The antagonistic pleiotropy hypothesis was first proposed by
George C. Williams in 1957 as an
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
ary explanation for
senescence.
Pleiotropy is the phenomenon where one
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
controls for more than one phenotypic trait in an organism.
Antagonistic pleiotropy is when one gene controls for more than one trait, where at least one of these traits is beneficial to the organism's fitness early on in life and at least one is detrimental to the organism's fitness later on due to a decline in the force of natural selection.
The theme of G.C. William's idea about antagonistic pleiotropy was that if a gene caused both increased reproduction in early life and aging in later life, then senescence would be adaptive in evolution. For example, one study suggests that since
follicular depletion in human females causes both more regular cycles in early life and loss of fertility later in life through menopause, it can be selected for by having its early benefits outweigh its late costs.
[Wood, J.W., K.A. O'Conner, D.J. Holman, E. Bringle, S.H. Barsom, M.A. Grimes. 2001. The evolution of menopause by antagonistic pleiotropy. Center for Demography and Ecology, Working Paper.]
As a constraint on perfection
Antagonistic pleiotropy is one of the several reasons evolutionary biologists give for organisms never being able to reach perfection through
natural selection
Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Cha ...
. Antagonistically pleiotropic genes are the explanation for
fitness trade-offs.
This means that genes that are pleiotropic control for some beneficial traits and some detrimental traits; thus, if they happen to persist through natural selection, this will prevent organisms from reaching perfection because if they possess the benefits of the gene, they must also possess the imperfections or faults. An example of this would be female rodents that live in a nest with other females and may end up feeding young that are not theirs due to their intense parental drive. This strong parental drive will be selected for, but the organisms will still make the mistake of feeding young that are not theirs and misallocating their resources.
Benefits and costs
Antagonistic pleiotropy has several negative consequences. It results in delayed
adaptation, an altered path of
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
, and reduced adaptation of other traits.
In addition, the overall benefit of alleles is cut down significantly (by about half) by pleiotropy. Still, antagonistic pleiotropy has some evolutionary benefits. In fact, the conservation of genes is directly related to the pleiotropic character of an organism.
This implies that genes that control for multiple traits, even if the traits have different implications for the organism's fitness, have more staying power in an evolutionary context.
Role in sexual selection
It is generally accepted that the evolution of secondary sexual characteristics persists until the relative costs of survival outweigh the benefits of reproductive success.
At the level of
genes, this means a trade-off between variation and expression of selected traits. Strong, persistent sexual selection should result in decreased genetic variation for these traits. However, higher levels of variation have been reported in sexually-selected traits compared to non-sexually selected traits.
This phenomenon is especially clear in
lek
Lek or LEK may refer to:
* Lek mating, mating in a lek, a type of animal territory in which males of a species gather
* Albanian lek, the currency of Albania
* Lek (magazine), a Norwegian softcore pornographic magazine
* Lek (pharmaceutical comp ...
species, where males' courtship behavior confers no immediate advantage to the female. Female choice presumably depends on correlating male displays (secondary sexual characteristics) with overall genetic quality. If such directional sexual selection depletes variation in males, why would female choice continue to exist? Rowe and Houle answer this question (the
lek paradox
The lek paradox is the conundrum of how additive or beneficial genetic variation is maintained in lek mating species, in the face of consistent female preferences, sexual selection. While many studies have attempted to explain how the lek paradox ...
) using the notion of
genetic capture, which couples the sexually-selected traits with the overall condition of the organism. They posit that the genes for secondary sexual characteristics must be pleiotropically linked to condition, a measure of the organism's fitness. In other words, the genetic variation in secondary sexual characteristics is maintained due to variation in the organism's condition.
Role in disease
The survival of many serious genetic disorders in our long evolutionary history has led researchers to reassess the role of antagonistic
pleiotropy in disease. If genetic disorders are defined by the existence of deleterious alleles, then
natural selection
Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Cha ...
acting over evolutionary time would result in a lower frequency of mutations than are currently observed.
In a recent article, Carter and Nguyen identify several genetic disorders, arguing that far from being a rare phenomenon, antagonistic pleiotropy might be a fundamental mechanism for the survival of these non-optimal alleles.
In one of these studies, 99 individuals with
Laron syndrome
Laron syndrome (LS), also known as growth hormone insensitivity or growth hormone receptor deficiency (GHRD), is an autosomal recessive disorder characterized by a lack of insulin-like growth factor 1 (IGF-1; somatomedin) production in response t ...
(a rare form of dwarfism) were monitored alongside their non-dwarf kin for a period of ten years. Patients with Laron syndrome possess one of three genotypes for the
growth hormone receptor
Growth hormone receptor is a protein that in humans is encoded by the ''GHR'' gene. GHR orthologs have been identified in most mammals.
Structure
Growth hormone receptor (GHR) is a transmembrane protein consisting of 620 amino acids. The recep ...
gene (GHR). Most patients have an A->G
splice site mutation in position 180 in exon 6. Some others possess a
nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
(R43X), while the rest are heterozygous for the two mutations. Laron syndrome patients experienced a lower incidence of cancer mortality and diabetes compared to their non-dwarf kin.
This suggests a role for antagonistic pleiotropy, whereby a deleterious mutation is preserved in a population because it still confers some survival benefit.
Another instance of antagonistic pleiotropy is manifested in
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
, a rare
neurodegenerative
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
disorder characterized by a high number of CAG repeats within the
Huntingtin
Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role and also fo ...
gene. The onset of Huntington's is usually observed post-reproductive age and generally involves involuntary muscle spasms, cognitive difficulties and psychiatric problems. Incidentally, the high number of CAG repeats is associated with increased activity of
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
, a tumor suppressing protein that participates in
apoptosis. It has been hypothesized that this explains the lower rates of cancer among Huntington's patients. Huntington's disease is also correlated with high
fecundity
Fecundity is defined in two ways; in human demography, it is the potential for reproduction of a recorded population as opposed to a sole organism, while in population biology, it is considered similar to fertility, the natural capability to pr ...
.
Additionally, it was found that individuals with a higher pro-inflammatory ratio TNFα/IL-10 had a significantly higher incidence of death due to cardiovascular disease in old age. Yet, it was hypothesized that this genotype was prevalent because higher ratios of TNFα/IL-10 allow individuals to more effectively combat infection during reproductive years.
Sickle cell anemia
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red bl ...
,
Beta-thalassemia
Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to cl ...
, and
cystic fibrosis are some other examples of the role antagonistic pleiotropy may play in genetic disorders.
Ubiquity
Although there are so many negative effects related to genes that are antagonistically pleiotropic, it is still present among most forms of life. Indeed, pleiotropy is one of the most common traits possessed by genes overall.
In addition to that, pleiotropy is under strong
stabilizing selection
Stabilizing selection (not to be confused with negative or purifying selection) is a type of natural selection in which the population mean stabilizes on a particular non-extreme trait value. This is thought to be the most common mechanism of a ...
.
In one experiment with mice and the morphology of the
mandible
In anatomy, the mandible, lower jaw or jawbone is the largest, strongest and lowest bone in the human facial skeleton. It forms the lower jaw and holds the lower teeth in place. The mandible sits beneath the maxilla. It is the only movable bone ...
, 1/5 of the loci had effects of pleiotropy for the entire
mandible
In anatomy, the mandible, lower jaw or jawbone is the largest, strongest and lowest bone in the human facial skeleton. It forms the lower jaw and holds the lower teeth in place. The mandible sits beneath the maxilla. It is the only movable bone ...
.
One other example was in the Russian biologist Dmitry K. Belyaev's study on the domestication of the fox. In Dmitry K. Belyaev's farm-fox experiment, wild foxes were bred for docile behavior alone. After 40 generations, other physiological changes had surfaced including shortened tails, floppy ears, a white star in the forehead, rolled tails, shorter legs. Since the only thing being selected for was behavior, this leads scientists to believe that these secondary characteristics were controlled by the same gene or genes as docile behavior.
Adaptivity and senescence
An antagonistically pleiotropic gene can be selected for if it has beneficial effects in early life while having its negative effects in later life because genes tend to have larger impacts on fitness in an organism's prime than in their old age.
An example of this is
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
levels in male humans. Higher levels of this hormone lead to increased fitness in early life, while causing decreased fitness in later life due to a higher risk for prostate cancer. This is an example of antagonistic pleiotropy being an explanation for senescence. Senescence is the act of ageing in individuals; it's the failure over time of the individual's life processes by natural causes. Williams's theory has been the motivation for many of the experimental studies on the reasons for aging in the last 25 years.
[Fox, C.W. and J.B. Wolf. 2006. Evolutionary Genetics: Concepts and Case Studies.] However, there is more than one theory out there for aging. The competing model to explain senescence is Medawar's "
mutation accumulation
Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution ( mutation accumulation ...
" hypothesis, saying that "over evolutionary time, late-acting mutations will accumulate at a much faster rate than early-acting mutation. These late-acting mutations will thus lead to declining
viability and/or fertility as an organism ages."
Medawar's theory is based around the older concept of
selection shadow
The selection shadow is a concept involved with the evolutionary theories of aging that states that selection pressures on an individual decrease as an individual ages and passes sexual maturity, resulting in a "shadow" of time where selective f ...
that had been discussed throughout the early 1900s and led to Medawar's theory after discussions with
J. B. S. Haldane
John Burdon Sanderson Haldane (; 5 November 18921 December 1964), nicknamed "Jack" or "JBS", was a British-Indian scientist who worked in physiology, genetics, evolutionary biology, and mathematics. With innovative use of statistics in biolog ...
in the 1940s.
Potential Examples
DNA repair
DNA Damage Theory of Aging
A prominent explanation for aging at the molecular level is the
DNA damage theory of aging
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear D ...
. It has been proposed that genetic elements that regulate
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
in
somatic cells may constitute an important example of age-dependent pleiotropic "genes".
[Bernstein C, Bernstein H. (1991) Aging, Sex, and DNA Repair. Academic Press, San Diego. ] As pointed out by Vijg,
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
repair and maintenance is beneficial early in life by swiftly eliminating
DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
or damaged cells. However, studies of DNA repair in the brain
and in muscle
indicate that the transition from
mitotic cell division to the post-mitotic condition that occurs early in life is accompanied by a reduction in DNA repair. The reduced expression of DNA repair is presumably part of an evolutionary adaptation for diverting the resources of the cell that were previously used for DNA repair, as well as for replication and cell division, to more essential neuronal and muscular functions.
The harmful effect of this genetically controlled reduction in expression is to allow increased accumulation of DNA damage. Reduced DNA repair causes increased impairment of transcription and progressive loss of cell and tissue function. However, these harmful effects of DNA damage are cumulative and most severe in chronologically older individuals whose numbers diminish with time (by causes of death that can be independent of senescence). As a consequence, the beneficial effects of the genetic elements that control the reduction of DNA repair early in life would predominate. Thus regulatory genetic elements that reduce expression of DNA repair genes in post-mitotic cells appear to be important examples of the postulated pleiotropic "genes" that are beneficial in youth but deleterious at an older age.
Telomere Theory
Another example related to aging is the
Telomere
A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
theory. Telomere theory proposes that telomeres shorten with repeated cell division which attribute to cell senescence and tissue damage.
The end replication problem explains the mechanism behind the inability of DNA polymerase to commence the RNA primer to perform its function in completing the lagging strand due to the shortening of DNA. Telomere shortening is common in somatic cells. However, germ line and stem cells prevent the end replication problem with the help of telomerase. Telomerase elongates the 3’ end that is then formed into a t-loop to prevent the cell from entering the G0 phase and cell senescence.
Inflammation and damage to tissue are the underlying problems due to increased senescent cells. In several studies shortened telomeres have been associated with age related sarcopenia, atherosclerotic cardiovascular disease, and cancer. However, there is still the question whether telomere length causes these diseases or if the diseases cause shortened telomeres. Hence, the shortening of telomeres complies with antagonistic pleiotropy theory. The trade-off exists as the cell benefits from telomerase which prevents permanent growth arrest but telomere shortening is associated with functional loss.
Free Radical Theory
Another example related to aging is the Free Radical theory. Free Radical Theory suggests that the free radicals, which are being produced by aerobic respiration, are causing oxidative stress to be put on the body. This oxidative stress will result in aging and lead to death. Oxygen centered radicals are very reactive and can cause the accumulation of damage on lipids, nucleic acids as well as proteins within the body. This accumulation of damage on the biological molecules changes the framework and leads to a reduction in the molecules' activity levels. Lipid peroxides accumulate in the membrane phospholipids, which in turn diminishes the mitochondrial membrane's effectiveness as a barrier. The process of DNA transcription and translation also acquires oxidative damage. The result is alterations in the base pairings of the DNA sequence. Research has found that DNA mutations from free radical damage are highly uncommon but would still lead to the build up of damaged proteins as well as decreased biological activity.
However, a large body of research has shown that
antioxidants (compounds that defuse free radicals) do not slow aging or age-related diseases, putting the popular free radical theory into doubt.
See also
*
Evolution of ageing
Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution (mutation accumulation, ...
References
{{senescence
Genetics
Theories of ageing
Theories of biological ageing
Evolutionary theories of biological ageing