# Antagonistic pleiotropy hypothesis

The antagonistic pleiotropy hypothesis (APT) is a theory in evolutionary biology that suggests certain genes may confer beneficial effects early in an organism's life, enhancing reproductive success, while also causing detrimental effects later in life, contributing to the aging process.
APT was first proposed in a 1952 paper on the evolutionary theory of ageing by Peter Medawar and developed further in a paper by George C. Williams in 1957 as an explanation for senescence. Pleiotropy is the phenomenon where a single gene influences more than one phenotypic trait in an organism. It is one of the most commonly observed attributes of genes. A gene is considered to exhibit antagonistic pleiotropy if it controls more than one phenotypic trait, where at least one of these traits is beneficial to the organism's fitness and at least one is detrimental to fitness.
This line of genetic research began as an attempt to answer the following question: if survival and reproduction should always be favoured by natural selection, why should ageing – which in evolutionary terms can be described as the age-related decline in survival rate and reproduction – be nearly ubiquitous in the natural world?" The antagonistic pleiotropy hypothesis provides a partial answer to this question. As an evolutionary explanation for ageing, the hypothesis relies on the fact that reproductive capacity declines with age in many species and, therefore, the strength of natural selection also declines with age (because there can be no natural selection without reproduction). Since the strength of selection declines over the life cycles of human and most other organisms, natural selection in these species tends to favor "alleles that have early beneficial effects, but later deleterious effects".
Antagonistic pleiotropy also provides a framework for understanding why many genetic disorders, even those causing life threatening health impacts (e.g. sickle cell anaemia), are found to be relatively prevalent in populations. Seen through the lens of simple evolutionary processes, these genetic disorders should be observed at very low frequencies due to the force of natural selection. Genetic models of populations show that antagonistic pleiotropy allows genetic disorders to be maintained at reasonably high frequencies "even if the fitness benefits are subtle". In this sense, antagonistic pleiotropy forms the basis of a "genetic trade-off between different fitness components."

## Trade-offs

In the theory of evolution, the concept of fitness has two components: mortality and reproduction. Antagonistic pleiotropy gets fixed in genomes by creating viable trade-offs between or within these two components. The existence of these trade-offs has been clearly demonstrated in human, botanical and insect species. For example, an analysis of global gene expression in the fruit fly, Drosophila melanogaster, revealed 34 genes whose expression coincided with the genetic trade-off between larval survival and adult size. The joint expression of these candidate 'trade-off' genes explained 86.3% of the trade-off. These tradeoffs can result from selection at the level of the organism or, more subtly, via mechanisms for the allocation of scarce resources in cellular metabolism.
Another example is found in a study of the yellow monkey flower, an annual plant. The study documents a trade-off between days-to-flower and reproductive capacity. This genetic balancing act determines how many individuals survive to flower in a short growing season (viability) while also influencing the seed set of survivors (fecundity). The authors find that tradeoffs between plant viability and fecundity can engender a stable polymorphism under surprisingly general conditions. Thus, for this annual flower, they reveal a tradeoff between mortality and fecundity and, according to the authors, this tradeoff is also relevant for other annual, flowering plants.

### Role in fecundity and senescence

Senescence refers to the process of physiological change in individual members of a species as they age. An antagonistically pleiotropic gene can be selected for if it has beneficial effects in early life while manifesting 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. Williams's 1957 article has motivated many follow-up studies on the evolutionary causes of ageing. These studies show clear trade-offs involving early increases in fecundity and later increases in mortality. For example, two experiments with Drosophila melanogaster have shown that increased fertility is associated with reduced longevity. Likewise, for humans, infertile women live longer on average than fertile women.
One such study tests the hypothesis that death due to cardiovascular disease in women is linked to an antagonistic pleiotropy operating through inflammation and linked to fertility. Because the human immune system evolved in an ancestral environment characterized by abundant pathogens, protective, pro-inflammatory responses (which helped individuals to avoid and survive infections) were undoubtedly selected for in these environments. However, in terms of cardiovascular risk, these same inflammatory responses have turned out to be harmful as the material conditions of human existence improved – in affluent countries, where life expectancy is much longer than in the ancestral environment, strong inflammatory responses carry greater risks of cardiovascular disease as individuals age. The study looks at mortality, over a period of 3 to 5 years, in a group of 311, 85-year old Dutch women. Information on their reproductive history as well the results of blood tests, genetic tests and physical examinations was recorded. The study 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. It also linked specific alleles to a combination of higher fertility, stronger inflammatory response and greater cardiovascular problems in old age. This finding supports the hypothesis that this gene was prevalent because it helped women in the ancestral environment to more effectively combat infection during their reproductive years. However, the pleiotropic costs of the gene in terms of cardiovascular risks are now clear because people live long enough to die of cardiovascular disease.

### Role in disease

The survival of many serious genetic disorders in human evolutionary history has led researchers to explore the role of antagonistic pleiotropy in disease. If genetic disorders are caused by mutations to a single deleterious allele, then natural selection should eliminate carriers of this allele over evolutionary time, thereby lowering the frequency of mutations. Yet, research shows that the incidence of such alleles in studied populations is often stable and relatively high. In a 2011 review article, Carter and Nguyen discuss several genetic disorders, arguing that, far from being a rare phenomenon, antagonistic pleiotropy might be a fundamental mechanism by which "alleles with severe deleterious health effects can be maintained at medically relevant frequencies with only minor beneficial pleiotropic effects."
An example of this is sickle cell anaemia, which results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. Possessors of the deleterious allele have much lower life expectancies, with homozygotes rarely reaching 50 years of age. However, this allele also enhances resistance to malaria. Thus, in regions where malaria exerts or has in the past exerted a strong selective pressure, sickle cell anaemia has been selected for its conferred partial resistance to the disease. While homozygotes will have either no protection from malaria or a dramatic propensity to sickle cell anemia, heterozygotes have fewer physiological effects and a partial resistance to malaria. Thus, the gene that is responsible for sickle cell disease has fixed itself with relatively high frequencies in populations threatened by malaria by engendering a viable tradeoff between death from this non-communicable disease and death from malaria.
In another study of genetic diseases, 99 individuals with Laron syndrome (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 gene (GHR). Most patients have an A->G splice site mutation in position 180 in exon 6. Some others possess a nonsense mutation (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, a rare neurodegenerative disorder characterized by a high number of CAG repeats within the Huntingtin gene. The onset of Huntington's is usually observed post-reproductive age and generally involves involuntary muscle spasms, cognitive difficulties and psychiatric problems. The high number of CAG repeats is associated with increased activity of p53, 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.
Other pleiotropic diseases include: beta-thalassemia (also protects against malaria in the heterozygous state); cystic fibrosis (increased fertility); and osteoporosis in old age (reduced risk of osteoporosis in youth).

### Role in sexual selection

Sexual selection is a process of natural selection in which individuals of one sex choose to mate with individuals of the other sex based on certain observable characteristics (intersexual selection, the exaggerated tail in peacocks, for example) or they compete with other individuals of the same sex for access to mating opportunities with individuals of the opposite sex (intrasexual selection, as when males of certain mammalian species fight for the right to mate). 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 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) 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 DNA repair

DNA repair capability in hamsters is relatively high during development in early mitotic brain cells, but is present at a reduced level in post-mitotic brain cells throughout adulthood. In humans DNA repair capability declines in older individuals. These findings suggest that DNA repair activity is regulated at a level that facilitates vigorous function during youth, but at an insufficient level during maturity that results in aging. Thus proteins that regulate the level of DNA repair activity appear to have the antagonistic pleiotrophic effect of being beneficial during youthful development, but insufficient to prevent aging during maturity.

## Ubiquity in population genetics

Advances in genome mappings have greatly facilitated research into antagonistic pleiotropy. Such research is now often carried out in laboratories, but also in wild populations. The latter context for testing has the advantage of introducing the full complexity of the selection experience – competitors, predators, and parasites – though it has the disadvantage of introducing idiosyncratic factors that are specific to given locations. In order to be able to assert with confidence that a given pleiotropy is, indeed, an antagonistic pleiotropy and not due to some other competing cause (e.g. the mutation accumulation hypothesis), one must have knowledge of the precise gene that is pleiotropic. This is now increasingly possible with organisms that have detailed genomic mappings (e.g. mice, fruit flies and humans). A 2018 review of this research finds that "antagonistic pleiotropy is somewhere between very common or ubiquitous in the animal world .... and potentially all living domains... ".