Antagonistic pleiotropy hypothesis

The antagonistic pleiotropy hypothesis was first proposed by George C. Williams in 1957 as an evolutionary explanation for senescence.[1] Pleiotropy is the phenomenon where one gene controls for more than one phenotypic trait in an organism.[2] 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 and at least one is detrimental to the organism's fitness.[3] 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.[4]

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. Antagonistically pleiotropic genes are the explanation for fitness trade-offs.[3] 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.[5] This strong parental drive will be selected for, but the organisms will still make the mistake of feeding young that are not theirs and mis-allocating their resources.

Benefits and costs

Antagonistic pleiotropy has several negative consequences. It results in delayed adaptation, an altered path of evolution, and reduced adaptation of other traits.[6] 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.[7] 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.[8] 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.[9] This phenomenon is especially clear in lek species, where males confer 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 a maintained due to variation in the organism’s condition.[10]

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 acting over evolutionary time would result in a lower frequency of mutations than are currently observed.[11] 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 (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. Interestingly, Laron Syndrome patients experienced a lower incidence of cancer mortality and diabetes compared to their non-dwarf kin.[12] 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. Incidentally, 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.[11]

Sickle cell anemia, Beta-thalassemia, and cystic fibrosis are some other examples of the role antagonistic pleiotropy may play in genetic disorders.[11]

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.[7] In addition to that, pleiotropy is under strong stabilizing selection.[6] In one experiment with mice and the morphology of the mandible, 1/5 of the loci had effects of pleiotropy for the entire mandible.[2] One other example was in the Russian biologist Dmitry K. Belyaev's study on the domestication of the fox.[13] 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.[4] An example of this is testosterone 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.[14] 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.[15] Williams's theory has been the motivation for many of the experimental studies on the reasons for aging in the last 25 years.[16] However there is more than one theory out there for aging. The competing model to explain senescence is Medawar's "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."[16] Medawar's theory is based around the older concept of selection shadow that had been discussed throughout the early 1900s and led to Medawar's theory after discussions with J. B. S. Haldane in the 1940s.[17]

See also

References

  1. ↑ Williams G.C. (1957). "Pleiotropy, natural selection, and the evolution of senescence". Evolution 11: 398–411. doi:10.2307/2406060.
  2. 1 2 Cheverud J (1996). "Developmental integration and the evolution of pleiotropy". American Zoology 36: 44–50. doi:10.1093/icb/36.1.44.
  3. 1 2 Elena S.F., Sanjuán R. (2003). "Climb every mountain?". Science 302 (5653): 2074–2075. doi:10.1126/science.1093165.
  4. 1 2 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.
  5. ↑ Alcock, J. 2005. Animal Behavior: eighth edition
  6. 1 2 Otto S.P. (2004). "Two steps forward, one step back: the pleiotropic effects of favoured alleles". Proc. Biol. Sci 271 (1540): 705–714. doi:10.1098/rspb.2003.2635.
  7. 1 2 He X., Zhang J. (2006). "Toward a Molecular Understanding of Pleiotropy". Genetics 173: 1885–1891. doi:10.1534/genetics.106.060269.
  8. ↑ Bolstad, Geir; Pelabon, Cristophe; Larsen, Line-K; Fleming, Ian A.; Viken, Aslaug; Rosenqvist, Gunilla (2012). "The Effect of Purging on Sexually Selected Traits through Antagonistic Pleiotropy with Survival". Ecology and Evolution 2 (6): 1184–191. doi:10.1002/ece3.246. PMC 3402193. PMID 22833793.
  9. ↑ Pomiankowski, A; AP Moller (1995). "A Resolution of the Lek Paradox". Proceedings of the Royal Society of London 260: 21–29. doi:10.1098/rspb.1995.0054.
  10. ↑ Rowe, L; D. Houle (1996). "The Lek Paradox and the Capture of Genetic Variance by Condition Dependent Traits". Proceedings of the Royal Society of London 263: 1415–1421. doi:10.1098/rspb.1996.0207.
  11. 1 2 3 Carter, Ashley; Andrew Q. Nguyen (2011). "Antagonistic Pleiotropy as a Widespread Mechanism for the Maintenance of Polymorphic Disease Alleles". BMC Medical Genetics 12: 160. doi:10.1186/1471-2350-12-160.
  12. ↑ Guevara-Aguirre, J.; Balasubramanian, P.; Guevara-Aguirre, M.; Wei, M.; Madia, F.; Chang, C.W.; Hwang, D. (2011). "Growth Hormone Receptor Deficiency is Associated with a Major Reduction in Pro-aging Signaling, Cancer, and Diabetes in Humans". Science Translational Medicine 3 (70): 70ra13. doi:10.1126/scitranslmed.3001845. PMC 3357623. PMID 21325617.
  13. ↑ Trut L.N. (1996). "Early canid domestication: the farm-fox experiment". American Scientist 87 (2): 160–159.
  14. ↑ Gann P.H., Hennekens C.H., Ma J., Longcope C., Stampfer M.J. (1996). "Prospective Study of Sex Hormone Levels and Risk of Prostate Cancer". Journal of the National Cancer Institute 88 (16): 1118–1126. doi:10.1093/jnci/88.16.1118. PMID 8757191.
  15. ↑ Promislow D.E.L. (2004). "Protein networks, pleiotropy and the evolution of senescence". Proc. Biol. Sci 271 (1545): 1225–1234. doi:10.1098/rspb.2004.2732.
  16. 1 2 Fox, C.W. and J.B. Wolf. 2006. Evolutionary Genetics: Concepts and Case Studies.
  17. ↑ Fabian, Daniel; Flatt, Thomas (2011). "The Evolution of Aging". Scitable. Nature Publishing Group. Retrieved May 20, 2014.
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