Mutation accumulation theory

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Older man from Faridabad, Haryana, India Ageing Gracefully (4145379809).jpg
Older man from Faridabad, Haryana, India

The mutation accumulation theory of aging was first proposed by Peter Medawar in 1952 as an evolutionary explanation for biological aging and the associated decline in fitness that accompanies it. [1] Medawar used the term 'senescence' to refer to this process. The theory explains that, in the case where harmful mutations are only expressed later in life, when reproduction has ceased and future survival is increasingly unlikely, then these mutations are likely to be unknowingly passed on to future generations. [2] In this situation the force of natural selection will be weak, and so insufficient to consistently eliminate these mutations. Medawar posited that over time these mutations would accumulate due to genetic drift and lead to the evolution of what is now referred to as aging.

Contents

Background and history

Despite Charles Darwin's completion of his theory of biological evolution in the 19th century, the modern logical framework for evolutionary theories of aging wouldn't emerge until almost a century later. Though August Weismann did propose his theory of programmed death, it was met with criticism and never gained mainstream attention. [3] It wasn't until 1930 that Ronald Fisher first noted the conceptual insight which prompted the development of modern aging theories. This concept, namely that the force of natural selection on an individual decreases with age, was analysed further by J. B. S. Haldane, who suggested it as an explanation for the relatively high prevalence of Huntington's disease despite the autosomal dominant nature of the mutation. Specifically, as Huntington's only presents after the age of 30, the force of natural selection against it would have been relatively low in pre-modern societies. [2] It was based on the ideas of Fisher and Haldane that Peter Medawar was able to work out the first complete model explaining why aging occurs, which he presented in a lecture in 1951 and then published in 1952 [1]

Mechanism of action

(a) The survival rate within a population decreases with age, while the reproduction rate remains constant. (b) The reproduction probability peaks early in life, at sexual maturity, and then steadily decreases as an individual ages, with the remaining share of the population decreasing with age as they enter the selection shadow. Selection shadow.svg
(a) The survival rate within a population decreases with age, while the reproduction rate remains constant. (b) The reproduction probability peaks early in life, at sexual maturity, and then steadily decreases as an individual ages, with the remaining share of the population decreasing with age as they enter the selection shadow.

Amongst almost all populations, the likelihood that an individual will reproduce is related directly to their age. [1] Starting at 0 at birth, the probability increases to its maximum in young adulthood once sexual maturity has been reached, before gradually decreasing with age. This decrease is caused by the increasing likelihood of death due to external pressures such as predation or illness, as well as the internal pressures inherent to organisms that experience senescence. In such cases deleterious mutations which are expressed early on are strongly selected against due to their major impact on the number of offspring produced by that individual. [3] Mutations that present later in life, by contrast, are relatively unaffected by selective pressure, as their carriers have already passed on their genes, assuming they survive long enough for the mutation to be expressed at all. The result, as predicted by Medawar, is that deleterious late-life mutations will accumulate and result in the evolution of aging as it is known colloquially. [2] This concept is portrayed graphically by Medawar through the concept of a "selection shadow". The shaded region represents the 'shadow' of time during which selective pressure has no effect. [4] Mutations that are expressed within this selection shadow will remain as long as reproductive probability within that age range remains low.[ citation needed ]

Evidence supporting the mutation accumulation theory

Predation and Delayed Senescence

In populations where extrinsic mortality is low, the drop in reproductive probability after maturity is less severe than in other cases. The mutation accumulation theory therefore predicts that such populations would evolve delayed senescence. [5] One such example of this scenario can be seen when comparing birds to organisms of equivalent size. It has been suggested that their ability to fly, and therefore lower relative risk of predation, is the cause of their longer than expected life span. [6] The implication that flight, and therefore lower predation, increases lifespan is further born out by the fact that bats live on average 3 times longer than similarly sized mammals with comparable metabolic rates. [7] Providing further evidence, insect populations are known to experience very high rates of extrinsic mortality, and as such would be expected to experience rapid senescence and short life spans. The exception to this rule, however, is found in the longevity of eusocial insect queens. As expected when applying the mutation accumulation theory, established queens are at almost no risk of predation or other forms of extrinsic mortality, and consequently age far more slowly than others of their species. [8]

Age-specific reproductive success of Drosophila Melanogaster

In the interest of finding specific evidence for the mutation accumulation theory, separate from that which also supports the similar antagonistic pleiotropy hypothesis, an experiment was conducted involving the breeding of successive generations of Drosophila Melanogaster. Genetic models predict that, in the case of mutation accumulation, elements of fitness, such as reproductive success and survival, will show age-related increases in dominance, homozygous genetic variance and additive variance. Inbreeding depression will also increase with age. This is because these variables are proportional to the equilibrium frequencies of deleterious alleles, which are expected to increase with age under mutation accumulation but not under the antagonistic pleiotropy hypothesis. This was tested experimentally by measuring age specific reproductive success in 100 different genotypes of Drosophila Melanogaster, with findings ultimately supporting the mutation accumulation theory of aging. [9]

Criticisms of the mutation accumulation theory

Under most assumptions, the mutation accumulation theory predicts that mortality rates will reach close to 100% shortly after reaching post-reproductive age. [10] Experimental populations of Drosophila Melanogaster, and other organisms, however, exhibit age-specific mortality rates that plateau well before reaching 100%, making mutation accumulation alone an insufficient explanation. It is suggested instead that mutation accumulation is only one factor among many, which together form the cause of aging. In particular, the mutation accumulation theory, the antagonistic pleiotropy hypothesis and the disposable soma theory of aging are all believed to contribute in some way to senescence. [11]

Related Research Articles

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. Whole organism senescence involves an increase in death rates or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

<span class="mw-page-title-main">Neutral theory of molecular evolution</span> Theory of evolution by changes at the molecular level

The neutral theory of molecular evolution holds that most evolutionary changes occur at the molecular level, and most of the variation within and between species are due to random genetic drift of mutant alleles that are selectively neutral. The theory applies only for evolution at the molecular level, and is compatible with phenotypic evolution being shaped by natural selection as postulated by Charles Darwin.

Population genetics is a subfield of genetics that deals with genetic differences within and among populations, and is a part of evolutionary biology. Studies in this branch of biology examine such phenomena as adaptation, speciation, and population structure.

In evolutionary genetics, mutational meltdown is a sub class of extinction vortex in which the environment and genetic predisposition mutually reinforce each other. Mutational meltdown is the accumulation of harmful mutations in a small population, which leads to loss of fitness and decline of the population size, which may lead to further accumulation of deleterious mutations due to fixation by genetic drift.

<span class="mw-page-title-main">Pleiotropy</span> Influence of a single gene on multiple phenotypic traits

Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic gene may have an effect on several traits simultaneously, due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.

Genetic load is the difference between the fitness of an average genotype in a population and the fitness of some reference genotype, which may be either the best present in a population, or may be the theoretically optimal genotype. The average individual taken from a population with a low genetic load will generally, when grown in the same conditions, have more surviving offspring than the average individual from a population with a high genetic load. Genetic load can also be seen as reduced fitness at the population level compared to what the population would have if all individuals had the reference high-fitness genotype. High genetic load may put a population in danger of extinction.

The age of onset is the age at which an individual acquires, develops, or first experiences a condition or symptoms of a disease or disorder. For instance, the general age of onset for the spinal disease scoliosis is "10-15 years old," meaning that most people develop scoliosis when they are of age between ten and fifteen years.

Life history theory (LHT) is an analytical framework designed to study the diversity of life history strategies used by different organisms throughout the world, as well as the causes and results of the variation in their life cycles. It is a theory of biological evolution that seeks to explain aspects of organisms' anatomy and behavior by reference to the way that their life histories—including their reproductive development and behaviors, post-reproductive behaviors, and lifespan —have been shaped by natural selection. A life history strategy is the "age- and stage-specific patterns" and timing of events that make up an organism's life, such as birth, weaning, maturation, death, etc. These events, notably juvenile development, age of sexual maturity, first reproduction, number of offspring and level of parental investment, senescence and death, depend on the physical and ecological environment of the organism.

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 suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

Biodemography is the science dealing with the integration of biological theory and demography.

The history of molecular evolution starts in the early 20th century with "comparative biochemistry", but the field of molecular evolution came into its own in the 1960s and 1970s, following the rise of molecular biology. The advent of protein sequencing allowed molecular biologists to create phylogenies based on sequence comparison, and to use the differences between homologous sequences as a molecular clock to estimate the time since the last common ancestor. In the late 1960s, the neutral theory of molecular evolution provided a theoretical basis for the molecular clock, though both the clock and the neutral theory were controversial, since most evolutionary biologists held strongly to panselectionism, with natural selection as the only important cause of evolutionary change. After the 1970s, nucleic acid sequencing allowed molecular evolution to reach beyond proteins to highly conserved ribosomal RNA sequences, the foundation of a reconceptualization of the early history of life.

<span class="mw-page-title-main">Antagonistic pleiotropy hypothesis</span> Proposed evolutionary explanation for senescence

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.

Bateman's principle, in evolutionary biology, is that in most species, variability in reproductive success is greater in males than in females. It was first proposed by Angus John Bateman (1919–1996), an English geneticist. Bateman suggested that, since males are capable of producing millions of sperm cells with little effort, while females invest much higher levels of energy in order to nurture a relatively small number of eggs, the female plays a significantly larger role in their offspring's reproductive success. Bateman's paradigm thus views females as the limiting factor of parental investment, over which males will compete in order to copulate successfully.

Interlocus sexual conflict is a type of sexual conflict that occurs through the interaction of a set of antagonistic alleles at two or more different loci, or the location of a gene on a chromosome, in males and females, resulting in the deviation of either or both sexes from the fitness optima for the traits. A co-evolutionary arms race is established between the sexes in which either sex evolves a set of antagonistic adaptations that is detrimental to the fitness of the other sex. The potential for reproductive success in one organism is strengthened while the fitness of the opposite sex is weakened. Interlocus sexual conflict can arise due to aspects of male–female interactions such as mating frequency, fertilization, relative parental effort, female remating behavior, and female reproductive rate.

A behaviour mutation is a genetic mutation that alters genes that control the way in which an organism behaves, causing their behavioural patterns to change.

<span class="mw-page-title-main">Selection shadow</span>

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 fitness is not considered. Over generations, this results in maladaptive mutations that accumulate later in life due to aging being non-adaptive toward reproductive fitness. The concept was first worked out by J. B. S. Haldane and Peter Medawar in the 1940s, with Medawar creating the first graphical model.

<span class="mw-page-title-main">Peter Keightley</span>

Peter D. Keightley is a British geneticist who is Professor of Evolutionary Genetics at the Institute of Evolutionary Biology in School of Biological Sciences at the University of Edinburgh.

In biogerontology, the disposable soma theory of aging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance. Formulated by British biologist Thomas Kirkwood, the disposable soma theory explains that an organism only has a limited amount of resources that it can allocate to its various cellular processes. Therefore, a greater investment in growth and reproduction would result in reduced investment in DNA repair maintenance, leading to increased cellular damage, shortened telomeres, accumulation of mutations, compromised stem cells, and ultimately, senescence. Although many models, both animal and human, have appeared to support this theory, parts of it are still controversial. Specifically, while the evolutionary trade-off between growth and aging has been well established, the relationship between reproduction and aging is still without scientific consensus, and the cellular mechanisms largely undiscovered.

Extrinsic mortality is the sum of the effects of external factors, such as predation, starvation and other environmental factors not under control of the individual that cause death. This is opposed to intrinsic mortality, which is the sum of the effects of internal factors contributing to normal, chronologic aging, such as, for example, mutations due to DNA replication errors, and which determined species maximum lifespan. Extrinsic mortality plays a significant role in evolutionary theories of aging, as well as the discussion of health barriers across socioeconomic borders.

A mutation accumulation (MA) experiment is a genetic experiment in which isolated and inbred lines of organisms are maintained such that the effect of natural selection is minimized, with the aim of quantitatively estimating the rates at which spontaneous mutations occur in the studied organism. Spontaneous mutation rates may be directly estimated using molecular techniques such as DNA sequencing, or indirectly estimated using phenotypic assays.

References

  1. 1 2 3 Medawar, Peter Brian (1952). An unsolved problem of Biology. London: H. K. Lewis & Co. Ltd.
  2. 1 2 3 Fabian, Daniel (2011). "The Evolution of Aging". Nature Education Knowledge. 3: 1–10.
  3. 1 2 Gavrilov, Leonid A.; Gavrilova, Natalia S. (2002). "Evolutionary Theories of Aging and Longevity". The Scientific World Journal. 2: 339–356. doi: 10.1100/tsw.2002.96 . ISSN   1537-744X. PMC   6009642 . PMID   12806021.
  4. ↑ Flatt, Thomas; Schmidt, Paul S. (2009). "Integrating evolutionary and molecular genetics of aging". Biochimica et Biophysica Acta (BBA) - General Subjects. 1790 (10): 951–962. doi:10.1016/j.bbagen.2009.07.010. ISSN   0304-4165. PMC   2972575 . PMID   19619612.
  5. ↑ Hughes, Kimberly A.; Reynolds, Rose M. (2005). "Evolutionary and Mechanistic Theories of Aging". Annual Review of Entomology. 50 (1): 421–445. doi:10.1146/annurev.ento.50.071803.130409. ISSN   0066-4170. PMID   15355246.
  6. ↑ HOLMES, DONNA J.; AUSTAD, STEVEN N. (1995). "The Evolution of Avian Senescence Patterns: Implications for Understanding Primary Aging Processes". American Zoologist. 35 (4): 307–317. doi: 10.1093/icb/35.4.307 . ISSN   0003-1569.
  7. ↑ Austad, S. N.; Fischer, K. E. (1991-03-01). "Mammalian Aging, Metabolism, and Ecology: Evidence From the Bats and Marsupials". Journal of Gerontology. 46 (2): B47–B53. doi:10.1093/geronj/46.2.b47. ISSN   0022-1422. PMID   1997563.
  8. ↑ Keller, Laurent; Genoud, Michel (October 1997). "Extraordinary lifespans in ants: a test of evolutionary theories of aging". Nature. 389 (6654): 958–960. Bibcode:1997Natur.389..958K. doi:10.1038/40130. ISSN   0028-0836. S2CID   4423161.
  9. ↑ Hughes, K. A., Alipaz, J. A., Drnevich, J. M., & Reynolds, R. M. (2002). A test of evolutionary theories of aging. Proceedings of the National Academy of Sciences, 99(22), 14286-14291.
  10. ↑ Pletcher, Scott D.; Curtsinger, James W. (April 1998). "Mortality Plateaus and the Evolution of Senescence: Why are Old-Age Mortality Rates so Low?". Evolution. 52 (2): 454–464. doi:10.2307/2411081. ISSN   0014-3820. JSTOR   2411081. PMID   28568338.
  11. ↑ Le Bourg, Eric (2001-02-08). "A mini-review of the evolutionary theories of ageing". Demographic Research. 4: 1–28. doi: 10.4054/demres.2001.4.1 . ISSN   1435-9871.
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