Selfish genetic elements (historically also referred to as selfish genes, ultra-selfish genes, selfish DNA, parasitic DNA, genomic outlaws) are genetic segments that can enhance their own transmission at the expense of other genes in the genome, even if this has no or a negative effect on organismal fitness. [ 1 – 6 ] Genomes have traditionally been viewed as cohesive units, with genes acting together to improve the fitness of the organism. However, when genes have some control over their own transmission, the rules can change, and so just like all social groups, genomes are vulnerable to selfish behaviour by their parts . Early observations of selfish genetic elements were made almost a century ago, but the topic did not get widespread attention until several decades later. Inspired by the gene-centred views of evolution popularized by George Williams [ 7 ] and Richard Dawkins ,[ 8 ] two papers were published back-to-back in Nature in 1980—by Leslie Orgel and Francis Crick [ 9 ] and Ford Doolittle and Carmen Sapienza[ 10 ] respectively—introducing the concept of selfish genetic elements (at the time called “selfish DNA”) to the wider scientific community. Both papers emphasized that genes can spread in a population regardless of their effect on organismal fitness as long as they have a transmission advantage. Selfish genetic elements have now been described in most groups of organisms, and they demonstrate a remarkable diversity in the ways by which they promote their own transmission.[ 11 ] Though long dismissed as genetic curiosities, with little relevance for evolution, they are now recognized to affect a wide swath of biological processes, ranging from genome size and architecture to speciation.[ 12 ]

Funding: This research was supported by a fellowship from the Sweden-American Foundation to JAÅ and by funds from NIH R01 GM116113 to R. Wing, M. Long and AGC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2018 Ågren, Clark. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

If the Selfish DNA papers marked the beginning of the serious study of selfish genetic elements, the subsequent decades have seen an explosion in theoretical advances and empirical discoveries. Leda Cosmides and John Tooby wrote a landmark review about the conflict between maternally inherited cytoplasmic genes and biparentally inherited nuclear genes.[ 28 ] The paper also provided a comprehensive introduction to the logic of genomic conflicts, foreshadowing many themes that would later be subject of much research. Then in 1988, John H. Werren and colleagues wrote the first major empirical review of the topic.[ 1 ] This paper achieved three things. First, it coined the term selfish genetic element, putting an end to a sometimes confusingly diverse terminology (selfish genes, ultra-selfish genes, selfish DNA, parasitic DNA, genomic outlaws). Second, it formally defined the concept of selfish genetic elements. Finally, it was the first paper to bring together all different kinds of selfish genetic elements known at the time (genomic imprinting, for example, was not covered). In the late 1980s, most molecular biologists considered selfish genetic element to be the exception, and that genomes were best thought of as highly integrated networks with a coherent effect on organismal fitness. In 2006, when Austin Burt and Robert Trivers published the first book-length treatment of the topic, a comprehensive piece that remains the go-to source on the topic, the tide was changing. While their role in evolution long remained controversial, in a recent review, a century after their first discovery, William R. Rice concluded that “nothing in genetics makes sense except in the light of genomic conflicts”.[ 29 ]

In 1980, two high profile papers published back-to-back in Nature by Leslie Orgel and Francis Crick , and Ford Doolittle and Carmen Sapienza respectively, brought the study of selfish genetic elements to the centre of biological debate.[ 9 – 10 ] The papers took their starting point in the contemporary debate of the so-called C-value paradox (see below), the lack of correlation between genome size and perceived complexity of a species. Both papers attempted to counter the prevailing view of the time that the presence of differential amounts of non-coding DNA and transposable elements is best explained from the perspective of individual fitness, described as the”phenotypic paradigm” by Doolittle and Sapienza. Instead, the authors argued that much of the genetic material in eukaryotic genomes persists, not because of its phenotypic effects, but can be understood from a gene’s-eye view, without invoking individual-level explanations. The two papers led to a series of exchanges in Nature.[ 24 – 27 ]

”If we allow ourselves the license of talking about genes as if they had conscious aims, always reassuring ourselves that we could translate our sloppy language back into respectable terms if we wanted to, we can ask the question, what is a single selfish gene trying to do?”—Richard Dawkins The Selfish Gene [ 8 ] p. 88

The empirical study of selfish genetic elements benefited greatly from the emergence of the so-called gene’s-eye view of evolution in the nineteen sixties and seventies.[ 19 ] In contrast with Darwin’s original formulation of the theory of evolution by natural selection that focused on individual organisms, the gene’s-eye view takes the gene to be the central unit of selection in evolution.[ 20 ] It conceives evolution by natural selection as a process involving two separate entities: replicators (entities that produce faithful copies of themselves, usually genes) and vehicles (or interactors; entities that interact with the ecological environment, usually organisms).[ 21 – 23 ] Since organisms are temporary occurrences, present in one generation and gone in the next, genes (replicators) are the only entity faithfully transmitted from parent to offspring. Viewing evolution as a struggle between competing replicators made it easier to recognize that not all genes in an organism would share the same evolutionary fate.

Around the same time, several other examples of selfish genetic elements were reported. For example, the American maize geneticist Marcus Rhoades described how chromosomal knobs led to female meiotic drive in maize.[ 15 ] Similarly, this was also when it was first suggested that a conflict between uniparentally inherited mitochondrial genes and biparentally inherited nuclear genes could lead to cytoplasmic male sterility in plants.[ 16 ] Then, in the early 1950s, Barbara McClintock published a series of papers describing the existence of transposable elements, which are now recognized to be among the most successful selfish genetic elements. [ 17 , 18 ] The discovery of transposable elements led to her being awarded the Nobel Prize in Medicine or Physiology in 1983.

”In many cases these chromosomes have no useful function at all to the species carrying them, but that they often lead an exclusively parasitic existence … [B chromosomes] need not be useful for the plants. They need only be useful to themselves.”—Gunnar Östergren[ 14 ]

Observations of what we now refer to as selfish genetic elements go back to the early days in the history of genetics . Already in 1928, Russian geneticist Sergey Gershenson reported the discovery of a driving X chromosome in Drosophila obscura.[ 13 ] Crucially, he noted that the resulting female-biased sex ratio may drive a population extinct (see Consequences to the Host of Selfish Genetic Elements : Species extinction below). The earliest clear statement of how chromosomes may spread in a population not because of their positive fitness effects on the individual organism, but because of their own”parasitic” nature came from the Swedish botanist and cytogeneticist Gunnar Östergren in 1945.[ 14 ] Discussing B chromosomes in plants he wrote:

The presence of selfish genetic elements can be difficult to detect in natural populations. Instead, their phenotypic consequences often become apparent in hybrids. The first reasons for this is that some selfish genetic elements rapidly sweep to fixation, and the phenotypic effects will therefore not be segregating the in the population. Hybridization events, however, will produce offspring with and without the selfish genetic elements and so reveal their presence. The second reason is that host genomes have evolved mechanisms to suppress the activity of the selfish genetic elements, for example the small RNA administered silencing of transposable elements.[ 40 ] The co-evolution between selfish genetic elements and their suppressors can be rapid, and follow a Red Queen dynamics , which may mask the presence of selfish genetic elements in a population. Hybrid offspring, on the other hand, may inherit a given selfish genetic element, but not the corresponding suppressor and so reveal the phenotypic effect of the selfish genetic element.[ 41 , 42 ]

Highly self-fertilizing or asexual genomes are expected to experience less conflict between selfish genetic elements and the rest of the host genome than outcrossing sexual genomes.[ 31 – 33 ] There are several reasons for this. First, sex and outcrossing put selfish genetic elements into new genetic lineages. In contrast, in a highly selfing or asexual lineage, any selfish genetic element is essentially stuck in that lineage, which should increase variation in fitness among individuals. The increased variation should result in stronger purifying selection in selfers/asexuals, as a lineage without the selfish genetic elements should out-compete a lineage with the selfish genetic element. Second, the increased homozygosity in selfers removes the opportunity for competition among homologous alleles. Third, theoretical work has shown that the greater linkage disequilibrium in selfing compared to outcrossing genomes may in some, albeit rather limited, cases cause selection for reduced transposition rates.[ 34 ] Overall, this reasoning leads to the prediction that asexuals/selfers should experience a lower load of selfish genetic elements. One caveat to this is that the evolution of selfing is associated with a reduction in the effective population size .[ 35 ] A reduction in the effective population size should reduce the efficacy of selection and therefore leads to the opposite prediction: higher accumulation of selfish genetic elements in selfers relative to outcrossers. Empirical evidence for the importance of sex and outcrossing comes from a variety of selfish genetic elements, including transposable elements,[ 36 , 37 ] self-promoting plasmids,[ 38 ] and B chromosomes.[ 39 ]

Sexual reproduction involves the mixing of genes from two individuals. According to Mendel’s Law of Segregation , alleles in a sexually reproducing organism have a 50% chance of being passed from parent to offspring. Meiosis is therefore sometimes referred to as “fair”.[ 30 ]

Though selfish genetic elements show a remarkable diversity in the way they promote their own transmission, some generalizations about their biology can be made. In a classic 2001 review, Gregory D.D. Hurst and John H. Werren proposed two ‘rules’ of selfish genetic elements.[ 4 ]

Examples of selfish genetic elements

Segregation distorters Some selfish genetic elements manipulate the genetic transmission process to their own advantage, and so end up being overrepresented in the gametes (Fig 2). Such distortion can occur in various ways, and the umbrella term that encompasses all of them is segregation distortion. Some elements can preferentially be transmitted in egg cells as opposed to polar bodies during meiosis, where only the former will be fertilized and transmitted to the next generation. Any gene that can manipulate the odds of ending up in the egg rather than the polar body will have a transmission advantage, and will increase in frequency in a population. PPT PowerPoint slide

PowerPoint slide PNG larger image

larger image TIFF original image Download: Fig 2. Segregation distorters (here shown in red) get transmitted to >50% of the gametes. https://doi.org/10.1371/journal.pgen.1007700.g002 Segregation distortion can happen in several ways. When this process occurs during meiosis it is referred to as meiotic drive. Many forms of segregation distortion occur in male gamete formation, where there is differential mortality of spermatids during the process of sperm maturation or spermiogenesis. The Segregation Distorter (SD) in Drosophila melanogaster is the best studied example, and it involves a nuclear envelope protein Ran-GAP and the X-linked repeat array called Responder (Rsp), where the SD allele of Ran-GAP favors its own transmission only in the presence of a Rspsensitive allele on the homologous chromosome.[43–48] SD acts to kill RSPsensitive sperm, in a post-meiotic process (hence it is not strictly speaking meiotic drive). Systems like this can have interesting rock-paper-scissors dynamics, oscillating between the SD-RSPinsensitive, SD+-RSPinsensitive and SD+-RSPsensitive haplotypes. The SD-RSPsensitive haplotype is not seen because it essentially commits suicide. When segregation distortion acts on sex chromosomes, they can skew the sex ratio. The SR system in Drosophila pseudoobscura, for example, is on the X chromosome, and XSR/Y males produce only daughters, whereas females undergo normal meiosis with Mendelian proportions of gametes.[49,50] Segregation distortion systems would drive the favored allele to fixation, except that most of the cases where these systems have been identified have the driven allele opposed by some other selective force. One example is the lethality of the t-haplotype in mice,[51]another is the effect on male fertility of the Sex Ratio system in D. pseudoobscura.[49]

Homing endonucleases A phenomenon closely related to segregation distortion is homing endonucleases.[52–54] These are enzymes that cut DNA in a sequence-specific way, and those cuts, generally double-strand breaks, are then “healed” by the regular DNA repair machinery. Homing endonucleases insert themselves into the genome at the site homologous to the first insertion site, resulting in a conversion of a heterozygote into a homozygote bearing a copy of the homing endonuclease on both homologous chromosomes (Fig 3). This gives homing endonucleases an allele frequency dynamics rather similar to a segregation distortion system, and generally unless opposed by strong countervailing selection, they are expected to go to fixation in a population. CRISPR-Cas9 technology allows the artificial construction of homing endonuclease systems. These so-called “gene drive” systems pose a combination of great promise for biocontrol but also potential risk[55,56] (see below). PPT PowerPoint slide

PowerPoint slide PNG larger image

larger image TIFF original image Download: Fig 3. Homing endonucleases can recognize a target sequence, cut it, and then use it own sequence as a template during double strand break repair. This converts a heterozygote into a homozygote. https://doi.org/10.1371/journal.pgen.1007700.g003

Transposable elements Transposable elements (TEs) include a wide variety of DNA sequences that all have the ability to move to new locations in the genome of their host. Transposons do this by a direct cut-and-paste mechanism, whereas retrotransposons need to produce an RNA intermediate to move. TEs were first discovered in maize by Barbara McClintock in the 1940s[17] and their ability to occur in both active and quiescent states in the genome was also first elucidated by McClintock.[57] TEs have been referred to as selfish genetic elements because they have some control over their own propagation in the genome (Fig 4). Most random insertions into the genome appear to be relatively innocuous, but they can disrupt critical gene functions with devastating results.[58] For example, TEs have been linked to a variety of human diseases, ranging from cancer to haemophilia.[59] TEs that tend to avoid disrupting vital functions in the genome tend to remain in the genome longer, and hence we are more likely to find them in innocuous locations. PPT PowerPoint slide

PowerPoint slide PNG larger image

larger image TIFF original image Download: Fig 4. Transposable elements self-replicate through two main mechanisms: via an RNA intermediate ("copy-and-paste"; class 1) or straight excision-insertion ("cut-and-paste"; class 2). https://doi.org/10.1371/journal.pgen.1007700.g004 Both plant and animal hosts have evolved means for reducing the fitness impact of TEs, both by directly silencing them and by reducing their ability to transpose in the genome. It would appear that hosts in general are fairly tolerant of TEs in their genomes, since a sizable portion (30–80%) of the genome of many animals and plants is TEs.[60,61] When the host is able to stop their movement, TEs can simply be frozen in place, and it then can take millions of years for them to mutate away. The fitness of a TE is a combination of its ability to expand in numbers within a genome, to evade host defences, but also to avoid eroding host fitness too drastically. The effect of TEs in the genome is not entirely selfish. Because their insertion into the genome can disrupt gene function, sometimes those disruptions can have positive fitness value for the host. Many adaptive changes in Drosophila[62] and dogs[63] for example, are associated with TE insertions.

B chromosomes B chromosomes refer to chromosomes that are not required for the viability or fertility of the organism, but exist in addition to the normal (A) set.[64] They persist in the population and accumulate because they have the ability to propagate their own transmission independently of the A chromosomes (Fig 5). They often vary in copy number between individuals of the same species. PPT PowerPoint slide

PowerPoint slide PNG larger image

larger image TIFF original image Download: Fig 5. Genetic conflicts often arise because not all genes are inherited in the same way. Examples include cytoplasmic male sterility (see Selfish mitochondria). While mitochondrial and chloroplast genes are generally maternally inherited, B chromosomes can be preferentially transmitted through both males and females. https://doi.org/10.1371/journal.pgen.1007700.g005 B chromosomes were first detected over a century ago.[65] Though typically smaller than normal chromosomes, their gene poor, heterochromatin-rich structure made them visible to early cytogenetic techniques. B chromosomes have been thoroughly studied and are estimated to occur in 15% of all eukaryotic species.[66] In general, they appear to be particularly common among eudicot plants, rare in mammals, and absent in birds.In 1945, they were the subject of Gunnar Östergren’s classic paper”Parasitic nature of extra fragment chromosomes”, where he argues that the variation in abundance of B chromosomes between and within species is because of the parasitic properties of the Bs (see above).[14] This was the first time genetic material was referred to as”parasitic” or”selfish”. B chromosome number correlates positively with genome size[67] and has also been linked to a decrease in egg production in the grasshopper Eyprepocnemis plorans.[68]

Selfish mitochondria Genomic conflicts often arise because not all genes are inherited in the same way. Probably the best example of this is the conflict between uniparentally (usually but not always, maternally) inherited mitochondrial and biparentally inherited nuclear genes. Indeed, one of the earliest clear statement about the possibility of genomic conflict was made by the English botanist Dan Lewis in reference to the conflict between maternally inherited mitochondrial and biparentally inherited nuclear genes over sex allocation in hermaphroditic plants (Fig 5).[16] A single cell typically contains multiple mitochondria, creating a situation for competition over transmission. Uniparental inheritance been suggested to be a way to reduce the opportunity for selfish mitochondria to spread, as it ensures all mitochondria share the same genome, thus removing the opportunity for competition. [28,69,70] This view remains widely held, but has been challenged.[71] Why inheritance ended up being maternal, rather than paternal, is also much debated, but one key hypothesis is that the mutation rate is lower in female compared to male gametes.[72] The conflict between mitochondrial and nuclear genes is especially easy to study in flowering plants.[73,74] Flowering plants are typically hermaphrodites,[75] and the conflict thus occurs within a single individual. Mitochondrial genes are typically only transmitted through female gametes, and therefore from their point of view the production of pollen leads to an evolutionary dead end. Any mitochondrial mutation that can affect the amount of resources the plant invests in the female reproductive functions at the expense of the male reproductive functions improves its own chance of transmission. Cytoplasmic male sterility is the loss of male fertility, typically through loss of functional pollen production, resulting from a mitochondrial mutation.[76] In many species where cytoplasmic male sterility occurs, the nuclear genome has evolved so-called restorer genes, which repress the effects of the cytoplasmic male sterility genes and restore the male function, making the plant a hermaphrodite again.[77,78] The co-evolutionary arms race between selfish mitochondrial genes and nuclear compensatory alleles can often be detected by crossing individuals from different species that have different combinations of male sterility genes and nuclear restorers, resulting in hybrids with a mismatch.[79] Another consequence of the maternal inheritance of the mitochondrial genome is the so-called Mother's Curse.[80] Because genes in the mitochondrial genome are strictly maternally inherited, mutations that are beneficial in females can spread in a population even if they are deleterious in males.[81] Explicit screens in fruit flies have successfully identified such female-neutral but male-harming mtDNA mutations.[82,83] Furthermore, a 2017 paper showed how a mitochondrial mutation causing Leber's hereditary optic neuropathy, a male-biased eye disease, was brought over by one of the Filles du roi that arrived in Quebec, Canada, in the 17th century and subsequently spread among many descendants.[84]

Genomic imprinting Another sort of conflict that genomes face is that between the mother and father competing for control of gene expression in the offspring, including the complete silencing of one parental allele. Due to differences in methylation status of gametes, there is an inherent asymmetry to the maternal and paternal genomes that can be used to drive a differential parent-of-origin expression. This results in a violation of Mendel’s rules at the level of expression, not transmission, but if the gene expression affects fitness, it can amount to a similar end result. Imprinting seems like a maladaptive phenomenon, since it essentially means giving up diploidy, and heterozygotes for one defective allele are in trouble if the active allele is the one that is silenced. Several human diseases, such as Prader-Willi and Angelman syndromes, are associated with defects in imprinted genes. The asymmetry of maternal and paternal expression suggests that some kind of conflict between these two genomes might be driving the evolution of imprinting. In particular, several genes in placental mammals display expression of paternal genes that maximize offspring growth, and maternal genes that tend to keep that growth in check (Fig 6). Many other conflict-based theories about the evolution of genomic imprinting have been put forward.[85,86] PPT PowerPoint slide

PowerPoint slide PNG larger image

larger image TIFF original image Download: Fig 6. Igf2 is an example of genomic imprinting. In mice, the insulin-like growth factor 2 gene, Igf2, which is linked to hormone production and increased offspring growth is paternally expressed (maternally silenced) and the insulin-like growth factor 2 receptor gene Igf2r, which binds the growth protein and so slows growth, is maternally expressed (paternally silenced). The offspring is normal sized when both genes are present, or both genes are absent. When the maternally expressed gene (Igf2r) is experimentally knocked out the offspring has an unusually large size, and when the paternally expressed gene (Igf2) is knocked out, the offspring is unusually small. https://doi.org/10.1371/journal.pgen.1007700.g006 At the same time, genomic or sexual conflict are not the only possible mechanisms whereby imprinting can evolve.[87] Several molecular mechanisms for genomic imprinting have been described, and all have the aspect that maternally and paternally derived alleles are made to have distinct epigenetic marks, in particular the degree of methylation of cytosines. An important point to note regarding genomic imprinting is that it is quite heterogeneous, with different mechanisms and different consequences of having single parent-of-origin expression. For example, examining the imprinting status of closely related species allows one to see that a gene that is moved by an inversion into close proximity of imprinted genes may itself acquire an imprinted status, even if there is no particular fitness consequence of the imprinting.