haploid and diploid stages of their life cycle and have a 100% chance of passing their genes into their offspring.[9]

The two-fold cost of sex may be compensated for in some species in many ways. Females may eat males after mating, males may be much smaller or rarer, or males may help raise offspring.
Some species avoid the cost of 50% of sexual reproduction, although they have "sex" (in the sense of genetic recombination). In these species (e.g., bacteria and ciliates), "sex" and reproduction occurs separately. [12]

Promotion of genetic variation

August Weismann proposed in 1889[13] an explanation for the evolution of sex, where the advantage of sex is the creation of variation among siblings. It was then subsequently explained in genetics terms by Fisher[14] and Muller[15] and has been recently summarised by Burt in 2000.[16]

George C. Williams gave an example based around the elm tree. In the forest of this example, empty patches between trees can support one individual each. When a patch becomes available because of the death of a tree, other trees' seeds will compete to fill the patch. Since the chance of a seed's success in occupying the patch depends upon its genotype, and a parent cannot anticipate which genotype is most successful, each parent will send many seeds, creating competition between siblings. Natural selection therefore favours parents which can produce a variety of offspring (see lottery principle).

A similar hypothesis is named the tangled bank hypothesis after a passage in Charles Darwin's The Origin of Species:
"It is interesting to contemplate an entangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent on each other in so complex a manner, have all been produced by laws acting around us."
The hypothesis, proposed by Michael Ghiselin in his 1974 book, The Economy of Nature and the Evolution of Sex, suggests that a diverse set of siblings may be able to extract more food from its environment than a clone, because each sibling uses a slightly different niche. One of the main proponents of this hypothesis is Graham Bell of McGill University. The hypothesis has been criticised for failing to explain how asexual species developed sexes. In his book, Evolution and Human Behavior (MIT Press, 2000), John Cartwright comments:
"Although once popular, the tangled bank hypothesis now seems to face many problems, and former adherents are falling away. The theory would predict a greater interest in sex among animals that produce lots of small offspring that compete with each other. In fact, sex is invariably associated with organisms that produce a few large offspring, whereas organisms producing small offspring frequently engage in parthenogenesis [asexual reproduction]. In addition, the evidence from fossils suggests that species go for vast periods of [geologic] time without changing much."
In contrast to the view that sex promotes genetic variation, Heng[17] and Gorelick and Heng[18] reviewed evidence that sex actually acts as a constraint on genetic variation. They consider that sex acts as a coarse filter, weeding out major genetic changes, such as chromosomal rearrangements, but permitting minor variation, such as changes at the nucleotide or gene level (that are often neutral) to pass through the sexual sieve.

Spread of advantageous traits

Novel genotypes

This diagram illustrates how sex might create novel genotypes more rapidly. Two advantageous alleles A and B occur at random. The two alleles are recombined rapidly in a sexual population (top), but in an asexual population (bottom) the two alleles must independently arise because of clonal interference.

Sex could be a method by which novel genotypes are created. Because sex combines genes from two individuals, sexually reproducing populations can more easily combine advantageous genes than can asexual populations. If, in a sexual population, two different advantageous alleles arise at different loci on a chromosome in different members of the population, a chromosome containing the two advantageous alleles can be produced within a few generations by recombination. However, should the same two alleles arise in different members of an asexual population, the only way that one chromosome can develop the other allele is to independently gain the same mutation, which would take much longer. Several studies have addressed whether this model is sufficiently robust to explain the predominance of sexual versus asexual reproduction. These studies, including arguments for and against the model, were summarized by Birdsell and Wills [pp. 73–86][19]

Ronald Fisher also suggested that sex might facilitate the spread of advantageous genes by allowing them to escape their genetic surroundings, if they should arise on a chromosome with deleterious genes.

Supporters of these theories respond to the balance argument that the individuals produced by sexual and asexual reproduction may differ in other respects too – which may influence the persistence of sexuality. For example, in water fleas of the genus Cladocera, sexual offspring form eggs which are better able to survive the winter.

Increased resistance to parasites

One of the most widely discussed theories to explain the persistence of sex is that it is maintained to assist sexual individuals in resisting parasites, also known as the Red Queen's Hypothesis.[11][20][21] and (pp. 113–117) of Birdsell and Wills[19]

When an environment changes, previously neutral or deleterious alleles can become favourable. If the environment changed sufficiently rapidly (i.e. between generations), these changes in the environment can make sex advantageous for the individual. Such rapid changes in environment are caused by the co-evolution between hosts and parasites.

Imagine, for example that there is one gene in parasites with two alleles p and P conferring two types of parasitic ability, and one gene in hosts with two alleles h and H, conferring two types of parasite resistance, such that parasites with allele p can attach themselves to hosts with the allele h, and P to H. Such a situation will lead to cyclic changes in allele frequency - as p increases in frequency, h will be disfavoured.

In reality, there will be several genes involved in the relationship between hosts and parasites. In an asexual population of hosts, offspring will only have the different parasitic resistance if a mutation arises. In a sexual population of hosts, however, offspring will have a new combination of parasitic resistance alleles.

In other words, like Lewis Carroll's Red Queen, sexual hosts are continually adapting in order to stay ahead of their parasites.

Evidence for this explanation for the evolution of sex is provided by comparison of the rate of molecular evolution of genes for kinases and immunoglobulins in the immune system with genes coding other proteins. The genes coding for immune system proteins evolve considerably faster.[22][23]
Further evidence for the Red Queen hypothesis were provided by observing long‐term dynamics and parasite coevolution in a "mixed" (sexual and asexual) population of snails (Potamopyrgus antipodarum). The number of sexuals, the number asexuals, and the rates of parasite infection for both were monitored. It was found that clones that were plentiful at the beginning of the study became more susceptible to parasites over time. As parasite infections increased, the once plentiful clones dwindled dramatically in number. Some clonal types disappeared entirely. Meanwhile, sexual snail populations remained much more stable over time.[24][25]

However, Hanley et al.[26] studied mite infestations of a parthenogenetic gecko species and its two related sexual ancestral species. Contrary to expectation based on the Red Queen hypothesis, they found that the prevalence, abundance and mean intensity of mites in sexual geckos was significantly higher than in asexuals sharing the same habitat.

In 2011, researchers used the microscopic roundworm Caenorhabditis elegans as a host and the pathogenic bacteria Serratia marcescens to generate a host-parasite coevolutionary system in a controlled environment, allowing them to conduct more than 70 evolution experiments testing the Red Queen Hypothesis. They genetically manipulated the mating system of C. elegans, causing populations to mate either sexually, by self-fertilization, or a mixture of both within the same population. Then they exposed those populations to the S. marcescens parasite. It was found that the self-fertilizing populations of C. elegans were rapidly driven extinct by the coevolving parasites while sex allowed populations to keep pace with their parasites, a result consistent with the Red Queen Hypothesis.[27][28]

Critics of the Red Queen hypothesis question whether the constantly changing environment of hosts and parasites is sufficiently common to explain the evolution of sex. In particular, Otto and Nuismer [29] presented results showing that species interactions (e.g. host vs parasite interactions) typically select against sex. They concluded that, although the Red Queen hypothesis favors sex under certain circumstances, it alone does not account for the ubiquity of sex. Otto and Gerstein [30] further stated that “it seems doubtful to us that strong selection per gene is sufficiently commonplace for the Red Queen hypothesis to explain the ubiquity of sex.” Parker [31] reviewed numerous genetic studies on plant disease resistance and failed to uncover a single example consistent with the assumptions of the Red Queen hypothesis.

Deleterious mutation clearance

Mutations can have many different effects upon an organism. It is generally believed that the majority of non-neutral mutations are deleterious, which means that they will cause a decrease in the organism's overall fitness.[32] If a mutation has a deleterious effect, it will then usually be removed from the population by the process of natural selection. Sexual reproduction is believed to be more efficient than asexual reproduction in removing those mutations from the genome.[33]

There are two main hypotheses which explain how sex may act to remove deleterious genes from the genome.

Maintenance of mutation-free individuals

In a finite asexual population under the pressure of deleterious mutations, the random loss of individuals without such mutations is inevitable. This is known as Muller's ratchet. In a sexual population, however, mutation-free genotypes can be restored by recombination of genotypes containing deleterious mutations.

This comparison will only work for a small population - in a large population, random loss of the most fit genotype becomes unlikely even in an asexual population. [see Birdsell and Wills (pp. 86–103)[19] for a review of this topic]

Removal of deleterious genes

Diagram illustrating different relationships between numbers of mutations and fitness. Kondrashov's model requires synergistic epistasis, which is represented by the red line[34][35] - each mutation has a disproproportionately large effect on the organism's fitness.

This hypothesis was proposed by Alexey Kondrashov, and is sometimes known as the deterministic mutation hypothesis.[33] It assumes that the majority of deleterious mutations are only slightly deleterious, and affect the individual such that the introduction of each additional mutation has an increasingly large effect on the fitness of the organism. This relationship between number of mutations and fitness is known as synergistic epistasis.

By way of analogy, think of a car with several minor faults. Each is not sufficient alone to prevent the car from running, but in combination, the faults combine to prevent the car from functioning.
Similarly, an organism may be able to cope with a few defects, but the presence of many mutations could overwhelm its backup mechanisms.

Kondrashov argues that the slightly deleterious nature of mutations means that the population will tend to be composed of individuals with a small number of mutations. Sex will act to recombine these genotypes, creating some individuals with fewer deleterious mutations, and some with more. Because there is a major selective disadvantage to individuals with more mutations, these individuals die out. In essence, sex compartmentalises the deleterious mutations.

There has been much criticism of Kondrashov's theory, since it relies on two key restrictive conditions. The first requires that the rate of deleterious mutation should exceed one per genome per generation in order to provide a substantial advantage for sex. While there is some empirical evidence for it (for example in Drosophila[36] and E. coli[37]), there is also strong evidence against it. Thus, for instance, for the sexual species Saccharomyces cerevisiae (yeast) and Neurospora crassa (fungus), the mutation rate per genome per replication are 0.0027 and 0.0030 respectively. For the nematode worm Caenorhabditis elegans, the mutation rate per effective genome per sexual generation is 0.036.[38] Secondly, there should be strong interactions among loci (synergistic epistasis), a mutation-fitness relation for which there is only limited evidence. Conversely, there is also the same amount of evidence that mutations show no epistasis (purely additive model) or antagonistic interactions (each additional mutation has a disproportionally small effect).

Other explanations

Speed of evolution

Ilan Eshel suggested that sex prevents rapid evolution. He suggests that recombination breaks up favourable gene combinations more often than it creates them, and sex is maintained because it ensures selection is longer-term than in asexual populations - so the population is less affected by short-term changes.[see Eshel and Feldman[39] and reviewed in Birdsell and Wills[19] (pp. 85–86)]. This explanation is not widely accepted, as its assumptions are very restrictive.

It has recently been shown in experiments with Chlamydomonas algae that sex can remove the speed limit[clarification needed] on evolution.[40]

DNA repair and complementation

As discussed in the earlier part of this article, sexual reproduction is conventionally explained as an adaptation for producing genetic variation through allelic recombination. As acknowledged above, however, serious problems with this explanation have led many biologists to conclude that the benefit of sex is a major unsolved problem in evolutionary biology.

An alternative "informational" approach to this problem has led to the view that the two fundamental aspects of sex, genetic recombination and outcrossing, are adaptive responses to the two major sources of "noise" in transmitting genetic information. Genetic noise can occur as either physical damage to the genome (e.g. chemically altered bases of DNA or breaks in the chromosome) or replication errors (mutations)[41][42][43] This alternative view is referred to as the repair and complementation hypothesis, to distinguish it from the traditional variation hypothesis.

The repair and complementation hypothesis assumes that genetic recombination is fundamentally a DNA repair process, and that when it occurs during meiosis it is an adaptation for repairing the genomic DNA which is passed on to progeny. Recombinational repair is the only repair process known which can accurately remove double-strand damages in DNA, and such damages are both common in nature and ordinarily lethal if not repaired. For instance, double-strand breaks in DNA occur about 50 times per cell cycle in human cells [see DNA damage (naturally occurring)].
Recombinational repair is prevalent from the simplest viruses to the most complex multicellular eukaryotes. It is effective against many different types of genomic damage, and in particular is highly efficient at overcoming double-strand damages. Studies of the mechanism of meiotic recombination indicate that meiosis is an adaptation for repairing DNA.[44][45] These considerations form the basis for the first part of the repair and complementation hypothesis.

In some lines of descent from the earliest organisms, the diploid stage of the sexual cycle, which was at first transient, became the predominant stage, because it allowed complementation — the masking of deleterious recessive mutations (i.e. hybrid vigor or heterosis). Outcrossing, the second fundamental aspect of sex, is maintained by the advantage of masking mutations and the disadvantage of inbreeding (mating with a close relative) which allows expression of recessive mutations (commonly observed as inbreeding depression). This is in accord with Charles Darwin,[46] who concluded that the adaptive advantage of sex is hybrid vigor; or as he put it, "the offspring of two individuals, especially if their progenitors have been subjected to very different conditions, have a great advantage in height, weight, constitutional vigor and fertility over the self fertilised offspring from either one of the same parents."

However, outcrossing may be abandoned in favor of parthogenesis or selfing (which retain the advantage of meiotic recombinational repair) under conditions in which the costs of mating are very high. For instance, costs of mating are high when individuals are rare in a geographic area, such as when there has been a forest fire and the individuals entering the burned area are the initial ones to arrive. At such times mates are hard to find, and this favors parthenogenic species.

In the view of the repair and complementation hypothesis, the removal of DNA damage by recombinational repair produces a new, less deleterious form of informational noise, allelic recombination, as a by-product. This lesser informational noise generates genetic variation, viewed by some as the major effect of sex, as discussed in the earlier parts of this article.

Libertine bubble theory

The evolution of sex can alternatively be described as a kind of gene exchange that is independent from reproduction.[47] According to the Thierry Lodé's "libertine bubble theory", sex originated from an archaic gene transfer process among prebiotic bubbles.[48][49] The contact among the pre-biotic bubbles could, through simple food or parasitic reactions, promote the transfer of genetic material from one bubble to another. That interactions between two organisms be in balance appear to be a sufficient condition to make these interactions evolutionarily efficient, i.e. to select bubbles that tolerate these interactions (“libertine” bubbles) through a blind evolutionary process of self-reinforcing gene correlations and compatibility.[50]

The "libertine bubble theory" proposes that meiotic sex evolved in proto-eukaryotes to solve a problem that bacteria did not have,[51] namely a large amount of DNA material, occurring in an archaic step of proto-cell formation and genetic exchanges. So that, rather than providing selective advantages through reproduction, sex could be thought of as a series of separate events which combines step-by-step some very weak benefits of recombination, meiosis, gametogenesis and syngamy.[52] Therefore, current sexual species could be descendants of primitive organisms that practiced more stable exchanges in the long term, while asexual species have emerged, much more recently in evolutionary history, from the conflict of interest resulting from anisogamy.

Origin of sexual reproduction

In the eukaryotic fossil record, sexual reproduction first appeared by 1200 million years ago in the Proterozoic Eon.[53] All sexually reproducing eukaryotic organisms derive from a common ancestor which was a single celled species.[1][45][54][55] Many protists reproduce sexually, as do the multicellular plants, animals, and fungi. There are a few species which have secondarily lost this feature, such as Bdelloidea and some parthenocarpic plants.

Organisms need to replicate their genetic material in an efficient and reliable manner. The necessity to repair genetic damage is one of the leading theories explaining the origin of sexual reproduction. Diploid individuals can repair a damaged section of their DNA via homologous recombination, since there are two copies of the gene in the cell and one copy is presumed to be undamaged. A mutation in a haploid individual, on the other hand, is more likely to become resident, as the DNA repair machinery has no way of knowing what the original undamaged sequence was.[41] The most primitive form of sex may have been one organism with damaged DNA replicating an undamaged strand from a similar organism in order to repair itself.[56]

If, as evidence indicates, sexual reproduction arose very early in eukaryotic evolution, the essential features of meiosis may have already been present in the prokaryotic ancestors of eukaryotes.[54][57] In extant organisms, proteins with central functions in meiosis are similar to key proteins in bacterial transformation. For example, recA recombinase, that catalyses the key functions of DNA homology search and strand exchange in the bacterial sexual process of transformation, has orthologs in eukaryotes that perform similar functions in meiotic recombination (see Wikipedia articles RecA, RAD51 and DMC1). Both bacterial transformation and meiosis in eukaryotic microorganisms are induced by stressful circumstances such as overcrowding, resource depletion and DNA damaging conditions.[50] This suggests that these sexual processes are adaptations for dealing with stress, particularly stress that causes DNA damage. In bacteria, these stresses induce an altered physiologic state, termed competence, that allows active take-up of DNA from a donor bacterium and the integration of this DNA into the recipient genome (see Natural competence) allowing recombinational repair of the recipients’ damaged DNA.[58] If environmental stresses leading to DNA damage were a persistent challenge to the survival of early microorganisms, then selection would likely have been continuous through the prokaryote to eukaryote transition,[52] and adaptative adjustments would have followed a course in which bacterial transformation naturally gave rise to sexual reproduction in eukaryotes.

Sex may also have been present even earlier, in the RNA world that is considered to have preceded DNA cellular life forms.[59] A proposal for the origin of sex in the RNA world was based on the type of sexual interaction that is known to occur in extant single-stranded segmented RNA viruses such as influenza virus, and in extant double-stranded segmented RNA viruses such as reovirus.[60] Exposure to conditions that cause RNA damage could have led to blockage of replication and death of these early RNA life forms. Sex would have allowed re-assortment of segments between two individuals with damaged RNA, permitting undamaged combinations of RNA segments to come together, thus allowing survival. Such a regeneration phenomenon, known as multiplicity reactivation, occurs in influenza virus[61] and reovirus[62]

Another theory is that sexual reproduction originated from selfish parasitic genetic elements that exchange genetic material (that is: copies of their own genome) for their transmission and propagation. In some organisms, sexual reproduction has been shown to enhance the spread of parasitic genetic elements (e.g.: yeast, filamentous fungi).[63] Bacterial conjugation, a form of genetic exchange that some sources describe as sex, is not a form of reproduction, but rather an example of horizontal gene transfer. However, it does support the selfish genetic element theory, as it is propagated through such a "selfish gene", the F-plasmid.[56] Similarly, it has been proposed that sexual reproduction evolved from ancient haloarchaea through a combination of jumping genes, and swapping plasmids.[64]

A third theory is that sex evolved as a form of cannibalism. One primitive organism ate another one, but rather than completely digesting it, some of the 'eaten' organism's DNA was incorporated into the 'eater' organism.[56]

Sex may also be derived from another prokaryotic process. A comprehensive 'origin of sex as vaccination' theory proposes that eukaryan sex-as-syngamy (fusion sex) arose from prokaryan unilateral sex-as-infection when infected hosts began swapping nuclearised genomes containing coevolved, vertically transmitted symbionts that provided protection against horizontal superinfection by more virulent symbionts. Sex-as-meiosis (fission sex) then evolved as a host strategy to uncouple (and thereby emasculate) the acquired symbiont genomes.[65]

Mechanistic origin of sexual reproduction

Though theories positing benefits that lead to the origin of sex are often problematic, several additional theories on the evolution of the mechanisms of sexual reproduction have been proposed.

Viral eukaryogenesis

The viral eukaryogenesis (VE) theory proposes that eukaryotic cells arose from a combination of a lysogenic virus, an archaeon and a bacterium. This model suggests that the nucleus originated when the lysogenic virus incorporated genetic material from the archaeon and the bacterium and took over the role of information storage for the amalgam. The archaeal host transferred much of its functional genome to the virus during the evolution of cytoplasm but retained the function of gene translation and general metabolism. The bacterium transferred most of its functional genome to the virus as it transitioned into a mitochondrion.[66]

For these transformations to lead to the eukaryotic cell cycle, the VE hypothesis specifies a pox-like virus as the lysogenic virus. A pox-like virus is a likely ancestor because of its fundamental similarities with eukaryotic nuclei. These include a double stranded DNA genome, a linear chromosome with short telomeric repeats, a complex membrane bound capsid, the ability to produce capped mRNA, and the ability to export the capped mRNA across the viral membrane into the cytoplasm. The presence of a lysogenic pox-like virus ancestor explains the development of meiotic division, an essential component of sexual reproduction.[67]

Meiotic division in the VE hypothesis arose because of the evolutionary pressures placed on the lysogenic virus as a result of its inability to enter into the lytic cycle. This selective pressure resulted in the development of processes allowing the viruses to spread horizontally throughout the population. The outcome of this selection was cell-to-cell fusion. (This is distinct from the conjugation methods used by bacterial plasmids under evolutionary pressure, with important consequences.)[66] The possibility of this kind of fusion is supported by the presence of fusion proteins in the envelopes of the pox viruses that allow them to fuse with host membranes. These proteins could have been transferred to the cell membrane during viral reproduction, enabling cell-to-cell fusion between the virus host and an uninfected cell. The theory proposes meiosis originated from the fusion between two cells infected with related but different viruses which recognised each other as uninfected. After the fusion of the two cells, incompatibilities between the two viruses result in a meiotic-like cell division.[67]

The two viruses established in the cell would initiate replication in response to signals from the host cell. A mitosis-like cell cycle would proceed until the viral membranes dissolved, at which point linear chromosomes would be bound together with centromeres. The homologous nature of the two viral centromeres would incite the grouping of both sets into tetrads. It is speculated that this grouping may be the origin of crossing over, characteristic of the first division in modern meiosis.
The partitioning apparatus of the mitotic-like cell cycle the cells used to replicate independently would then pull each set of chromosomes to one side of the cell, still bound by centromeres. These centromeres would prevent their replication in subsequent division, resulting in four daughter cells with one copy of one of the two original pox-like viruses. The process resulting from combination of two similar pox viruses within the same host closely mimics meiosis.[67]

Neomuran revolution

An alternative theory, proposed by Thomas Cavalier-Smith, was labeled the Neomuran revolution. The designation "Neomuran revolution" refers to the appearances of the common ancestors of eukaryotes and archaea. Cavalier-Smith proposes that the first neomurans emerged 850 million years ago. Other molecular biologists assume that this group appeared much earlier, but Cavalier-Smith dismisses these claims because they are based on the "theoretically and empirically" unsound model of molecular clocks. Cavalier-Smith's theory of the Neomuran revolution has implications for the evolutionary history of the cellular machinery for recombination and sex. It suggests that this machinery evolved in two distinct bouts separated by a long period of stasis; first the appearance of recombination machinery in a bacterial ancestor which was maintained for 3 Gy,[clarification needed] until the neomuran revolution when the mechanics were adapted to the presence of nucleosomes. The archaeal products of the revolution maintained recombination machinery that was essentially bacterial, whereas the eukaryotic products broke with this bacterial continuity. They introduced cell fusion and ploidy cycles into cell life histories. Cavalier-Smith argues that both bouts of mechanical evolution were motivated by similar selective forces: the need for accurate DNA replication without loss of viability.[68]



From Wikipedia, the free encyclopedia
For the unfolding of an organism or the theory that plants and animals (including humans) develop in this way, see epigenesis (biology). For epigenetics in robotics, see developmental robotics.

Epigenetics is the study of changes in gene expression caused by certain base pairs in DNA, or RNA, being "turned off" or "turned on" again, through chemical reactions. In biology, and specifically genetics, epigenetics is mostly the study of heritable changes that are not caused by changes in the DNA sequence; to a lesser extent, epigenetics also describes the study of stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. Unlike simple genetics based on changes to the DNA sequence (the genotype), the changes in gene expression or cellular phenotype of epigenetics have other causes, thus use of the term epi- (Greek: επί- over, outside of, around) -genetics.[1]

The term also refers to the changes themselves: functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Examples of mechanisms that produce such changes are DNA methylation and histone modification, each of which alters how genes are expressed without altering the underlying DNA sequence. Gene expression can be controlled through the action of repressor proteins that attach to silencer regions of the DNA. These epigenetic changes may last through cell divisions for the duration of the cell's life, and may also last for multiple generations even though they do not involve changes in the underlying DNA sequence of the organism;[2] instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.[3] (There are objections to the use of the term epigenetic to describe chemical modification of histone, since it remains unclear whether or not histone modifications are heritable.)[4]

One example of an epigenetic change in eukaryotic biology is the process of cellular differentiation. During morphogenesis, totipotent stem cells become the various pluripotent cell lines of the embryo, which in turn become fully differentiated cells. In other words, as a single fertilized egg cell – the zygote – continues to divide, the resulting daughter cells change into all the different cell types in an organism, including neurons, muscle cells, epithelium, endothelium of blood vessels, etc., by activating some genes while inhibiting the expression of others.[5]

In 2011, it was demonstrated that the methylation of mRNA plays a critical role in human energy homeostasis. The obesity-associated FTO gene is shown to be able to demethylate N6-methyladenosine in RNA. This discovery launched the subfield of RNA epigenetics.[6][7]

Historical usage of term

Epigenetics (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the words epigenesis and genetics.[8] Epigenesis is an old[9] word that has more recently been used (see preformationism for historical background) to describe the differentiation of cells from their initial totipotent state in embryonic development. When Waddington coined the term the physical nature of genes and their role in heredity was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype; he used the phrase "epigenetic landscape" as a metaphor for biological development. Waddington held that cell fates were established in development much like a marble rolls down to the point of lowest local elevation.[10] Waddington suggested visualising increasing irreversibility of cell type differentiation as ridges rising between the valleys where the marbles (cells) are travelling.[11] In recent times Waddington's notion of the epigenetic landscape has been rigorously formalized in the context of the systems dynamics state approach to the study of cell-fate.[12]

The term "epigenetics" has also been used in developmental psychology to describe psychological development as the result of an ongoing, bi-directional interchange between heredity and the environment.[13] Interactivist ideas of development have been discussed in various forms and under various names throughout the 19th and 20th centuries. An early version was proposed, among the founding statements in embryology, by Karl Ernst von Baer and popularized by Ernst Haeckel. A radical epigenetic view (physiological epigenesis) was developed by Paul Wintrebert. Another variation, probabilistic epigenesis, was presented by Gilbert Gottlieb in 2003.[14] This view encompasses all of the possible developing factors on an organism and how they not only influence the organism and each other but how the organism also influences its own development.

Noted developmental psychologist Erik Erikson used the term epigenetic principle in his book Identity: Youth and Crisis (1968), and used it to encompass the notion that we develop through an unfolding of our personality in predetermined stages, and that our environment and surrounding culture influence how we progress through these stages. This biological unfolding in relation to our socio-cultural settings is done in stages of psychosocial development, where "progress through each stage is in part determined by our success, or lack of success, in all the previous stages."[15][16][17]

Contemporary usage of term

Epigenetic mechanisms

Robin Holliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."[18] Thus epigenetic can be used to describe anything other than DNA sequence that influences the development of an organism.
The more recent usage of the word in science has a stricter definition. It is, as defined by Arthur Riggs and colleagues, "the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence."[19] The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" genetics; thus epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.

The term "epigenetics", however, has been used to describe processes which have not been demonstrated to be heritable such as histone modification; there are therefore attempts to redefine it in broader terms that would avoid the constraints of requiring heritability. For example, Sir Adrian Bird defined epigenetics as "the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states."[2] This definition would be inclusive of transient modifications associated with DNA repair or cell-cycle phases as well as stable changes maintained across multiple cell generations, but exclude others such as templating of membrane architecture and prions unless they impinge on chromosome function. Such redefinitions however are not universally accepted and are still subject to dispute.[4] The NIH "Roadmap Epigenomics Project," ongoing as of 2013, uses the following definition: "Epigenetics is an emerging frontier of science that involves the study of changes in the regulation of gene activity and expression that are not dependent on gene sequence. For purposes of this program, epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. While epigenetics refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome."[20]

In 2008, a consensus definition of the epigenetic trait, "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence", was made at a Cold Spring Harbor meeting.[21]

The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "genome", and refers to the overall epigenetic state of a cell. The phrase "genetic code" has also been adapted—the "epigenetic code" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for in an epigenomic map, a diagrammatic representation of the gene expression, DNA methylation and histone modification status of a particular genomic region. More typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the histone code or DNA methylation patterns.

Molecular basis

Epigenetic changes can modify the activation of certain genes, but not the sequence of DNA.
Additionally, the chromatin proteins associated with DNA may be activated or silenced. This is why the differentiated cells in a multi-cellular organism express only the genes that are necessary for their own activity. Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if gene inactivation occurs in a sperm or egg cell that results in fertilization, then some epigenetic changes can be transferred to the next generation.[22] This raises the question of whether or not epigenetic changes in an organism can alter the basic structure of its DNA (see Evolution, below), a form of Lamarckism.

Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.

DNA damage can also cause epigenetic changes.[23][24][25] DNA damages are very frequent, occurring on average about 10,000 times a day per cell of the human body (see DNA damage (naturally occurring)). These damages are largely repaired, but at the site of a DNA repair, epigenetic changes can remain.[26] In particular, a double strand break in DNA can initiate unprogrammed epigenetic gene silencing both by causing DNA methylation as well as by promoting silencing types of histone modifications (chromatin remodeling) (see next section).[27] In addition, the enzyme Parp1 (poly(ADP)-ribose polymerase) and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of a repair process.[28] This accumulation, in turn, directs recruitment and activation of the chromatin remodeling protein ALC1 that can cause nucleosome remodeling.[29] Nucleosome remodeling has been found to cause, for instance, epigenetic silencing of DNA repair gene MLH1.[19][30] DNA damaging chemicals, such as benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene, cause considerable hypomethylation of DNA, some through the activation of oxidative stress pathways.[31]

Foods are known to alter the epigenetics of rats on different diets.[32] Some food components epigenetically increase the levels of DNA repair enzymes such as MGMT and MLH1[33] and p53.[34][35] Other food components can reduce DNA damage, such as soy isoflavones[36][37] and bilberry anthocyanins.[38]

Epigenetic research uses a wide range of molecular biologic techniques to further our understanding of epigenetic phenomena, including chromatin immunoprecipitation (together with its large-scale variants ChIP-on-chip and ChIP-Seq), fluorescent in situ hybridization, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification (DamID) and bisulfite sequencing. Furthermore, the use of bioinformatic methods is playing an increasing role (computational epigenetics).

Computer simulations and molecular dynamics approaches revealed the atomistic motions associated with the molecular recognition of the histone tail through an allosteric mechanism.[39]


Several types of epigenetic inheritance systems may play a role in what has become known as cell memory,[40] note however that not all of these are universally accepted to be examples of epigenetics.

DNA methylation and chromatin remodeling

Because DNA methylation and chromatin remodeling play such a central role in many types of epigenic inheritance, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodeling is not always inherited, and not all epigenetic inheritance involves chromatin remodeling.[41]
DNA associates with histone proteins to form chromatin.

Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression. One way that genes are regulated is through the remodeling of chromatin.
Chromatin is the complex of DNA and the histone proteins with which it associates. If the way that
DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:
  1. The first way is post translational modification of the amino acids that make up histone proteins. Histone proteins are made up of long chains of amino acids. If the amino acids that are in the chain are changed, the shape of the histone might be modified. DNA is not completely unwound during replication. It is possible, then, that the modified histones may be carried into each new copy of the DNA. Once there, these histones may act as templates, initiating the surrounding new histones to be shaped in the new manner. By altering the shape of the histones around them, these modified histones would ensure that a lineage-specific transcription program is maintained after cell division.
  2. The second way is the addition of methyl groups to the DNA, mostly at CpG sites, to convert cytosine to 5-methylcytosine. 5-Methylcytosine performs much like a regular cytosine, pairing with a guanine in double-stranded DNA. However, some areas of the genome are methylated more heavily than others, and highly methylated areas tend to be less transcriptionally active, through a mechanism not fully understood. Methylation of cytosines can also persist from the germ line of one of the parents into the zygote, marking the chromosome as being inherited from one parent or the other (genetic imprinting).
Mechanisms of heritability of histone state are not well understood; however, much is known about the mechanism of heritability of DNA methylation state during cell division and differentiation.
Heritability of methylation state depends on certain enzymes (such as DNMT1) that have a higher affinity for 5-methylcytosine than for cytosine. If this enzyme reaches a "hemimethylated" portion of DNA (where 5-methylcytosine is in only one of the two DNA strands) the enzyme will methylate the other half.

Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation, ubiquitylation, phosphorylation, sumoylation, ribosylation and citrullination. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally related to transcriptional competence.

One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, thus loosening the DNA from the histone. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA and allow transcription to occur. This is the "cis" model of epigenetic function. In other words, changes to the histone tails have a direct effect on the DNA itself.

Another model of epigenetic function is the "trans" model. In this model, changes to the histone tails act indirectly on the DNA. For example, lysine acetylation may create a binding site for chromatin-modifying enzymes (or transcription machinery as well). This chromatin remodeler can then cause changes to the state of the chromatin. Indeed, a bromodomain — a protein domain that specifically binds acetyl-lysine — is found in many enzymes that help activate transcription, including the SWI/SNF complex. It may be that acetylation acts in this and the previous way to aid in transcriptional activation.

The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein HP1 recruits HP1 to K9 methylated regions. One example that seems to refute this biophysical model for methylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.

It has been shown that the histone lysine methyltransferase (KMT) is responsible for this methylation activity in the pattern of histones H3 & H4. This enzyme utilizes a catalytically active site called the SET domain (Suppressor of variegation, Enhancer of zeste, Trithorax). The SET domain is a 130-amino acid sequence involved in modulating gene activities. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone.[42]

Differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently from acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code, although the idea that histone state can be read linearly as a digital information carrier has been largely debunked. One of the best-understood systems that orchestrates chromatin-based silencing is the SIR protein based silencing of the yeast hidden mating type loci HML and HMR.

DNA methylation frequently occurs in repeated sequences, and helps to suppress the expression and mobility of 'transposable elements':[43] Because 5-methylcytosine can be spontaneously deaminated (replacing nitrogen by oxygen) to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B, the loss of any of which is lethal in mice.[44] DNMT1 is the most abundant methyltransferase in somatic cells,[45] localizes to replication foci,[46] has a 10–40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).[47]

By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after DNA replication, and therefore is often referred to as the ‘maintenance' methyltransferase.[48] DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.[44][49] To emphasize the difference of this molecular mechanism of inheritance from the canonical Watson-Crick base-pairing mechanism of transmission of genetic information, the term 'Epigenetic templating' was introduced.[50] Furthermore, in addition to the maintenance and transmission of methylated DNA states, the same principle could work in the maintenance and transmission of histone modifications and even cytoplasmic (structural) heritable states.[51]

Histones H3 and H4 can also be manipulated through demethylation using histone lysine demethylase (KDM). This recently identified enzyme has a catalytically active site called the Jumonji domain (JmjC). The demethylation occurs when JmjC utilizes multiple cofactors to hydroxylate the methyl group, thereby removing it. JmjC is capable of demethylating mono-, di-, and tri-methylated substrates.[52]

Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Epigenetic control is often associated with alternative covalent modifications of histones.[53] The stability and heritability of states of larger chromosomal regions are suggested to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes.[54] A simplified stochastic model for this type of epigenetics is found here.[55][56]

It has been suggested that chromatin-based transcriptional regulation could be mediated by the effect of small RNAs. Small interfering RNAs can modulate transcriptional gene expression via epigenetic modulation of targeted promoters.[57]

RNA transcripts and their encoded proteins

Sometimes a gene, after being turned on, transcribes a product that (directly or indirectly) maintains the activity of that gene. For example, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. RNA signalling includes differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development.[58] Other epigenetic changes are mediated by the production of different splice forms of RNA, or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effect phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.[59]


MicroRNAs (miRNAs) are members of non-coding RNAs that range in size from 17 to 25 nucleotides. As indicated by Wang et al.,[60] miRNAs regulate a large variety of biological functions in plants and animals. So far, in 2013, about 2000 miRNAs have been discovered in humans and these can be found online in an miRNA database.[61] Each miRNA expressed in a cell may target about 100 to 200 messenger RNAs that it downregulates.[62] Most of the downregulation of mRNAs occurs by causing the decay of the targeted mRNA, while some downregulation occurs at the level of translation into protein.[63]

It appears that about 60% of human protein coding genes are regulated by miRNAs.[64] Many miRNAs are epigenetically regulated. About 50% of miRNA genes are associated with CpG islands,[60] that may be repressed by epigenetic methylation. Transcription from methylated CpG islands is strongly and heritably repressed.[65] Other miRNAs are epigenetically regulated by either histone modifications or by combined DNA methylation and histone modification.[60]


sRNAs are small (50-250 nucleotides), highly structured, non-coding RNA fragments found in bacteria. They control gene expression including virulence genes in pathogens and are viewed as new targets in the fight against drug-resistant bacteria.[66] They play an important role in many biological processes, binding to mRNA and protein targets in prokaryotes. Their phylogenetic analyses, for example through sRNA–mRNA target interactions or protein binding properties, are used to build comprehensive databases.[67] sRNA-gene maps based on their targets in microbial genomes are also constructed.[68]


Prions are infectious forms of proteins. In general, proteins fold into discrete units that perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of infectious disease, prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.[69]

Fungal prions are considered by some to be epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast in 1965 and 1971, are the two best studied of this type of prion.[70][71] Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop codons, an effect that results in suppression of nonsense mutations in other genes.[72] The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to switch into a PSI+ state and express dormant genetic features normally terminated by stop codon mutations.[73][74][75][76]

Structural inheritance systems

In ciliates such as Tetrahymena and Paramecium, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.[77][78][79]

Functions and consequences


Somatic epigenetic inheritance through epigenetic modifications, particularly through DNA methylation and chromatin remodeling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate into many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a "memory". In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, such as in neurogenesis, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodeling, it has been hypothesised that some kinds of plant cells do not use or require "cellular memories", resetting their gene expression patterns using positional information from the environment and surrounding cells to determine their fate.[80]

Epigenetics can be divided into predetermined and probabilistic epigenesis. Predetermined epigenesis is a unidirectional movement from structural development in DNA to the functional maturation of the protein. "Predetermined" here means that development is scripted and predictable. Probabilistic epigenesis on the other hand is a bidirectional structure-function development with experiences and external molding development.[81]


Epigenetics has many and varied potential medical applications as it tends to be multidimensional in nature.[82] Congenital genetic disease is well understood, and it is also clear that epigenetics can play a role, for example, in the case of Angelman syndrome and Prader-Willi syndrome. These are normal genetic diseases caused by gene deletions or inactivation of the genes, but are unusually common because individuals are essentially hemizygous because of genomic imprinting, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.[83]


Epigenetics can impact evolution when epigenetic changes are heritable. A sequestered germ line or Weismann barrier is specific to animals, and epigenetic inheritance is more common in plants and microbes. Eva Jablonka and Marion Lamb have argued that these effects may require enhancements to the standard conceptual framework of the modern evolutionary synthesis.[84][85] Other evolutionary biologists have incorporated epigenetic inheritance into population genetics models[86] or are openly skeptical.[87]

Two important ways in which epigenetic inheritance can be different from traditional genetic inheritance, with important consequences for evolution, are that rates of epimutation can be much faster than rates of mutation[88] and the epimutations are more easily reversible.[89] An epigenetically inherited element such as the PSI+ system can act as a "stop-gap", good enough for short-term adaptation that allows the lineage to survive for long enough for mutation and/or recombination to genetically assimilate the adaptive phenotypic change.[90] The existence of this possibility increases the evolvability of a species.

Current research findings and examples of effects

Epigenetic changes have been observed to occur in response to environmental exposure—for example, mice given some dietary supplements have epigenetic changes affecting expression of the agouti gene, which affects their fur color, weight, and propensity to develop cancer.[91][92]

One study indicates that traumatic experiences can produce fearful memories which are passed to future generations via epigenetics. A study carried out on mice in 2013 found that mice could produce offspring which had an aversion to certain items which had been the source of negative experiences for their ancestors.[93][94] Reports stated that:
For the study, author Brian Dias and co-author Kerry Ressler trained mice, using foot shocks, to fear an odour that resembles cherry blossoms. Later, they tested the extent to which the animals' offspring startled when exposed to the same smell. The younger generation had not even been conceived when their fathers underwent the training, and had never smelt the odour before the experiment. 
The offspring of trained mice were "able to detect and respond to far less amounts of odour... suggesting they are more sensitive" to it, Ressler told AFP of the findings published in the journal Nature Neuroscience. They did not react the same way to other odours, and compared to the offspring of non-trained mice, their reaction to the cherry blossom whiff was about 200 percent stronger, he said. 
The scientists then looked at a gene, M71, that governs the functioning of an odour receptor in the nose that responds specifically to the cherry blossom smell. The gene, inherited through the sperm of trained mice, had undergone no change to its DNA encoding, the team found. But the gene did carry epigenetic marks that could alter its behaviour and cause it to be "expressed more" in descendants, said Dias. This in turn caused a physical change in the brains of the trained mice, their sons and grandsons, who all had a larger glomerulus—a section in the olfactory (smell) unit of the brain.
In the case of humans with different environmental exposures, Fraga et al.[95] studied young monozygotic (identical) twins and older monozygotic twins. They found that although such twins were epigenetically indistinguishable during their early years, older twins had remarkable differences in the overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation. The twin pairs who had spent less of their lifetime together and/or had greater differences in their medical histories were those who showed the largest differences in their levels of 5methylcytosine DNA and acetylation of histones H3 and H4.

More than 100 cases of transgenerational epigenetic inheritance phenomena have been reported in a wide range of organisms, including prokaryotes, plants, and animals.[96] For instance, Mourning Cloak butterflies will change color through hormone changes in response to experimentation of varying temperatures.[97]

Recent analyses have suggested that members of the APOBEC/AID family of cytosine deaminases are capable of simultaneously mediating genetic and epigenetic inheritance using similar molecular mechanisms.[98]

Epigenetic effects in humans

Genomic imprinting and related disorders

Some human disorders are associated with genomic imprinting, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their germ cells.[99] The best-known case of imprinting in human disorders is that of Angelman syndrome and Prader-Willi syndrome—both can be produced by the same genetic mutation, chromosome 15q partial deletion, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.[100] This is due to the presence of genomic imprinting in the region. Beckwith-Wiedemann syndrome is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.

Transgenerational epigenetic observations

In the Överkalix study, Marcus Pembrey and colleagues observed that the paternal (but not maternal) grandsons[101] of Swedish men who were exposed during preadolescence to famine in the 19th century were less likely to die of cardiovascular disease. If food was plentiful, then diabetes mortality in the grandchildren increased, suggesting that this was a transgenerational epigenetic inheritance.[102]
The opposite effect was observed for females—the paternal (but not maternal) granddaughters of women who experienced famine while in the womb (and therefore while their eggs were being formed) lived shorter lives on average.[103]

Cancer and developmental abnormalities

A variety of compounds are considered as epigenetic carcinogens—they result in an increased incidence of tumors, but they do not show mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include diethylstilbestrol, arsenite, hexachlorobenzene, and nickel compounds.

Many teratogens exert specific effects on the fetus by epigenetic mechanisms.[104][105] While epigenetic effects may preserve the effect of a teratogen such as diethylstilbestrol throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence.[106] However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.[107] FDA label information for Vidaza, a formulation of 5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development.[108] In rats, endocrine differences were observed in offspring of males exposed to morphine.[109] In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.[110]
Recent studies have shown that the mixed-lineage leukemia (MLL) gene causes leukemia by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control.[111]

Other investigations have concluded that alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer.[112] Gene expression in the prostate can be modulated by nutrition and lifestyle changes.[113]

In 2008, the National Institutes of Health announced that $190 million had been earmarked for epigenetics research over the next five years. In announcing the funding, government officials noted that epigenetics has the potential to explain mechanisms of aging, human development, and the origins of cancer, heart disease, mental illness, as well as several other conditions. Some investigators, like Randy Jirtle, PhD, of Duke University Medical Center, think epigenetics may ultimately turn out to have a greater role in disease than genetics.[114]

DNA methylation in cancer

DNA methylation is an important regulator of gene transcription and a large body of evidence has demonstrated that aberrant DNA methylation is associated with unscheduled gene silencing, and the genes with high levels of 5-methylcytosine in their promoter region are transcriptionally silent. DNA methylation is essential during embryonic development, and in somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with a high fidelity. Aberrant DNA methylation patterns have been associated with a large number of human malignancies and found in two distinct forms: hypermethylation and hypomethylation compared to normal tissue.
Hypermethylation is one of the major epigenetic modifications that repress transcription via promoter region of tumour suppressor genes. Hypermethylation typically occurs at CpG islands in the promoter region and is associated with gene inactivation. Global hypomethylation has also been implicated in the development and progression of cancer through different mechanisms.[115]

DNA repair epigenetics in cancer

Germ line (familial) mutations have been identified in 34 different DNA repair genes that cause a high risk of cancer, including, for example BRCA1 and ATM. These are listed in the article DNA repair-deficiency disorder. However, cancers caused by such germ line mutations make up only a very small proportion of cancers. For instance, germ line mutations cause only 2% to 5% of colon cancer cases.[116]

Epigenetic reductions in expression of DNA repair genes, however, are very frequent in sporadic (non-germ line) cancers, as shown among some representative cancers in the table in this section, while mutations in DNA repair genes in sporadic cancer are very rare.[117]

Epigenetic changes in DNA repair genes in sporadic cancers
CancerGeneEpigenetic changeFrequencyRef.
BreastBRCA1CpG island methylation13%1
WRNCpG island methylation17%2
OvarianWRNCpG island methylation36%3
BRCA1CpG island methylation5%-30%1,11,12
FANCFCpG island methylation21%11
RAD51CCpG island methylation3%11
ColorectalMGMTCpG island methylation40%-90%4-8
WRNCpG island methylation38%2
MLH1CpG island methylation2%-65%2,5,9
MSH2CpG island methylation13%6
ERCC1epigenetic type unknown100%10
Xpfepigenetic type unknown55%10
MGMTCpG island methylation35%-57%13-16
MLH1CpG island methylation27%-33%17,19,20
NEIL1CpG island methylation62%13
FANCBCpG island methylation46%13
MSH4CpG island methylation46%13
ATMCpG island methylation25%18

References in the table are given here: 1,[118] 2,[119] 3,[120] 4,[121] 5,[122] 6,[123] 7,[124] 8,[125] 9,[126] 10,[127] 11,[128] 12,[129] 13,[130] 14,[131] 15,[132] 16,[133] 17,[134] 18,[135] 19,[136] 20[137]

Deficiencies in expression of DNA repair genes cause increased mutation rates. Mutations rates increase in mice defective for mismatch DNA repair genes PMS2, MLH1, MSH2, MSH3 or MSH6[138][139] or for DNA repair gene BRCA2,[140] while chromosomal rearrangements and aneuploidy are noted to increase in humans defective in DNA repair gene BLM.[141] Thus, deficiency in DNA repair causes genome instability and this genome instability is likely the main underlying cause of the genetic alterations leading to cancer. In fact, as indicated by Nowak et al.[142] through a mathematical calculation, the first event in many sporadic neoplasias is a heritable alteration that affects genetic instability, and we note that epigenetic defects in DNA repair are somatically heritable.

Variant histones H2A in cancer

The histone variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many nuclear processes by altering chromatin structure. One of the key H2A variants, H2A.X, marks DNA damage, facilitating the recruitment of DNA repair proteins to restore genomic integrity. Another variant, H2A.Z, plays an important role in both gene activation and repression. A high level of H2A.Z expression is ubiquitously detected in many cancers and is significantly associated with cellular proliferation and genomic instability.[115] Histone variant macroH2A1 is important in the pathogenesis of many types of cancers, for instance in hepatocellular carcinoma.[143]

Cancer treatment

Current research has shown that epigenetic pharmaceuticals could be a putative replacement or adjuvant therapy for currently accepted treatment methods such as radiation and chemotherapy, or could enhance the effects of these current treatments.[144] It has been shown that the epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones directly affects the formation and progression of cancer.[145] Epigenetics also has the factor of reversibility, a characteristic that other cancer treatments do not offer.[112]

Drug development has focused mainly on histone acetyltransferase (HAT) and histone deacetylase (HDAC), and has included the introduction to the market of the new pharmaceutical vorinostat, an HDAC inhibitor.[146] HDAC has been shown to play an integral role in the progression of oral squamous cancer.[145]

Current front-runner candidates for new drug targets are histone lysine methyltransferases (KMT) and protein arginine methyltransferases (PRMT).[147]

Twin studies

Recent studies involving both dizygotic and monozygotic twins have produced some evidence of epigenetic influence in humans.[148][149][150]

Direct comparisons between identical twins constitute the ideal experimental model for testing environmental epigenetics, because DNA sequence differences that would be abundant in a singleton-based study do not interfere with the analysis. Research has shown that a difference in the environment can produce long-term epigenetic effects, and different developmental monozygotic twin subtypes may be different with respect to their susceptibility to be discordant from an epigenetic point of view.[151]

One of the first high-throughput studies of epigenetic differences between monozygotic twins focused in comparing global and locus-specific changes in DNA methylation and histone modifications in a sample of 40 monozygotic twin pairs.[152] In this case, only healthy twin pairs were studied, but a wide range of ages was represented, between 3 and 74 years. One of the major conclusions from this study was that there is an age-dependent accumulation of epigenetic differences between the two siblings of twin pairs. This accumulation suggests the existence of epigenetic “drift”.
A more recent study, where 114 monozygotic twins and 80 dizygotic twins were analyzed for the DNA methylation status of around 6000 unique genomic regions, concluded that epigenetic similarity at the time of blastocyst splitting may also contribute to phenotypic similarities in monozygotic co-twins. This supports the notion that microenvironment at early stages of embryonic development can be quite important for the establishment of epigenetic marks.[153]

Epigenetics in microorganisms

Escherichia coli bacteria

Bacteria make widespread use of postreplicative DNA methylation for the epigenetic control of DNA-protein interactions. Bacteria make use of DNA adenine methylation (rather than DNA cytosine methylation) as an epigenetic signal. DNA adenine methylation is important in bacteria virulence in organisms such as Escherichia coli, Salmonella, Vibrio, Yersinia, Haemophilus, and Brucella. In Alphaproteobacteria, methylation of adenine regulates the cell cycle and couples gene transcription to DNA replication. In Gammaproteobacteria, adenine methylation provides signals for DNA replication, chromosome segregation, mismatch repair, packaging of bacteriophage, transposase activity and regulation of gene expression.[154][155]

The filamentous fungus Neurospora crassa is a prominent model system for understanding the control and function of cytosine methylation. In this organisms, DNA methylation is associated with relics of a genome defense system called RIP (repeat-induced point mutation) and silences gene expression by inhibiting transcription elongation.[156]

The yeast prion PSI is generated by a conformational change of a translation termination factor, which is then inherited by daughter cells. This can provide a survival advantage under adverse conditions. This is an example of epigenetic regulation enabling unicellular organisms to respond rapidly to environmental stress. Prions can be viewed as epigenetic agents capable of inducing a phenotypic change without modification of the genome.[155]

Direct detection of epigenetic marks in microorganisms is possible with single molecule real time sequencing, in which polymerase sensitivity allows for measuring methylation and other modifications as a DNA molecule is being sequenced.[157] Several projects have demonstrated the ability to collect genome-wide epigenetic data in bacteria.[158][159][160][161]