6.5: Mutations - Biology

6.5: Mutations - Biology

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Learning Objectives

  • Compare point mutations and frameshift mutations
  • Describe the differences between missense, nonsense, and silent mutations
  • Explain how different mutagens act
  • Compare different types o f repair mechanisms
  • Explain why the Ames test can be used to detect carcinogens
  • Analyze sequences of DNA and identify examples of types of mutations

A mutation is a heritable change in the DNA sequence of an organism. The resulting organism, called a mutant, may have a recognizable change in phenotype compared to the wild type, which is the phenotype most commonly observed in nature. A change in the DNA sequence is conferred to mRNA through transcription, and may lead to an altered amino acid sequence in a protein on translation. Because proteins carry out the vast majority of cellular functions, a change in amino acid sequence in a protein may lead to an altered phenotype for the cell and organism.

Effects of Mutations on DNA Sequence

There are several types of mutations that are classified according to how the DNA molecule is altered. One type, called a point mutation, affects a single base and most commonly occurs when one base is substituted or replaced by another. Mutations also result from the addition of one or more bases, known as an insertion, or the removal of one or more bases, known as a deletion.

Exercise (PageIndex{1})

What type of a mutation occurs when a gene has two fewer nucleotides in its sequence?

Effects of Mutations on Protein Structure and Function

Point mutations may have a wide range of effects on protein function (Figure (PageIndex{1})). As a consequence of the degeneracy of the genetic code, a point mutation will commonly result in the same amino acid being incorporated into the resulting polypeptide despite the sequence change. This change would have no effect on the protein’s structure, and is thus called a silent mutation. A missense mutation results in a different amino acid being incorporated into the resulting polypeptide. The effect of a missense mutation depends on how chemically different the new amino acid is from the wild-type amino acid. The location of the changed amino acid within the protein also is important. For example, if the changed amino acid is part of the enzyme’s active site, then the effect of the missense mutation may be significant. Many missense mutations result in proteins that are still functional, at least to some degree. Sometimes the effects of missense mutations may be only apparent under certain environmental conditions; such missense mutations are called conditional mutations. Rarely, a missense mutation may be beneficial. Under the right environmental conditions, this type of mutation may give the organism that harbors it a selective advantage. Yet another type of point mutation, called a nonsense mutation, converts a codon encoding an amino acid (a sense codon) into a stop codon (a nonsense codon). Nonsense mutations result in the synthesis of proteins that are shorter than the wild type and typically not functional.

Deletions and insertions also cause various effects. Because codons are triplets of nucleotides, insertions or deletions in groups of three nucleotides may lead to the insertion or deletion of one or more amino acids and may not cause significant effects on the resulting protein’s functionality. However, frameshift mutations, caused by insertions or deletions of a number of nucleotides that are not a multiple of three are extremely problematic because a shift in the reading frame results (Figure (PageIndex{1})). Because ribosomes read the mRNA in triplet codons, frameshift mutations can change every amino acid after the point of the mutation. The new reading frame may also include a stop codon before the end of the coding sequence. Consequently, proteins made from genes containing frameshift mutations are nearly always nonfunctional.

Exercise (PageIndex{2})

  1. What are the reasons a nucleotide change in a gene for a protein might not have any effect on the phenotype of that gene?
  2. Is it possible for an insertion of three nucleotides together after the fifth nucleotide in a protein-coding gene to produce a protein that is shorter than normal? How or how not?

A Beneficial Mutation

Since the first case of infection with human immunodeficiency virus (HIV) was reported in 1981, nearly 40 million people have died from HIV infection,1 the virus that causes acquired immune deficiency syndrome (AIDS). The virus targets helper T cells that play a key role in bridging the innate and adaptive immune response, infecting and killing cells normally involved in the body’s response to infection. There is no cure for HIV infection, but many drugs have been developed to slow or block the progression of the virus. Although individuals around the world may be infected, the highest prevalence among people 15–49 years old is in sub-Saharan Africa, where nearly one person in 20 is infected, accounting for greater than 70% of the infections worldwide2 (Figure (PageIndex{2})). Unfortunately, this is also a part of the world where prevention strategies and drugs to treat the infection are the most lacking.

In recent years, scientific interest has been piqued by the discovery of a few individuals from northern Europe who are resistant to HIV infection. In 1998, American geneticist Stephen J. O’Brien at the National Institutes of Health (NIH) and colleagues published the results of their genetic analysis of more than 4,000 individuals. These indicated that many individuals of Eurasian descent (up to 14% in some ethnic groups) have a deletion mutation, called CCR5-delta 32, in the gene encoding CCR5. CCR5 is a coreceptor found on the surface of T cells that is necessary for many strains of the virus to enter the host cell. The mutation leads to the production of a receptor to which HIV cannot effectively bind and thus blocks viral entry. People homozygous for this mutation have greatly reduced susceptibility to HIV infection, and those who are heterozygous have some protection from infection as well.

It is not clear why people of northern European descent, specifically, carry this mutation, but its prevalence seems to be highest in northern Europe and steadily decreases in populations as one moves south. Research indicates that the mutation has been present since before HIV appeared and may have been selected for in European populations as a result of exposure to the plague or smallpox. This mutation may protect individuals from plague (caused by the bacterium Yersinia pestis) and smallpox (caused by the variola virus) because this receptor may also be involved in these diseases. The age of this mutation is a matter of debate, but estimates suggest it appeared between 1875 years to 225 years ago, and may have been spread from Northern Europe through Viking invasions.

This exciting finding has led to new avenues in HIV research, including looking for drugs to block CCR5 binding to HIV in individuals who lack the mutation. Although DNA testing to determine which individuals carry the CCR5-delta 32 mutation is possible, there are documented cases of individuals homozygous for the mutation contracting HIV. For this reason, DNA testing for the mutation is not widely recommended by public health officials so as not to encourage risky behavior in those who carry the mutation. Nevertheless, inhibiting the binding of HIV to CCR5 continues to be a valid strategy for the development of drug therapies for those infected with HIV.

Causes of Mutations

Mistakes in the process of DNA replication can cause spontaneous mutations to occur. The error rate of DNA polymerase is one incorrect base per billion base pairs replicated. Exposure to mutagens can cause induced mutations, which are various types of chemical agents or radiation (Table (PageIndex{1})). Exposure to a mutagen can increase the rate of mutation more than 1000-fold. Mutagens are often also carcinogens, agents that cause cancer. However, whereas nearly all carcinogens are mutagenic, not all mutagens are necessarily carcinogens.

Chemical Mutagens

Various types of chemical mutagens interact directly with DNA either by acting as nucleoside analogs or by modifying nucleotide bases. Chemicals called nucleoside analogs are structurally similar to normal nucleotide bases and can be incorporated into DNA during replication (Figure (PageIndex{3})). These base analogs induce mutations because they often have different base-pairing rules than the bases they replace. Other chemical mutagens can modify normal DNA bases, resulting in different base-pairing rules. For example, nitrous acid deaminates cytosine, converting it to uracil. Uracil then pairs with adenine in a subsequent round of replication, resulting in the conversion of a GC base pair to an AT base pair. Nitrous acid also deaminates adenine to hypoxanthine, which base pairs with cytosine instead of thymine, resulting in the conversion of a TA base pair to a CG base pair.

Chemical mutagens known as intercalating agents work differently. These molecules slide between the stacked nitrogenous bases of the DNA double helix, distorting the molecule and creating atypical spacing between nucleotide base pairs (Figure (PageIndex{4})). As a result, during DNA replication, DNA polymerase may either skip replicating several nucleotides (creating a deletion) or insert extra nucleotides (creating an insertion). Either outcome may lead to a frameshift mutation. Combustion products like polycyclic aromatic hydrocarbons are particularly dangerous intercalating agents that can lead to mutation-caused cancers. The intercalating agents ethidium bromide and acridine orange are commonly used in the laboratory to stain DNA for visualization and are potential mutagens.


Exposure to either ionizing or nonionizing radiation can each induce mutations in DNA, although by different mechanisms. Strong ionizing radiation like X-rays and gamma rays can cause single- and double-stranded breaks in the DNA backbone through the formation of hydroxyl radicals on radiation exposure (Figure (PageIndex{5})). Ionizing radiation can also modify bases; for example, the deamination of cytosine to uracil, analogous to the action of nitrous acid.3 Ionizing radiation exposure is used to kill microbes to sterilize medical devices and foods, because of its dramatic nonspecific effect in damaging DNA, proteins, and other cellular components.

Nonionizing radiation, like ultraviolet light, is not energetic enough to initiate these types of chemical changes. However, nonionizing radiation can induce dimer formation between two adjacent pyrimidine bases, commonly two thymines, within a nucleotide strand. During thymine dimer formation, the two adjacent thymines become covalently linked and, if left unrepaired, both DNA replication and transcription are stalled at this point. DNA polymerase may proceed and replicate the dimer incorrectly, potentially leading to frameshift or point mutations.

Table (PageIndex{1}): A Summary of Mutagenic Agents

Mutagenic AgentsMode of ActionEffect on DNAResulting Type of Mutation
Nucleoside analogs
2-aminopurineIs inserted in place of A but base pairs with CConverts AT to GC base pairPoint
5-bromouracilIs inserted in place of T but base pairs with GConverts AT to GC base pairPoint
Nucleotide-modifying agent
Nitrous oxideDeaminates C to UConverts GC to AT base pairPoint
Intercalating agents
Acridine orange, ethidium bromide, polycyclic aromatic hydrocarbonsDistorts double helix, creates unusual spacing between nucleotidesIntroduces small deletions and insertionsFrameshift
Ionizing radiation
X-rays, γ-raysForms hydroxyl radicalsCauses single- and double-strand DNA breaksRepair mechanisms may introduce mutations
X-rays, γ-raysModifies bases (e.g., deaminating C to U)Converts GC to AT base pairPoint
Nonionizing radiation
UltravioletForms pyrimidine (usually thymine) dimersCauses DNA replication errorsFrameshift or point

Exercise (PageIndex{3})

  1. How does a base analog introduce a mutation?
  2. How does an intercalating agent introduce a mutation?
  3. What type of mutagen causes thymine dimers?

DNA Repair

The process of DNA replication is highly accurate, but mistakes can occur spontaneously or be induced by mutagens. Uncorrected mistakes can lead to serious consequences for the phenotype. Cells have developed several repair mechanisms to minimize the number of mutations that persist.


Most of the mistakes introduced during DNA replication are promptly corrected by most DNA polymerases through a function called proofreading. In proofreading, the DNA polymerase reads the newly added base, ensuring that it is complementary to the corresponding base in the template strand before adding the next one. If an incorrect base has been added, the enzyme makes a cut to release the wrong nucleotide and a new base is added.

Mismatch Repair

Some errors introduced during replication are corrected shortly after the replication machinery has moved. This mechanism is called mismatch repair. The enzymes involved in this mechanism recognize the incorrectly added nucleotide, excise it, and replace it with the correct base. One example is the methyl-directed mismatch repair in E. coli. The DNA is hemimethylated. This means that the parental strand is methylated while the newly synthesized daughter strand is not. It takes several minutes before the new strand is methylated. Proteins MutS, MutL, and MutH bind to the hemimethylated site where the incorrect nucleotide is found. MutH cuts the nonmethylated strand (the new strand). An exonuclease removes a portion of the strand (including the incorrect nucleotide). The gap formed is then filled in by DNA pol III and ligase.

Repair of Thymine Dimers

Because the production of thymine dimers is common (many organisms cannot avoid ultraviolet light), mechanisms have evolved to repair these lesions. In nucleotide excision repair (also called dark repair), enzymes remove the pyrimidine dimer and replace it with the correct nucleotides (Figure (PageIndex{6})). In E. coli, the DNA is scanned by an enzyme complex. If a distortion in the double helix is found that was introduced by the pyrimidine dimer, the enzyme complex cuts the sugar-phosphate backbone several bases upstream and downstream of the dimer, and the segment of DNA between these two cuts is then enzymatically removed. DNA pol I replaces the missing nucleotides with the correct ones and DNA ligase seals the gap in the sugar-phosphate backbone.

The direct repair (also called light repair) of thymine dimers occurs through the process of photoreactivation in the presence of visible light. An enzyme called photolyase recognizes the distortion in the DNA helix caused by the thymine dimer and binds to the dimer. Then, in the presence of visible light, the photolyase enzyme changes conformation and breaks apart the thymine dimer, allowing the thymines to again correctly base pair with the adenines on the complementary strand. Photoreactivation appears to be present in all organisms, with the exception of placental mammals, including humans. Photoreactivation is particularly important for organisms chronically exposed to ultraviolet radiation, like plants, photosynthetic bacteria, algae, and corals, to prevent the accumulation of mutations caused by thymine dimer formation

Exercise (PageIndex{4})

  1. During mismatch repair, how does the enzyme recognize which is the new and which is the old strand?
  2. How does an intercalating agent introduce a mutation?
  3. What type of mutation does photolyase repair?

Identifying Bacterial Mutants

One common technique used to identify bacterial mutants is called replica plating. This technique is used to detect nutritional mutants, called auxotrophs, which have a mutation in a gene encoding an enzyme in the biosynthesis pathway of a specific nutrient, such as an amino acid. As a result, whereas wild-type cells retain the ability to grow normally on a medium lacking the specific nutrient, auxotrophs are unable to grow on such a medium. During replica plating (Figure (PageIndex{7})), a population of bacterial cells is mutagenized and then plated as individual cells on a complex nutritionally complete plate and allowed to grow into colonies. Cells from these colonies are removed from this master plate, often using sterile velvet. This velvet, containing cells, is then pressed in the same orientation onto plates of various media. At least one plate should also be nutritionally complete to ensure that cells are being properly transferred between the plates. The other plates lack specific nutrients, allowing the researcher to discover various auxotrophic mutants unable to produce specific nutrients. Cells from the corresponding colony on the nutritionally complete plate can be used to recover the mutant for further study.

Exercise (PageIndex{5})

Why are cells plated on a nutritionally complete plate in addition to nutrient-deficient plates when looking for a mutant?

The Ames Test

The Ames test, developed by Bruce Ames (1928–) in the 1970s, is a method that uses bacteria for rapid, inexpensive screening of the carcinogenic potential of new chemical compounds. The test measures the mutation rate associated with exposure to the compound, which, if elevated, may indicate that exposure to this compound is associated with greater cancer risk. The Ames test uses as the test organism a strain of Salmonella typhimurium that is a histidine auxotroph, unable to synthesize its own histidine because of a mutation in an essential gene required for its synthesis. After exposure to a potential mutagen, these bacteria are plated onto a medium lacking histidine, and the number of mutants regaining the ability to synthesize histidine is recorded and compared with the number of such mutants that arise in the absence of the potential mutagen (Figure (PageIndex{8})). Chemicals that are more mutagenic will bring about more mutants with restored histidine synthesis in the Ames test. Because many chemicals are not directly mutagenic but are metabolized to mutagenic forms by liver enzymes, rat liver extract is commonly included at the start of this experiment to mimic liver metabolism. After the Ames test is conducted, compounds identified as mutagenic are further tested for their potential carcinogenic properties by using other models, including animal models like mice and rats.

Exercise (PageIndex{6})

  1. What mutation is used as an indicator of mutation rate in the Ames test?
  2. Why can the Ames test work as a test for carcinogenicity?

Key Concepts and Summary

  • A mutation is a heritable change in DNA. A mutation may lead to a change in the amino-acid sequence of a protein, possibly affecting its function.
  • A point mutation affects a single base pair. A point mutation may cause a silent mutation if the mRNA codon codes for the same amino acid, a missense mutation if the mRNA codon codes for a different amino acid, or a nonsense mutation if the mRNA codon becomes a stop codon.
  • Missense mutations may retain function, depending on the chemistry of the new amino acid and its location in the protein. Nonsense mutations produce truncated and frequently nonfunctional proteins.
  • A frameshift mutation results from an insertion or deletion of a number of nucleotides that is not a multiple of three. The change in reading frame alters every amino acid after the point of the mutation and results in a nonfunctional protein.
  • Spontaneous mutations occur through DNA replication errors, whereas induced mutations occur through exposure to a mutagen.
  • Mutagenic agents are frequently carcinogenic but not always. However, nearly all carcinogens are mutagenic.
  • Chemical mutagens include base analogs and chemicals that modify existing bases. In both cases, mutations are introduced after several rounds of DNA replication.
  • Ionizing radiation, such as X-rays and γ-rays, leads to breakage of the phosphodiester backbone of DNA and can also chemically modify bases to alter their base-pairing rules.
  • Nonionizing radiation like ultraviolet light may introduce pyrimidine (thymine) dimers, which, during DNA replication and transcription, may introduce frameshift or point mutations.
  • Cells have mechanisms to repair naturally occurring mutations. DNA polymerase has proofreading activity. Mismatch repair is a process to repair incorrectly incorporated bases after DNA replication has been completed.
  • Pyrimidine dimers can also be repaired. In nucleotide excision repair (dark repair), enzymes recognize the distortion introduced by the pyrimidine dimer and replace the damaged strand with the correct bases, using the undamaged DNA strand as a template. Bacteria and other organisms may also use direct repair, in which the photolyase enzyme, in the presence of visible light, breaks apart the pyrimidines.
  • Through comparison of growth on the complete plate and lack of growth on media lacking specific nutrients, specific loss-of-function mutants called auxotrophs can be identified.
  • The Ames test is an inexpensive method that uses auxotrophic bacteria to measure mutagenicity of a chemical compound. Mutagenicity is an indicator of carcinogenic potential.


  1. 1 World Health Organization. “ Global Health Observatory (GHO) Data, HIV/AIDS.” Accessed August 5, 2016.
  2. 2 World Health Organization. Accessed August 5, 2016.
  3. 3 K.R. Tindall et al. “Changes in DNA Base Sequence Induced by Gamma-Ray Mutagenesis of Lambda Phage and Prophage.” Genetics 118 no. 4 (1988):551–560.

Mutation theory

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Mutation theory, idea that new species are formed from the sudden and unexpected emergence of alterations in their defining traits. Advanced at the beginning of the 20th century by Dutch botanist and geneticist Hugo de Vries in his Die Mutationstheorie (1901–03 The Mutation Theory), mutation theory joined two seemingly opposed traditions of evolutionary thought. First, its practitioners, often referred to as mutationists, accepted the primary contention of saltationist theory, which argued that new species are produced rapidly through discontinuous transformations. Saltationist theory contradicted Darwinism, which held that species evolved through the gradual accumulation of variation over vast epochs. Second, mutationists tended to hold the strict Darwinian line that all differentiation is for the good of the species, which differed from the saltationist idea that some organismic variations are inherently undesirable. The second argument was premised on the belief that more variation provided better opportunities for adaptation to a variable environment. The dovetailing of seemingly antithetical traditions made mutation theory one of the vanguard movements in early 20th-century evolutionary and genetic theory.

De Vries held that new species arrive suddenly and without prior precedent through the process of mutation, which he considered to be the change of one species into another due to the formation of “a new center of analogous variations.” Rather than simply argue that species are discontinuous from each other—as in the case of neo-Lamarckism—mutation theory suggested that variations themselves are discontinuous, as in the cases of dwarfism, giantism, and albinism. Based on his observations of common evening primrose ( Oenothera lamarckiana), which occasionally spawns offspring that differ significantly in leaf traits and overall size from parent generations and that sometimes cannot be crossed with parent generations, de Vries argued that new species came into existence fully formed and viable but lacking the defining characteristics of the parent generation. Thus, de Vries’s analysis focused on the creative force of discontinuity as a prime explanation for the origin of new species.

Mutation theory attempted to address a key lack in Darwinian analysis with respect to the incompleteness of the fossil record. Rather than insist that knowledge of the fossil record is insufficient to identify transitional stages in the gradual accumulation of incremental variations over time, de Vries’s mutation theory insisted that no such gaps in the genealogical trees of organisms existed. Thus, what appeared to be absences in the fossil record could be marshaled as evidence in favour of a Mendelian and saltationist-based theory of evolution.

Other mutationist theories were developed after de Vries’s work, including German-born American geneticist Richard Goldschmidt’s “hopeful monsters” theory and American paleontologists Stephen Jay Gould and Niles Eldredge’s punctuated equilibrium theory. Those ideas not only remained faithful to the saltationist basis for new species formation but also championed de Vries’s devotion to the pure Darwinian belief that allvariation proves beneficial. In doing so, mutationist theories recognized alternative viable organismic formations (often labeled “disabilities” at the human level) as examples of the creative force of new species coming into existence through mutation. That interpretation contradicted assertions by eugenicists and geneticists that some mutations are monstrosities or organismic abominations.

Selective and Environmental Pressures

Natural selection only acts on the population’s heritable traits: selecting for beneficial alleles and thus increasing their frequency in the population, while selecting against deleterious alleles and thereby decreasing their frequency—a process known as adaptive evolution. Natural selection does not act on individual alleles, however, but on entire organisms. An individual may carry a very beneficial genotype with a resulting phenotype that, for example, increases the ability to reproduce (fecundity), but if that same individual also carries an allele that results in a fatal childhood disease, that fecundity phenotype will not be passed on to the next generation because the individual will not live to reach reproductive age. Natural selection acts at the level of the individual it selects for individuals with greater contributions to the gene pool of the next generation, known as an organism’s evolutionary (Darwinian) fitness.

Fitness is often quantifiable and is measured by scientists in the field. However, it is not the absolute fitness of an individual that counts, but rather how it compares to the other organisms in the population. This concept, called relative fitness, allows researchers to determine which individuals are contributing additional offspring to the next generation, and thus, how the population might evolve.

There are several ways selection can affect population variation: stabilizing selection, directional selection, diversifying selection, frequency-dependent selection, and sexual selection. As natural selection influences the allele frequencies in a population, individuals can either become more or less genetically similar and the phenotypes displayed can become more similar or more disparate.

Stabilizing Selection

If natural selection favors an average phenotype, selecting against extreme variation, the population will undergo stabilizing selection (Figure 1a). In a population of mice that live in the woods, for example, natural selection is likely to favor individuals that best blend in with the forest floor and are less likely to be spotted by predators. Assuming the ground is a fairly consistent shade of brown, those mice whose fur is most closely matched to that color will be most likely to survive and reproduce, passing on their genes for their brown coat. Mice that carry alleles that make them a bit lighter or a bit darker will stand out against the ground and be more likely to fall victim to predation. As a result of this selection, the population’s genetic variance will decrease.

Directional Selection

When the environment changes, populations will often undergo directional selection (Figure 1b), which selects for phenotypes at one end of the spectrum of existing variation. A classic example of this type of selection is the evolution of the peppered moth in eighteenth- and nineteenth-century England. Prior to the Industrial Revolution, the moths were predominately light in color, which allowed them to blend in with the light-colored trees and lichens in their environment. But as soot began spewing from factories, the trees became darkened, and the light-colored moths became easier for predatory birds to spot. Over time, the frequency of the melanic form of the moth increased because they had a higher survival rate in habitats affected by air pollution because their darker coloration blended with the sooty trees. Similarly, the hypothetical mouse population may evolve to take on a different coloration if something were to cause the forest floor where they live to change color. The result of this type of selection is a shift in the population’s genetic variance toward the new, fit phenotype.

Diversifying Selection

Sometimes two or more distinct phenotypes can each have their advantages and be selected for by natural selection, while the intermediate phenotypes are, on average, less fit. Known as diversifying selection (Figure 1c), this is seen in many populations of animals that have multiple male forms. Large, dominant alpha males obtain mates by brute force, while small males can sneak in for furtive copulations with the females in an alpha male’s territory. In this case, both the alpha males and the “sneaking” males will be selected for, but medium-sized males, which can’t overtake the alpha males and are too big to sneak copulations, are selected against. Diversifying selection can also occur when environmental changes favor individuals on either end of the phenotypic spectrum. Imagine a population of mice living at the beach where there is light-colored sand interspersed with patches of tall grass. In this scenario, light-colored mice that blend in with the sand would be favored, as well as dark-colored mice that can hide in the grass. Medium-colored mice, on the other hand, would not blend in with either the grass or the sand, and would thus be more likely to be eaten by predators. The result of this type of selection is increased genetic variance as the population becomes more diverse.

Practice Question

Figure 1. Different types of natural selection can impact the distribution of phenotypes within a population. In (a) stabilizing selection, an average phenotype is favored. In (b) directional selection, a change in the environment shifts the spectrum of phenotypes observed. In (c) diversifying selection, two or more extreme phenotypes are selected for, while the average phenotype is selected against.

In recent years, factories have become cleaner, and less soot is released into the environment. What impact do you think this has had on the distribution of moth color in the population?

Frequency-dependent Selection

Figure 2. A yellow-throated side-blotched lizard is smaller than either the blue-throated or orange-throated males and appears a bit like the females of the species, allowing it to sneak copulations. (credit: “tinyfroglet”/Flickr)

Another type of selection, called frequency-dependent selection, favors phenotypes that are either common (positive frequency-dependent selection) or rare (negative frequency-dependent selection). An interesting example of this type of selection is seen in a unique group of lizards of the Pacific Northwest. Male common side-blotched lizards come in three throat-color patterns: orange, blue, and yellow. Each of these forms has a different reproductive strategy: orange males are the strongest and can fight other males for access to their females blue males are medium-sized and form strong pair bonds with their mates and yellow males (Figure 2) are the smallest, and look a bit like females, which allows them to sneak copulations. Like a game of rock-paper-scissors, orange beats blue, blue beats yellow, and yellow beats orange in the competition for females. That is, the big, strong orange males can fight off the blue males to mate with the blue’s pair-bonded females, the blue males are successful at guarding their mates against yellow sneaker males, and the yellow males can sneak copulations from the potential mates of the large, polygynous orange males.

In this scenario, orange males will be favored by natural selection when the population is dominated by blue males, blue males will thrive when the population is mostly yellow males, and yellow males will be selected for when orange males are the most populous. As a result, populations of side-blotched lizards cycle in the distribution of these phenotypes—in one generation, orange might be predominant, and then yellow males will begin to rise in frequency. Once yellow males make up a majority of the population, blue males will be selected for. Finally, when blue males become common, orange males will once again be favored.

Negative frequency-dependent selection serves to increase the population’s genetic variance by selecting for rare phenotypes, whereas positive frequency-dependent selection usually decreases genetic variance by selecting for common phenotypes.

Sexual Selection

Males and females of certain species are often quite different from one another in ways beyond the reproductive organs. Males are often larger, for example, and display many elaborate colors and adornments, like the peacock’s tail, while females tend to be smaller and duller in decoration. Such differences are known as sexual dimorphisms (Figure 3), which arise from the fact that in many populations, particularly animal populations, there is more variance in the reproductive success of the males than there is of the females. That is, some males—often the bigger, stronger, or more decorated males—get the vast majority of the total matings, while others receive none. This can occur because the males are better at fighting off other males, or because females will choose to mate with the bigger or more decorated males. In either case, this variation in reproductive success generates a strong selection pressure among males to get those matings, resulting in the evolution of bigger body size and elaborate ornaments to get the females’ attention. Females, on the other hand, tend to get a handful of selected matings therefore, they are more likely to select more desirable males.

Sexual dimorphism varies widely among species, of course, and some species are even sex-role reversed. In such cases, females tend to have a greater variance in their reproductive success than males and are correspondingly selected for the bigger body size and elaborate traits usually characteristic of males.

Figure 3. Sexual dimorphism is observed in (a) peacocks and peahens, (b) Argiope appensa spiders (the female spider is the large one), and in (c) wood ducks. (credit “spiders”: modification of work by “Sanba38″/Wikimedia Commons credit “duck”: modification of work by Kevin Cole)

The selection pressures on males and females to obtain matings is known as sexual selection it can result in the development of secondary sexual characteristics that do not benefit the individual’s likelihood of survival but help to maximize its reproductive success. Sexual selection can be so strong that it selects for traits that are actually detrimental to the individual’s survival. Think, once again, about the peacock’s tail. While it is beautiful and the male with the largest, most colorful tail is more likely to win the female, it is not the most practical appendage. In addition to being more visible to predators, it makes the males slower in their attempted escapes. There is some evidence that this risk, in fact, is why females like the big tails in the first place. The speculation is that large tails carry risk, and only the best males survive that risk: the bigger the tail, the more fit the male. This idea is known as the handicap principle.

The good genes hypothesis states that males develop these impressive ornaments to show off their efficient metabolism or their ability to fight disease. Females then choose males with the most impressive traits because it signals their genetic superiority, which they will then pass on to their offspring. Though it might be argued that females should not be picky because it will likely reduce their number of offspring, if better males father more fit offspring, it may be beneficial. Fewer, healthier offspring may increase the chances of survival more than many, weaker offspring.

In both the handicap principle and the good genes hypothesis, the trait is said to be an honest signal of the males’ quality, thus giving females a way to find the fittest mates— males that will pass the best genes to their offspring.

No Perfect Organism

Natural selection is a driving force in evolution and can generate populations that are better adapted to survive and successfully reproduce in their environments. But natural selection cannot produce the perfect organism. Natural selection can only select on existing variation in the population it does not create anything from scratch. Thus, it is limited by a population’s existing genetic variance and whatever new alleles arise through mutation and gene flow.

Natural selection is also limited because it works at the level of individuals, not alleles, and some alleles are linked due to their physical proximity in the genome, making them more likely to be passed on together (linkage disequilibrium). Any given individual may carry some beneficial alleles and some unfavorable alleles. It is the net effect of these alleles, or the organism’s fitness, upon which natural selection can act. As a result, good alleles can be lost if they are carried by individuals that also have several overwhelmingly bad alleles likewise, bad alleles can be kept if they are carried by individuals that have enough good alleles to result in an overall fitness benefit.

Furthermore, natural selection can be constrained by the relationships between different polymorphisms. One morph may confer a higher fitness than another, but may not increase in frequency due to the fact that going from the less beneficial to the more beneficial trait would require going through a less beneficial phenotype. Think back to the mice that live at the beach. Some are light-colored and blend in with the sand, while others are dark and blend in with the patches of grass. The dark-colored mice may be, overall, more fit than the light-colored mice, and at first glance, one might expect the light-colored mice be selected for a darker coloration. But remember that the intermediate phenotype, a medium-colored coat, is very bad for the mice—they cannot blend in with either the sand or the grass and are more likely to be eaten by predators. As a result, the light-colored mice would not be selected for a dark coloration because those individuals that began moving in that direction (began being selected for a darker coat) would be less fit than those that stayed light.

Finally, it is important to understand that not all evolution is adaptive. While natural selection selects the fittest individuals and often results in a more fit population overall, other forces of evolution, including genetic drift and gene flow, often do the opposite: introducing deleterious alleles to the population’s gene pool. Evolution has no purpose—it is not changing a population into a preconceived ideal. It is simply the sum of the various forces described in this chapter and how they influence the genetic and phenotypic variance of a population.

In Summary: Selective and Environmental Pressures

Because natural selection acts to increase the frequency of beneficial alleles and traits while decreasing the frequency of deleterious qualities, it is adaptive evolution. Natural selection acts at the level of the individual, selecting for those that have a higher overall fitness compared to the rest of the population. If the fit phenotypes are those that are similar, natural selection will result in stabilizing selection, and an overall decrease in the population’s variation. Directional selection works to shift a population’s variance toward a new, fit phenotype, as environmental conditions change. In contrast, diversifying selection results in increased genetic variance by selecting for two or more distinct phenotypes.

Other types of selection include frequency-dependent selection, in which individuals with either common (positive frequency-dependent selection) or rare (negative frequency-dependent selection) phenotypes are selected for. Finally, sexual selection results from the fact that one sex has more variance in the reproductive success than the other. As a result, males and females experience different selective pressures, which can often lead to the evolution of phenotypic differences, or sexual dimorphisms, between the two.


Nuclear and mitochondrial DNA are thought to be of separate evolutionary origin, with the mtDNA being derived from the circular genomes of bacteria engulfed by the early ancestors of today's eukaryotic cells. This theory is called the endosymbiotic theory. In the cells of extant organisms, the vast majority of the proteins present in the mitochondria (numbering approximately 1500 different types in mammals) are coded for by nuclear DNA, but the genes for some, if not most, of them are thought to have originally been of bacterial origin, having since been transferred to the eukaryotic nucleus during evolution. [8]

The reasons why mitochondria have retained some genes are debated. The existence in some species of mitochondrion-derived organelles lacking a genome [9] suggests that complete gene loss is possible, and transferring mitochondrial genes to the nucleus has several advantages. [10] The difficulty of targeting remotely-produced hydrophobic protein products to the mitochondrion is one hypothesis for why some genes are retained in mtDNA [11] colocalisation for redox regulation is another, citing the desirability of localised control over mitochondrial machinery. [12] Recent analysis of a wide range of mtDNA genomes suggests that both these features may dictate mitochondrial gene retention. [8]

Across all organisms, there are six main genome types found in mitochondrial genomes, classified by their structure (i.e. circular versus linear), size, presence of introns or plasmid like structures, and whether the genetic material is a singular molecule or collection of homogeneous or heterogeneous molecules. [13]

In many unicellular organisms (e.g., the ciliate Tetrahymena and the green alga Chlamydomonas reinhardtii), and in rare cases also in multicellular organisms (e.g. in some species of Cnidaria), the mtDNA is found as linearly organized DNA. Most of these linear mtDNAs possess telomerase-independent telomeres (i.e., the ends of the linear DNA) with different modes of replication, which have made them interesting objects of research because many of these unicellular organisms with linear mtDNA are known pathogens. [14]

Animals Edit

Most animals, specifically bilaterian animals, have a circular mitochondrial genome. Medusozoa and calcarea clades however have species with linear mitochondrial chromosomes. [15]

In terms of base pairs, the anemone Isarachnanthus nocturnus has the largest mitochondrial genome of any animal at 80,923 bp. [16]

In February 2020, a jellyfish-related parasite – Henneguya salminicola – was discovered that lacks mitochondrial genome but retains structures deemed mitochondrion-related organelles. Moreover, nuclear DNA genes involved in aerobic respiration and in mitochondrial DNA replication and transcription were either absent or present only as pseudogenes. This is the first multicellular organism known to have this absence of aerobic respiration and lives completely free of oxygen dependency. [17] [18]

Plants and fungi Edit

There are three different mitochondrial genome types found in plants and fungi. The first type is a circular genome that has introns (type 2) and may range from 19 to 1000 kbp in length. The second genome type is a circular genome (about 20–1000 kbp) that also has a plasmid-like structure (1 kb) (type 3). The final genome type that can be found in plants and fungi is a linear genome made up of homogeneous DNA molecules (type 5).

Great variation in mtDNA gene content and size exists among fungi and plants, although there appears to be a core subset of genes that are present in all eukaryotes (except for the few that have no mitochondria at all). [8] Some plant species have enormous mitochondrial genomes, with Silene conica mtDNA containing as many as 11,300,000 base pairs. [19] Surprisingly, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs. [20] The genome of the mitochondrion of the cucumber (Cucumis sativus) consists of three circular chromosomes (lengths 1556, 84 and 45 kilobases), which are entirely or largely autonomous with regard to their replication. [21]

Protists Edit

Protists contain the most diverse mitochondrial genomes, with five different types found in this kingdom. Type 2, type 3 and type 5 mentioned in the plant and fungal genomes also exist in some protists, as do two unique genome types. One of these unique types is a heterogeneous collection of circular DNA molecules (type 4) while the other is a heterogeneous collection of linear molecules (type 6). Genome types 4 and 6 each range from 1–200 kbp in size.

The smallest mitochondrial genome sequenced to date is the 5,967 bp mtDNA of the parasite Plasmodium falciparum. [22] [23]

Endosymbiotic gene transfer, the process by which genes that were coded in the mitochondrial genome are transferred to the cell's main genome, likely explains why more complex organisms such as humans have smaller mitochondrial genomes than simpler organisms such as protists.

Genome Type [13] Kingdom Introns Size Shape Description
1 Animal No 11–28 kbp Circular Single molecule
2 Fungi, Plant, Protista Yes 19–1000 kbp Circular Single molecule
3 Fungi, Plant, Protista No 20–1000 kbp Circular Large molecule and small plasmid like structures
4 Protista No 1–200 kbp Circular Heterogeneous group of molecules
5 Fungi, Plant, Protista No 1–200 kbp Linear Homogeneous group of molecules
6 Protista No 1–200 kbp Linear Heterogeneous group of molecules

Mitochondrial DNA is replicated by the DNA polymerase gamma complex which is composed of a 140 kDa catalytic DNA polymerase encoded by the POLG gene and two 55 kDa accessory subunits encoded by the POLG2 gene. [24] The replisome machinery is formed by DNA polymerase, TWINKLE and mitochondrial SSB proteins. TWINKLE is a helicase, which unwinds short stretches of dsDNA in the 5' to 3' direction. [25] All these polypeptides are encoded in the nuclear genome.

During embryogenesis, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo. [26] The resulting reduction in per-cell copy number of mtDNA plays a role in the mitochondrial bottleneck, exploiting cell-to-cell variability to ameliorate the inheritance of damaging mutations. [27] According to Justin St. John and colleagues, "At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm. [26] In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types." [26]

The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand. The heavy strand is rich in guanine and encodes 12 subunits of the oxidative phosphorylation system, two ribosomal RNAs (12S and 16S), and 14 tRNAs. The light strand encodes one subunit, and 8 tRNAs. So, altogether mtDNA encodes for two rRNAs, 22 tRNAs, and 13 proteins subunits, all of which are involved in the oxidative phosphorylation process. [28] [29]

The 37 genes of the Cambridge Reference Sequence for human mitochondrial DNA and their locations [30]
Gene Type Product Positions
in the mitogenome
MT-ATP8 protein coding ATP synthase, Fo subunit 8 (complex V) 08,366–08,572 (overlap with MT-ATP6) H
MT-ATP6 protein coding ATP synthase, Fo subunit 6 (complex V) 08,527–09,207 (overlap with MT-ATP8) H
MT-CO1 protein coding Cytochrome c oxidase, subunit 1 (complex IV) 05,904–07,445 H
MT-CO2 protein coding Cytochrome c oxidase, subunit 2 (complex IV) 07,586–08,269 H
MT-CO3 protein coding Cytochrome c oxidase, subunit 3 (complex IV) 09,207–09,990 H
MT-CYB protein coding Cytochrome b (complex III) 14,747–15,887 H
MT-ND1 protein coding NADH dehydrogenase, subunit 1 (complex I) 03,307–04,262 H
MT-ND2 protein coding NADH dehydrogenase, subunit 2 (complex I) 04,470–05,511 H
MT-ND3 protein coding NADH dehydrogenase, subunit 3 (complex I) 10,059–10,404 H
MT-ND4L protein coding NADH dehydrogenase, subunit 4L (complex I) 10,470–10,766 (overlap with MT-ND4) H
MT-ND4 protein coding NADH dehydrogenase, subunit 4 (complex I) 10,760–12,137 (overlap with MT-ND4L) H
MT-ND5 protein coding NADH dehydrogenase, subunit 5 (complex I) 12,337–14,148 H
MT-ND6 protein coding NADH dehydrogenase, subunit 6 (complex I) 14,149–14,673 L
MT-RNR2 protein coding Humanin
MT-TA transfer RNA tRNA-Alanine (Ala or A) 05,587–05,655 L
MT-TR transfer RNA tRNA-Arginine (Arg or R) 10,405–10,469 H
MT-TN transfer RNA tRNA-Asparagine (Asn or N) 05,657–05,729 L
MT-TD transfer RNA tRNA-Aspartic acid (Asp or D) 07,518–07,585 H
MT-TC transfer RNA tRNA-Cysteine (Cys or C) 05,761–05,826 L
MT-TE transfer RNA tRNA-Glutamic acid (Glu or E) 14,674–14,742 L
MT-TQ transfer RNA tRNA-Glutamine (Gln or Q) 04,329–04,400 L
MT-TG transfer RNA tRNA-Glycine (Gly or G) 09,991–10,058 H
MT-TH transfer RNA tRNA-Histidine (His or H) 12,138–12,206 H
MT-TI transfer RNA tRNA-Isoleucine (Ile or I) 04,263–04,331 H
MT-TL1 transfer RNA tRNA-Leucine (Leu-UUR or L) 03,230–03,304 H
MT-TL2 transfer RNA tRNA-Leucine (Leu-CUN or L) 12,266–12,336 H
MT-TK transfer RNA tRNA-Lysine (Lys or K) 08,295–08,364 H
MT-TM transfer RNA tRNA-Methionine (Met or M) 04,402–04,469 H
MT-TF transfer RNA tRNA-Phenylalanine (Phe or F) 00,577–00,647 H
MT-TP transfer RNA tRNA-Proline (Pro or P) 15,956–16,023 L
MT-TS1 transfer RNA tRNA-Serine (Ser-UCN or S) 07,446–07,514 L
MT-TS2 transfer RNA tRNA-Serine (Ser-AGY or S) 12,207–12,265 H
MT-TT transfer RNA tRNA-Threonine (Thr or T) 15,888–15,953 H
MT-TW transfer RNA tRNA-Tryptophan (Trp or W) 05,512–05,579 H
MT-TY transfer RNA tRNA-Tyrosine (Tyr or Y) 05,826–05,891 L
MT-TV transfer RNA tRNA-Valine (Val or V) 01,602–01,670 H
MT-RNR1 ribosomal RNA Small subunit : SSU (12S) 00,648–01,601 H
MT-RNR2 ribosomal RNA Large subunit : LSU (16S) 01,671–03,229 H

Between most (but not all) protein-coding regions, tRNAs are present (see the human mitochondrial genome map). During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleaved by specific enzymes. With the mitochondrial RNA processing, individual mRNA, rRNA, and tRNA sequences are released from the primary transcript. [31] Folded tRNAs therefore act as secondary structure punctuations. [32]

Regulation of transcription Edit

The promoters for the initiation of the transcription of the heavy and light strands are located in the main non-coding region of the mtDNA called the displacement loop, the D-loop. [28] There is evidence that the transcription of the mitochondrial rRNAs is regulated by the heavy-strand promoter 1 (HSP1), and the transcription of the polycistronic transcripts coding for the protein subunits are regulated by HSP2. [28]

Measurement of the levels of the mtDNA-encoded RNAs in bovine tissues has shown that there are major differences in the expression of the mitochondrial RNAs relative to total tissue RNA. [33] Among the 12 tissues examined the highest level of expression was observed in heart, followed by brain and steroidogenic tissue samples. [33]

As demonstrated by the effect of the trophic hormone ACTH on adrenal cortex cells, the expression of the mitochondrial genes may be strongly regulated by external factors, apparently to enhance the synthesis of mitochondrial proteins necessary for energy production. [33] Interestingly, while the expression of protein-encoding genes was stimulated by ACTH, the levels of the mitochondrial 16S rRNA showed no significant change. [33]

In most multicellular organisms, mtDNA is inherited from the mother (maternally inherited). Mechanisms for this include simple dilution (an egg contains on average 200,000 mtDNA molecules, whereas a healthy human sperm has been reported to contain on average 5 molecules), [34] [35] degradation of sperm mtDNA in the male genital tract and in the fertilized egg and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Whatever the mechanism, this single parent (uniparental inheritance) pattern of mtDNA inheritance is found in most animals, most plants and also in fungi.

In exceptional cases, human babies sometimes inherit mtDNA from both their fathers and their mothers resulting in mtDNA heteroplasmy. [36]

Female inheritance Edit

In sexual reproduction, mitochondria are normally inherited exclusively from the mother the mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. Also, mitochondria are only in the sperm tail, which is used for propelling the sperm cells and sometimes the tail is lost during fertilization. In 1999 it was reported that paternal sperm mitochondria (containing mtDNA) are marked with ubiquitin to select them for later destruction inside the embryo. [37] Some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may interfere with this.

The fact that mitochondrial DNA is mostly maternally inherited enables genealogical researchers to trace maternal lineage far back in time. (Y-chromosomal DNA, paternally inherited, is used in an analogous way to determine the patrilineal history.) This is usually accomplished on human mitochondrial DNA by sequencing the hypervariable control regions (HVR1 or HVR2), and sometimes the complete molecule of the mitochondrial DNA, as a genealogical DNA test. [38] HVR1, for example, consists of about 440 base pairs. These 440 base pairs are compared to the same regions of other individuals (either specific people or subjects in a database) to determine maternal lineage. Most often, the comparison is made with the revised Cambridge Reference Sequence. Vilà et al. have published studies tracing the matrilineal descent of domestic dogs from wolves. [39] The concept of the Mitochondrial Eve is based on the same type of analysis, attempting to discover the origin of humanity by tracking the lineage back in time.

The mitochondrial bottleneck Edit

Entities subject to uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet, the accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this through a developmental process known as the mtDNA bottleneck. The bottleneck exploits random processes in the cell to increase the cell-to-cell variability in mutant load as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo in which different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated, [40] [41] [42] [43] with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell. [27]

Male inheritance Edit

Male mitochondrial DNA inheritance has been discovered in Plymouth Rock chickens. [44] Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice, [45] [46] where the male-inherited mitochondria were subsequently rejected. It has also been found in sheep, [47] and in cloned cattle. [48] Rare cases of male mitochondrial inheritance have been documented in humans. [49] [50] [51] [52] Although many of these cases involve cloned embryos or subsequent rejection of the paternal mitochondria, others document in vivo inheritance and persistence under lab conditions.

Doubly uniparental inheritance of mtDNA is observed in bivalve mollusks. In those species, females have only one type of mtDNA (F), whereas males have F type mtDNA in their somatic cells, but M type of mtDNA (which can be as much as 30% divergent) in germline cells. [53] Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies, [54] [55] honeybees, [56] and periodical cicadas. [57]

Mitochondrial donation Edit

An IVF technique known as mitochondrial donation or mitochondrial replacement therapy (MRT) results in offspring containing mtDNA from a donor female, and nuclear DNA from the mother and father. In the spindle transfer procedure, the nucleus of an egg is inserted into the cytoplasm of an egg from a donor female which has had its nucleus removed, but still contains the donor female's mtDNA. The composite egg is then fertilized with the male's sperm. The procedure is used when a woman with genetically defective mitochondria wishes to procreate and produce offspring with healthy mitochondria. [58] The first known child to be born as a result of mitochondrial donation was a boy born to a Jordanian couple in Mexico on 6 April 2016. [59]

Susceptibility Edit

The concept that mtDNA is particularly susceptible to reactive oxygen species generated by the respiratory chain due to its proximity remains controversial. [60] mtDNA does not accumulate any more oxidative base damage than nuclear DNA. [61] It has been reported that at least some types of oxidative DNA damage are repaired more efficiently in mitochondria than they are in the nucleus. [62] mtDNA is packaged with proteins which appear to be as protective as proteins of the nuclear chromatin. [63] Moreover, mitochondria evolved a unique mechanism which maintains mtDNA integrity through degradation of excessively damaged genomes followed by replication of intact/repaired mtDNA. This mechanism is not present in the nucleus and is enabled by multiple copies of mtDNA present in mitochondria. [64] The outcome of mutation in mtDNA may be an alteration in the coding instructions for some proteins, [65] which may have an effect on organism metabolism and/or fitness.

Genetic illness Edit

Mutations of mitochondrial DNA can lead to a number of illnesses including exercise intolerance and Kearns–Sayre syndrome (KSS), which causes a person to lose full function of heart, eye, and muscle movements. Some evidence suggests that they might be major contributors to the aging process and age-associated pathologies. [66] Particularly in the context of disease, the proportion of mutant mtDNA molecules in a cell is termed heteroplasmy. The within-cell and between-cell distributions of heteroplasmy dictate the onset and severity of disease [67] and are influenced by complicated stochastic processes within the cell and during development. [27] [68]

Mutations in mitochondrial tRNAs can be responsible for severe diseases like the MELAS and MERRF syndromes. [69]

Mutations in nuclear genes that encode proteins that mitochondria use can also contribute to mitochondrial diseases. These diseases do not follow mitochondrial inheritance patterns, but instead follow Mendelian inheritance patterns. [70]

Use in disease diagnosis Edit

Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy. [71] [72] mtDNA alterations can be detected in the bio-fluids of patients with cancer. [73]

Relationship with aging Edit

Though the idea is controversial, some evidence suggests a link between aging and mitochondrial genome dysfunction. [74] In essence, mutations in mtDNA upset a careful balance of reactive oxygen species (ROS) production and enzymatic ROS scavenging (by enzymes like superoxide dismutase, catalase, glutathione peroxidase and others). However, some mutations that increase ROS production (e.g., by reducing antioxidant defenses) in worms increase, rather than decrease, their longevity. [60] Also, naked mole rats, rodents about the size of mice, live about eight times longer than mice despite having reduced, compared to mice, antioxidant defenses and increased oxidative damage to biomolecules. [75] Once, there was thought to be a positive feedback loop at work (a 'Vicious Cycle') as mitochondrial DNA accumulates genetic damage caused by free radicals, the mitochondria lose function and leak free radicals into the cytosol. A decrease in mitochondrial function reduces overall metabolic efficiency. [76] However, this concept was conclusively disproved when it was demonstrated that mice, which were genetically altered to accumulate mtDNA mutations at accelerated rate do age prematurely, but their tissues do not produce more ROS as predicted by the 'Vicious Cycle' hypothesis. [77] Supporting a link between longevity and mitochondrial DNA, some studies have found correlations between biochemical properties of the mitochondrial DNA and the longevity of species. [78] Extensive research is being conducted to further investigate this link and methods to combat aging. Presently, gene therapy and nutraceutical supplementation are popular areas of ongoing research. [79] [80] Bjelakovic et al. analyzed the results of 78 studies between 1977 and 2012, involving a total of 296,707 participants, and concluded that antioxidant supplements do not reduce all-cause mortality nor extend lifespan, while some of them, such as beta carotene, vitamin E, and higher doses of vitamin A, may actually increase mortality. [81]

Neurodegenerative diseases Edit

Increased mtDNA damage is a feature of several neurodegenerative diseases.

The brains of individuals with Alzheimer’s disease have elevated levels of oxidative DNA damage in both nuclear DNA and mtDNA, but the mtDNA has approximately 10-fold higher levels than nuclear DNA. [82] It has been proposed that aged mitochondria is the critical factor in the origin of neurodegeneration in Alzheimer’s disease. [83]

In Huntington’s disease, mutant huntingtin protein causes mitochondrial dysfunction involving inhibition of mitochondrial electron transport, higher levels of reactive oxygen species and increased oxidative stress. [84] Mutant huntingtin protein promotes oxidative damage to mtDNA, as well as nuclear DNA, that may contribute to Huntington’s disease pathology. [85]

The DNA oxidation product 8-oxoguanine (8-oxoG) is a well-established marker of oxidative DNA damage. In persons with amyotrophic lateral sclerosis (ALS), the enzymes that normally repair 8-oxoG DNA damages in the mtDNA of spinal motor neurons are impaired. [86] Thus oxidative damage to mtDNA of motor neurons may be a significant factor in the etiology of ALS.

Correlation of the mtDNA base composition with animal life spans Edit

Over the past decade, an Israeli research group led by Professor Vadim Fraifeld has shown that strong and significant correlations exist between the mtDNA base composition and animal species-specific maximum life spans. [87] [88] [89] As demonstrated in their work, higher mtDNA guanine + cytosine content (GC%) strongly associates with longer maximum life spans across animal species. An additional observation is that the mtDNA GC% correlation with the maximum life spans is independent of the well-known correlation between animal species metabolic rate and maximum life spans. The mtDNA GC% and resting metabolic rate explain the differences in animal species maximum life spans in a multiplicative manner (i.e., species maximum life span = their mtDNA GC% * metabolic rate). [88] To support the scientific community in carrying out comparative analyses between mtDNA features and longevity across animals, a dedicated database was built named MitoAge. [90]

Relationship with non-B (non-canonical) DNA structures Edit

Deletion breakpoints frequently occur within or near regions showing non-canonical (non-B) conformations, namely hairpins, cruciforms and cloverleaf-like elements. [91] Moreover, there is data supporting the involvement of helix-distorting intrinsically curved regions and long G-tetrads in eliciting instability events. In addition, higher breakpoint densities were consistently observed within GC-skewed regions and in the close vicinity of the degenerate sequence motif YMMYMNNMMHM. [92]

Unlike nuclear DNA, which is inherited from both parents and in which genes are rearranged in the process of recombination, there is usually no change in mtDNA from parent to offspring. Although mtDNA also recombines, it does so with copies of itself within the same mitochondrion. Because of this and because the mutation rate of animal mtDNA is higher than that of nuclear DNA, [93] mtDNA is a powerful tool for tracking ancestry through females (matrilineage) and has been used in this role to track the ancestry of many species back hundreds of generations.

The rapid mutation rate (in animals) makes mtDNA useful for assessing genetic relationships of individuals or groups within a species and also for identifying and quantifying the phylogeny (evolutionary relationships see phylogenetics) among different species. To do this, biologists determine and then compare the mtDNA sequences from different individuals or species. Data from the comparisons is used to construct a network of relationships among the sequences, which provides an estimate of the relationships among the individuals or species from which the mtDNAs were taken. mtDNA can be used to estimate the relationship between both closely related and distantly related species. Due to the high mutation rate of mtDNA in animals, the 3rd positions of the codons change relatively rapidly, and thus provide information about the genetic distances among closely related individuals or species. On the other hand, the substitution rate of mt-proteins is very low, thus amino acid changes accumulate slowly (with corresponding slow changes at 1st and 2nd codon positions) and thus they provide information about the genetic distances of distantly related species. Statistical models that treat substitution rates among codon positions separately, can thus be used to simultaneously estimate phylogenies that contain both closely and distantly related species [69]

Mitochondrial DNA was admitted into evidence for the first time ever in a United States courtroom in 1996 during State of Tennessee v. Paul Ware. [94]

In the 1998 United States court case of Commonwealth of Pennsylvania v. Patricia Lynne Rorrer, [95] mitochondrial DNA was admitted into evidence in the State of Pennsylvania for the first time. [96] [97] The case was featured in episode 55 of season 5 of the true crime drama series Forensic Files (season 5). [98]

Mitochondrial DNA was first admitted into evidence in California, United States, in the successful prosecution of David Westerfield for the 2002 kidnapping and murder of 7-year-old Danielle van Dam in San Diego: it was used for both human and dog identification. [99] This was the first trial in the U.S. to admit canine DNA. [100]

The remains of King Richard III, who died in 1485, were identified by comparing his mtDNA with that of two matrilineal descendants of his sister who were alive in 2013, 527 years after he died. [101]

mtDNA is conserved across eukaryotic organism given the critical role of mitochondria in cellular respiration. However, due to less efficient DNA repair (compared to nuclear DNA) it has a relatively high mutation rate (but slow compared to other DNA regions such as microsatellites) which makes it useful for studying the evolutionary relationships—phylogeny—of organisms. Biologists can determine and then compare mtDNA sequences among different species and use the comparisons to build an evolutionary tree for the species examined.

For instance, while most nuclear genes are nearly identical between humans and chimpanzees, their mitochondrial genomes are 9.8% different. Human and gorilla mitochondrial genomes are 11.8% different, suggesting that we may be more similar to chimps than gorillas. [102] However, when comparing nuclear DNA, humans and chimpanzees are at least 10% dissimilar, showing great discontinuity between the two species.

Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by electron microscopy as DNase-sensitive threads inside mitochondria, [103] and by Ellen Haslbrunner, Hans Tuppy and Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions. [104]

Several specialized databases have been founded to collect mitochondrial genome sequences and other information. Although most of them focus on sequence data, some of them include phylogenetic or functional information.

  • AmtDB: a database of ancient human mitochondrial genomes. [105]
  • InterMitoBase: an annotated database and analysis platform of protein-protein interactions for human mitochondria. [106] (apparently last updated in 2010, but still available)
  • MitoBreak: the mitochondrial DNA breakpoints database. [107]
  • MitoFish and MitoAnnotator: a mitochondrial genome database of fish. [108] See also Cawthorn et al. [109]
  • Mitome: a database for comparative mitochondrial genomics in metazoan animals [110] (no longer available)
  • MitoRes: a resource of nuclear-encoded mitochondrial genes and their products in metazoa [111] (apparently no longer being updated)
  • MitoSatPlant: Mitochondrial microsatellites database of viridiplantae. [112]
  • MitoZoa 2.0: a database for comparative and evolutionary analyses of mitochondrial genomes in Metazoa. [113] (no longer available)

Genome-wide association studies can reveal associations of mtDNA genes and their mutations with phenotypes including lifespan and disease risks. In 2021, the largest, UK Biobank-based, genome-wide association study of mitochondrial DNA unveiled 260 new associations with phenotypes including lifespan and disease risks for e.g. type 2 diabetes. [114] [115]

Mitochondrial mutation databases Edit

Several specialized databases exist that report polymorphisms and mutations in the human mitochondrial DNA, together with the assessment of their pathogenicity.

The Causes of Genetic Mutations

In Summary: Major Types of Mutations

DNA polymerase can make mistakes while adding nucleotides. Most mistakes are corrected, but if they are not, they may result in a mutation defined as a permanent change in the DNA sequence. Mutations can be of many types, such as substitution, deletion, insertion, and translocation. Mutations in repair genes may lead to serious consequences such as cancer. Mutations can be induced or may occur spontaneously.

5.10 Point Mutations Affect Gene Expression

Despite its fidelity, if DNA never incurred mistakes we would not have an evolutionary story to tell, and our world would not be characterized by such tremendous biodiversity. Mutations are mistakes that arise in DNA, either through random errors in DNA replication or through any one of a number of mutagenic agents—UV radiation, toxic compounds, etc. Mutations can affect whole chromosomes, large sections of chromosomes, or just a few nucleotides.

A type of mutation is the point mutation—a random change to one or a few DNA bases. These changes range from the “silent” mutation that has no effect, to mutations that alter amino acids without changing the fundamental nature of the protein, to mutations that render that gene nonfunctional,and may have detrimental effects at the organismal level.

Point mutations involve base substitutions, deletions, or insertions

A substitution mutation simply involves the replacement of one nucleotide for another. Substitutions may not change the amino acid sequence of a polypeptide. For example, a mutation in DNA that changes GAA to GAG will change the codon CUU to CUC either way, the translated amino acid is leucine and the polypeptide is unaltered. Even some aminoacid changes can have little effect on the expressed protein. However, simple substitutions can have profound consequences. For example, a simple substitution of a single base in the gene for hemoglobin results in the allele for sickle-cell anemia, a potentially fatal blood disorder.

A deletion mutation is caused by the removal of one or more nucleotides. A deletion of three bases will typically only affect one or two amino acids, but a deletion of one or two bases disrupts all the codons “downstream” of the mutation and affects the entire remaining reading frame of the gene (a frameshift mutation).

Figure 5.11 Two pairs of X chromosomes. In each pair, the chromosome on the left is unaffected, the one on the right has the mutation characteristic of fragile X syndrome. Fragile X is a example of a chromosomal mutation.

Many examples of the genetic disease cystic fibrosis are due to deletion mutations. Also, a deletion of 32 bases in a gene coding for a T-cell receptor protein (CCR5) alters the ability of HIV viruses to penetrate host cells. Individuals with this mutation (CCR5-del32) have decreased susceptibility to HIV infection, conferring some protection against AIDS.

Insertion mutations result from the addition of one or more nucleotides. Like deletions, insertions can affect the entire reading frame of the gene, or they can simply add one or more amino acids to the translated polypeptide. However, a number of three-nucleotide (or “trinucleotide”) repeat diseases exist and include Huntingtons disease and fragile X syndrome. In fragile X syndrome, several CAG triplets are inserted into the X chromosome. Individuals who inherit this disorder (especially males) may have profound mental retardation.

Figure 5.12 A summary of the types of point mutations discussed above.

Additional data files

The following additional data are available with the online version of this paper. Additional data file 1 contains replicate embryonic lethality measurements and corresponding P-values for synthetic lethality. Additional data file 2 contains data showing that double RNAi by soaking worms in dsRNA for two genes at once is an inefficient means of synthetic genetic analysis. Additional data file 3 lists primer sequences used in this study to amplify coding sequences from cDNA for use as templates for dsRNA.

6.5: Mutations - Biology

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.

Consequences of Point Mutations at the Molecular Level

Mutations that occur at a single nucleotide are called point mutations. When point mutations occur within genes, the consequences can vary in severity depending on what happens to the encoded amino acid sequence. A silent mutation does not change the amino acid identity and will have no effect on an organism. A missense mutation changes a single amino acid, and the effects might be serious if the change alters the function of the protein. A nonsense mutation produces a stop codon that truncates the protein, likely rendering it nonfunctional. Frameshift mutations occur when one or more nucleotides are inserted into or deleted from a protein-coding DNA sequence, affecting all of the codons downstream of the location of the mutation.

Chromosomal Alterations Are Large-Scale Mutations

The most drastic type of mutation, chromosomal alteration, changes the physical structure of a chromosome. Chromosomal alterations can include deletion, duplication, or inversion of large stretches of DNA within a single chromosome, or integration of a portion of a different chromosome. These mutations are typically far more serious than point mutations because they encompass many genes and regulatory elements. Chromosomal alterations can be detected by karyotyping the affected cell.

Only Germline Mutations Are Inherited

Mutations can occur in any cell, but only germline mutations&mdashthose present in egg and sperm cells&mdashcan be transmitted to offspring. For instance, hereditary diseases are a subtype of genetic disorder that are caused by deleterious germline mutations. They can be autosomal, occuring on chromosomes one through 22, or sex-linked, occurring on the X or Y chromosome. One example of a hereditary disease is cystic fibrosis (CF), a disease that primarily affects the lungs. It is caused by a deletion within the gene CFTR that removes a single amino acid from the CFTR protein. CF is an autosomal recessive disease, meaning that a person with one mutated copy of the gene and one normal copy will not develop the disease other diseases, like Huntington&rsquos disease, a neurodegenerative disorder, are autosomal dominant, meaning that only one mutated copy of the gene is necessary for the disease to develop.

Some Mutations Are Caused by Environmental Factors

Both somatic mutations&mdashthose that occur outside the germline&mdashand germline mutations can arise spontaneously during DNA replication, but they can also be caused by exposure to radiation or chemicals in the environment. External factors that damage DNA and cause mutations are called mutagens. One well-characterized environmental mutagen is ultraviolet (UV) radiation. UV radiation carries more energy than visible light and damages DNA by breaking the bonds between base pairs, causing thymine bases on the same strand of DNA to pair with one another in characteristic thymine dimers. The sun is a natural source of UV radiation. The most damaging wavelengths, UV-C, are intercepted high in the atmosphere, but UV-A and UV-B rays reach the surface of the Earth. Artificial sources of UV exposure include tanning beds, which transmit primarily UV-A rays with smaller amounts of UV-B. Fortunately, cells have mechanisms to repair damaged DNA, but sometimes the damage is not repaired before cell division in rapidly-dividing cells, such as skin cells. If the DNA damage occurs in a genomic region that is important for regulation of cell growth and division, it can lead to cancer if it is not repaired.

Mosaic Mutations May Not Be Rare

Anna Azvolinsky
Jun 5, 2015

WIKIMEDIA, DATABASE CENTER FOR LIFE SCIENCES Most novel mutations in an individual are thought to originate in the germline. Other mutations, somatic mosaic mutations&mdashwhich are only present in a subset of a person&rsquos cells&mdashcan either be passed down from a parent or originate during early development. Such mosaic mutations were thought to be fairly rare, but according to a study published today (June 5) in The American Journal of Human Genetics, they may contribute to as much as 6.5 percent of an individual&rsquos genomic variation. If confirmed, the results could affect how researchers estimate a person&rsquos risk of passing disease-linked alleles on to their children.

The findings &ldquohighlight that mosaicism may be more common than we had appreciated so far,&rdquo geneticist Anne Goriely of the University of Oxford wrote in an e-mail to The Scientist. &ldquoThe main value of the present study is an attempt to quantify.

Mosaicism can result when a de novo mutation arises after an embryo is formed. Using newer, more sensitive sequencing technologies, researchers have recently begun to identify mosaic mutations. For the present study, Alexander Hoischen of Radboud University Medical Center in Nijmegen, the Netherlands, and his colleagues used four different sequencing methods to estimate the frequency rate of this phenomenon in children.

Expanding on a previous sequencing effort to identify disease-causing de novo mutations in 50 children with intellectual disabilities by comparing their genomes to those of their two unaffected parents, the team produced three additional deep-sequencing data sets to assess the allelic ratios of 107 representative mutations. While a de novo mutation present in the child’s germline is typically present at a 50 percent allelic ratio, a lower ratio might suggest that that the mutation arose during embryogenesis.

Of these 107 mutations analyzed, seven (6.5 percent) were not detected in the parents’ germlines. Four de novo mutations—from a total of 4,081 suspected de novo mutations identified—occurred with a 50 percent frequency in the child but at a much lower frequency (about 3.5 frequency) in the blood samples of one of the parents. Despite the difference in frequency, the parent likely transmitted this mutation to the child through the germline, the researchers noted.

“Given the limitations of current sequencing technologies, this [frequency of mosaic mutations] may be just touching the tip of the iceberg,” said Philip Awadalla of the Ontario Institute for Cancer Research and the University of Toronto, who works on human population and medical genomics but was not involved in the current study.

Hoischen agreed. “This is probably a conservative estimate of these mutational events,” he said. While an allelic ratio between 20 percent and 40 percent hints at a mosaic mutation, currently genome-wide approaches cannot distinguish between noise and a low prevalence mutation for those mutations detected at a 10 percent ratio or less, he added.

The team also used modeling to determine the minimal allelic ratio for each of the sequencing techniques that likely reflects a true mosaic mutation rather than sequencing-related noise. While the current genomic sequencing standard is the need for at least 30-fold coverage, the authors suggested that at least 100-fold coverage is needed to identify true mosaic mutations present at an allelic frequency below 40 percent.

These results raise questions about the level of mosaicism in other tissues, the frequency with which these mutations are passed on to the next generation, and whether they might contribute to disease, said Awadalla.

“The textbook knowledge that our genome is identical in all the cells of our body is probably not true,” Hoischen told The Scientist.

“We consider ourselves as ‘individual’ partially because our genomic makeup is unique,” said Goriely. “But we are multicellular organisms, containing many populations of cells precisely organized into different tissues and organs. This study suggests that some of our cells carry different versions of our genomes. . . . The implication of this finding is profound, both from a clinical and a philosophical standpoint.”

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On Earth-1007, the X-Factor prevented a sterilization device from working on the mutants, instead reversing their gender. ⏟]

Blood Types

On Earth-11052, Wolverine's file stated his blood type was "D+Mutated", ⏠] instead of the classic blood types A, B, AB or O (+ or -).


For some reasons, mutants can't acquire AIDS, ⏡] unlike baseline humans.

They are for untold reasons also immune to possession from sentient bacterial-like early life beings such as That Which Endures, ⏢] the Harvester's doings ⏣] or Sublime. [citation needed]


The Terrigenesis (the use of Terrigen Mist in order to activate the Inhumans' powers) have variant effects on mutants (powered or not). It was poisonous and caused mutants to develop M-Pox.

For more information, please visit the Terrigenesis page, and the section regarding its effects on mutants.


On Earth-13270, two mutations can't grow and develop alongside each other: Peter Parker had his mutant genes repressed during his adolescence and adulthood, until he lost his mutate powers, and that was when his mutant status emerged. Ε]

Watch the video: Mutations u0026 Gene Transfer (October 2022).