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Mutation

  1. Raymond Devoret

Published Online: 11 MAR 2004

DOI: 10.1038/npg.els.0001882

eLS

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How to Cite

Devoret, R. 2004. Mutation. eLS. .

Author Information

  1. Curie Institute, Paris, France

Publication History

  1. Published Online: 11 MAR 2004

Introduction

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

Deoxyribonucleic acid (DNA) is the essential component of chromosomes in all known cells. Each chromosome is made of an extremely long DNA molecule with two intertwined complementary strands (a double helix). Each strand consists of a poly (phosphate–sugar) backbone, from which project adenine (A), cytosine (C), guanine (G), and thymine (T) bases at each sugar. The two strands form a duplex maintained by hydrogen bonds between complementary bases: A binds to T and G to C. The linear succession of combinations of A, C, G and T bases constitutes a genetic sequence (Figure 1).

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Figure 1. Types of mutation. (a) Wild-type original sequence; (b) transition from C to T; (c) transversion from G to C; (d) deletion (Del) of the sequence ACCTA, the sign indicates from where it has been removed; (e) insertion (Ins) of the sequence AAAGC, the two signs indicate where the sequence has been inserted.

The DNA of the whole set of chromosomes in a cell is called the genome. A bacterium like Escherichia coli, a natural resident of the intestinal tract of mammals, has one chromosome, whereas human cells carry 23 chromosome pairs. In general, the cells of complex organisms like mammals have more chromosomes per cell than lower organisms like microbes.

The main property of DNA is to code for the hereditary traits that are passed from parents to progeny. Recently, the long string of bases that constitutes the genome of many organisms, including humans, has been identified. This achievement has established the precise chromosome positioning of many genes that control hereditary traits. It was discovered that the genes that code for proteins performing DNA replication are similar in all living organisms. This emphasizes the strong conservation of the primary mechanism of cell division. Furthermore, the genes that control mutagenesis (the process leading to the production of mutations) are very much alike in different organisms. DNA is able to mutate so that living organisms can adapt to new environments.

Nature of Mutations

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

When a mutation occurs within a gene, the protein encoded by the gene is often altered (and 2c); this alteration may produce a visible change in the displayed characteristics (phenotype) of the organism studied. The actual mutation itself (genotype) is invisible to the naked eye.

Since a mutation is a DNA change, it must be defined in relation to a preceding, parental DNA sequence (Figure 1a). Note, however, that the parental genome sequence may already carry mutations; hence, geneticists have agreed to define a standard genetic sequence for each organism studied.

Three broad classes of mutation have been defined to characterize their effects on the organisms in which they arise: deleterious, neutral and advantageous. These qualifications are valid only in relation to a specific environment. For example, a human newborn has a 1/1600 probability of suffering from cystic fibrosis, a disease that prevents, in particular, the fluidity of lung secretions. This occurs if the child has received the two mutated cystic fibrosis gene copies from its parents. It means that 1/40 people carries one copy of the mutated gene; the afflicted individual has a ‘normal’ phenotype but exhibits resistance to acute infectious diarrhoea. The high frequency of that mutation in the population can be explained by its selective advantage. People die of cholera because a 20-litre diarrhoea per day kills them. People having one mutated allele of the cystic fibrosis gene survive because they lose much less water when infected with the cholera germ. In countries where cholera has long been endemic, one mutated cystic fibrosis allele can protect an individual against death from cholera.

Most Mutagens are DNA-damaging Agents

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

Naturally occurring mutations arise at low frequency. To obtain more mutations the geneticist Herman Muller irradiated germ cells of Drosophila with X-rays and discovered that radiation increases the frequency of mutations. Soon, it was found that chemicals such as mustard gas (yperite) also produce mutations at high frequency. Radiations and some chemicals produce mutations: they are called mutagens. Both X-rays and yperite break chromosomes. This property has been exploited in radiation therapy and chemotherapy for destroying tumours. Likewise, ultraviolet light and many chemicals alter DNA in numerous ways; these alterations are called DNA lesions.

DNA Lesions and Mutations

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

How can DNA-damaging agents produce mutations? In other words, how can a DNA lesion give rise to a mutation? DNA lesions display more than a hundred types of forms and shapes, yet 85% of the resulting mutations are just a change in one of the four known DNA bases; for example, adenine may change into cytosine, guanine or thymine.

Most chemicals, for example benzopyrene found in tobacco smoke, when absorbed are metabolized into compounds that stick to DNA to form adducts (grafts). DNA lesions are depicted with the vocabulary of chemistry, whereas mutations are described with a simple alphabet of four characters A, T, C and G, constituting the primary code of life.

It is wrong to consider DNA lesions as mutations. A whole set of biochemical reactions must proceed on the damaged DNA to restore a proper DNA sequence. Note that mutations are only observed in cells that have survived DNA damage: dead cells carry numerous lesions that have failed to be repaired.

Repair of DNA Lesions

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

Most DNA lesions block DNA replication. For a cell to survive, DNA lesions must either be removed from the chromosomes by repair processes or be bypassed by specific DNA polymerases. The polymerases generate a proper complementary single strand that will serve as the template to restore a double helix in a second round of replication.

Living organisms use at least 12 main repair processes to remove DNA lesions or to bypass them. Repair enzymes work with optimal efficiency when the number of lesions is low.

Interestingly, as soon as lesions are produced on DNA, they provoke the SOS response, which induces a cascade of repair processes. As repair fails at some DNA lesions, a mutagenic DNA polymerase inserts a base across the lesion, even if its coding value is incorrect. Structural restoration of a DNA double helix is primordial to permit replication and cell division.

Mutation Types, Reversions and Location

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

Since DNA is universal, one finds the same alphabet of four bases forming the genetic apparatus of all species. Mutation types are similar wherever they arise.

Point mutations

The most frequent are base substitutions. Substitutions between purines, adenine (A) and guanine (G), or between pyrimidines, cytosine (C) and thymine (T) (Figure 1b) are called transitions. An AT base pair may give rise to a GC (AT [RIGHTWARDS ARROW] GC) and, conversely, a GC base pair to an AT (GC [RIGHTWARDS ARROW] AT); the two-way reactions are represented as AT [LEFT RIGHT ARROW] GC.

Transversions are substitutions of a purine for a pyrimidine and vice versa (Figure 1c). There are four reciprocal base pair changes: AT [LEFT RIGHT ARROW] CG, AT [LEFT RIGHT ARROW] TA, GC [LEFT RIGHT ARROW] TA and GC [LEFT RIGHT ARROW] CG. Base substitutions occurring in protein-coding regions affect the expressed protein except when the change is in the third base of a codon (see neutral or synonymous mutation, Figure 2a).

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Figure 2. Types of substitutions in a protein-coding region: (a) synonymous, (b) missense, and (c) nonsense. In each case, the top sequence is wild type and the bottom sequence is mutated.

A mutation in a gene that may not cause any amino acid change in the expressed protein is called silent or synonymous, as it does not induce any change in the coded protein. In Figure 2a, the valine amino acid is conserved in the protein sequence, while molecular techniques reveal a DNA change.

A nonsynonymous mutation alters an amino acid, resulting in a missense or a nonsense mutation. A missense mutation modifies the affected codon, specifying an amino acid different from the one previously encoded, for instance, valine (Val) becomes phenylalanine (Phe) (Figure 2b). A nonsense mutation changes a codon into one of the three termination codons TAG, TAA or TGA. Then, a truncated protein is produced that rarely has activity, for instance, lysine (Lys) becomes a stop condon (Figure 2c).

Deletions and insertions

Examples of deletions and insertions are seen in Figure 1d. Moreover, an unequa crossing-over between two chromosomes results in the deletion of a DNA segment in one chromosome and an addition in the other.

Frameshifts

A small deletion or insertion within a gene, each involving a number of bases which is not a multiple of three, causes a shift in the reading frame, denoted frameshift (Figure 3a). In this case, the coding sequence downstream is read in a ‘wrong’ phase. This new phasing changes the encoded amino acids or else a new stop codon may be brought upstream into phase, thus producing a shortened protein. Figure 3a shows a protein that may not have normal activity. Figure 3b also shows that addition of a base produces a +1 frameshift, removing a preexisting stop signal and giving rise to an elongated protein.

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Figure 3. Examples of frameshifts caused by deletion or insertion. (a) A deletion of a G causes premature termination. (b) An insertion of a G obliterates a stop codon. Termination codons are underlined. In each case, the top sequence is wild type and the bottom sequence is mutated.

DNA rearrangements

Deletions of segments of genes or sets of genes reduce or eliminate protein functions (Figure 3). In addition, insertions of large DNA segments can also occur, as can duplications, inversions and other more complex DNA rearrangements. All these processes are the results of recombination between DNA sequences sharing some similarity. Agents that break chromosomes, such as X-rays and yperite, facilitate DNA rearrangements.

For instance, when a piece of human chromosome 14 carrying the Bcl2 gene, which prevents cell death, is translocated to chromosome 18, then the Bcl2 gene becomes expressed continuously. Cells will consequently produce mutated immunoglobulins, which are normally eliminated from the body by cell death but kept alive here because of the Bcl2 translocation. Thus, a pool of unhealthy cells builds gradually; point mutations accumulate in those unhealthy cells, which will eventually give rise to cancer cells.

Insertion of transposable genetic elements

Transposable genetic elements, also designated transposons or jumping genes, are found in almost every organism. Their most obvious behaviour is their mobility around chromosomes. If a transposon inserts into a gene encoding a protein, the gene is split into two pieces and the whole protein is no longer expressed. This is the negative aspect of transposon insertion. In contrast, there is a positive side when, in a gene regulatory region, an inserted transposon provides strong promoters that will increase the expression of downstream genes.

Mutation reversions: true or pseudoreversion of a mutation

Sometimes, after a few generations, a mutant organism reverts to the wild type. Has the mutation reverted to the original parental type? Not always, for the mutation may still remain in the DNA while a secondary mutation has occurred somewhere else, restoring a wild-type phenotype.

Mutation hotspots and mutations at regulatory sequences

Mutation hotspots

Mutations occur, on average, randomly along the genome, but more often than not, they crop up at some sites called hotspots. There is such a hotspot in the Escherichia coli chromosome: the dinucleotide CpG, in which the cytosine is frequently methylated and replicated, with introduction of an error, changes to TpG. Another mechanism is the deamination of methylcytosine, which produces thymine in the absence of replication. The dinucleotide TpT is a mutation hotspot in prokaryotes (but not in eukaryotes). Hotspots can be accounted for by the three-dimensional shape of DNA that generates some targets for specific enzymes like methylases.

In bacteria, regions within DNA containing short palindromes, i.e. sequences that read the same on the complementary strand, such as 5′GCCGGC3′, 5′GGCGCC3′ and 5′GGGCCC3′, are prone to mutate more frequently than other regions.

In eukaryotic genomes, short tandem repeats are often hotspots, resulting from slipped-strand mispairing (Figure 4).

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Figure 4. Generation of duplications or deletions by slipped-strand mispairing between contiguous repeats (bold red). Small arrows indicate the direction of DNA synthesis. Dots indicate base pairing. (a) A two-base slippage in a TA repeat during DNA replication. Slippage in the 3′ [RIGHTWARDS ARROW] 5′ direction results in the insertion of one TA unit (left panel). Slippage in the other direction results in the deletion of one repeat unit (right panel). The deletion shown in the right panel results from excision of the unpaired repeat unit (asterisks) at the 3′ end of the growing strands, presumably by the 3′ [RIGHTWARDS ARROW] 5′ exonuclease activity of DNA polymerase. (b) A two-base slippage in a TA repeat in nonreplicating DNA. Mismatched regions form single-stranded loops, which may be targets of excision or mismatch repair. The outcome (a deletion or an insertion) will depend on which strand is excised or repaired and which strand is used as template in the DNA repair process.

Mutations at regulatory sequences

DNA encodes sequences that control the expression of proteins, such as promoters and operators. These sequences, by undergoing a mutation, may alter the cell concentration of proteins encoded downstream of the regulatory sequence. Overexpression or underexpression of proteins may sharply modify the function of a gene in an organism. Since many proteins work in a concerted fashion, a sharp increase or decrease in the cell concentration of a protein may upset the organism.

Synonymous Mutations are Neutral

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

In a DNA sequence that codes for a protein, each of the sense codons can mutate to nine other codons by means of a single base substitution. For example, CCU, which codes for proline (Pro), can give rise to three synonymous substitutions CCC, CCA or CCG, which also code for Pro. In a different order, the triplet can give rise to six nonsynonymous substitutions, which code for different amino acids, UCU for serine (Ser), ACU for threonine (Thr), GCU for alanine (Ala), CUU for leucine (Leu), CAU for histidine (His), or CGU for arginine (Arg).

Since the genetic code defines 61 sense codons, the possible codon substitutions can be calculated to be 61 × 9 = 549. If we assume that base substitutions may occur at random and that all codons are equally frequent in regions coding for proteins, we can compute the expected proportion of the different types of base substitutions. Because of the structure of the genetic code, synonymous substitutions occur mainly at the third position of codons. Indeed, 69% of all the possible synonymous changes in a codon are at the third base position.

In contrast, substitutions at the second position of codons are nonsynonymous, and so are the vast majority of base changes at the first position (96%).

Synonymous amino acid replacements do not alter either protein structure or function. From an evolutionary viewpoint, these mutations are said to be neutral, as they do not seem to affect the fitness of the mutated organism. Such synonymous mutations accumulate with time as they are not counterselected. Indeed, synonymous mutations generate change at the DNA level, which has been visualized by the use of restriction enzymes and sequencing techniques. In the long run, the accumulation with time of synonymous mutations increases DNA divergence between individuals within a species. A new species can then emerge by segregation. Chimpanzees and humans have some proteins displaying a 99% similarity, but the DNA sequences in the two species have strongly diverged, preventing the formation of hybrid species by recombination.

A species is defined by the property of the individuals within a group to mate and give rise to progeny. At the molecular level, it means that the two parental DNAs are identical, so they can recombine. If genomic DNA accumulates third-base changes with time, the DNA of the mating pair becomes too divergent with respect to their common ancestor. The resulting diverged individuals may attempt to mate but they cannot give rise to a fertile progeny.

Mating is always followed by DNA recombination, which is successful only if it arises between two homologous DNAs. Mating is doomed to fail if it is forced to occur between two heterologous DNAs. The first step in recombination is the pairing of two DNA strands. When two heterologous DNA strands attempt to pair, base-to-base mismatches arise between the bases that should complement. Mismatches are removed by the induction of a very efficient repair process called mismatch repair. It has been shown that recombination between two heterologous DNAs is aborted by mismatch repair.

Mechanisms Generating Mutations

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

Spontaneous mutagenesis

Naturally occurring mutations may arise in any cell with no apparent cause. They result from four main mechanisms: (1) DNA polymerization errors; (2) spontaneous oxidative DNA damage; (3) loss of a purine base, or less frequently, loss of a pyrimidine base; and (4) deamination of cytosine and adenine.

Polymerization errors

Point mutations, usually transitions, arise as a result of two successive faulty processes: (1) an error in DNA replication; (2) an inefficient repair of the generated mismatches.

DNA polymerase incorporates an incorrect base at a frequency of about 10−6 to 10−7 per base pair per cell per generation. Normally, the incorrect base is removed by mismatch repair, which reduces the overall rate of replication and postreplication errors down to 10−9 to 10−10 per base pair per cell per generation (frequencies observed in E. coli).

Replication slippage, also called slipped-strand mispairing, is one of the major mechanisms that accounts for frameshift mutations occurring at contiguous short repeats (Figure 4).

Incorporation of an oxidized base

Exposed to oxygen, guanine is subject to oxidation, producing 8-oxo-G. This abnormal base slips into DNA, generating transversions. Fortunately, there is an elaborate repair system that either removes 8-oxo-G or decreases the consequences of its incorporation. Such a repair system is ubiquitous, protecting DNA from lesions due to oxygen.

In short, the oxygen we breathe is not harmless. Oxygen is a DNA-damaging agent and may play a role in the ageing process. The number of oxidative hits to DNA has been correlated with the amount of DNA breakdown products released in rat and human urine. The number of oxidative hits to DNA per cell per day is around 100 000 in the rat and about 10 000 in the human. The 10-fold difference may result in part from the greater metabolic rate of rodents, which is at least five times higher than that of mammals.

The mutagenic action of 8-oxo-G suggests that there is no clear-cut border between ‘natural’ and ‘artificial’ DNA-damaging agents. The difference between spontaneous and induced mutations is also blurred when th air we breathe induces the insertion of oxides into DNA.

Loss of a nucleic base

This is the most frequent spontaneously arising lesion. The bond between sugar and base can be severed, releasing a free base and leaving a gap in the sequence of bases, thus generating an abasic site (apurinic or apyrimidinic). Loss of a purine base is more frequent than loss of a pyrimidine base.

Replication over an abasic site may produce a point mutation, as the polymerase has no way of determining the identity of the missing base it has to copy. By a fortunate trick of Nature, adenine is frequently placed opposite the missing base. When the missing base is thymine, the placement of adenine restores the DNA code.

Deamination

This process may convert cytosine to uracil and adenine to hypoxanthine. Conversion of cytosine to uracil is favoured as the main cause of immunoglobin hypermutation, thus explaining how half a million of the antibodies constituting our immunological repertoire are made.

Induced mutations

They may result from three different mechanisms: (1) a base in the DNA is replaced by a base analogue that confuses the polymerase; (2) a base is chemically altered so that it mispairs with another base during replication; (3) a base is replaced by a DNA single-strand gap so that it does not convey any coding information. In the last case, a low-fidelity replicative mechanism (SOS mutagenic repair) is induced and bypasses the lesion.

Base replacement by a base analogue

2-Aminopurine is a base analogue because it mimics a normal base. When incorporated into DNA, it causes frequent mispairing.

Mispairing by alkylation of bases

Alkylating agents such as ethyl-methanesulfonate and MNNG (N-methyl-N′-nitro-N-nitrosoguanidine) produce mispairing. Although these agents modify different bases at various positions, alkylations at the O6 position of guanine and at the O4position of thymine cause specific mispairing with T and with G, leading to GC [LEFT RIGHT ARROW] AT and AT [LEFT RIGHT ARROW] GC transitions.

In vivo, mutations are mostly produced by O6-alkylguanine or O4-alkylthymine.

Noncoding lesions

Specific DNA lesions arise in DNA irradiated with ultraviolet light: pyrimidine dimers and 6–4 pyrimidine–pyrimidone compounds. Such lesions sharply bend DNA, thus preventing the precise pairing of bases during replication.

A Majority of Mutagens are Carcinogens. The Ames Test

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

Geneticists consider that spontaneous mutations are relatively rare. To increase the appearance of mutations, they have used various mutagens. We know that most mutagens damage DNA. Bruce Ames asked an interesting question: Do mutagens cause cancer? If they do, would it be possible to replace the usual lengthy cancer tests on mice (lasting months and years) with a short bacterial test?

Ames and his collaborators devised a mutagenicity test using Salmonella tester strains (his) that require histidine for their growth. The tester bacteria treated with a potential carcinogen were checked for the production of his+ mutations, enabling the bacteria to grow without histidine. To be efficient, the bacterial tester strains were engineered so as: (1) not to remove the DNA lesions produced by the chemical tested; (2) to increase the rate of mutation by a mutator plasmid; and (3) to render the tester strains permeable to chemical compounds. The chemical is mixed with rat liver enzymes to simulate metabolization of the compound by a human liver. In short, the test uses a transient physiological chimaera made of rat enzymes plus permeable bacteria.

It was observed that, even though bacteria are evolutionarily distant from rodents and humans, they provide an excellent tool for measuring mutagenicity and therefore potential carcinogenicity. The results of the tests have shown that 65% of the chemical compounds tested, which are carcinogens in rodents, are mutagens in bacteria. The converse is also true: most mutagens are active carcinogens. Use of the Salmonella test to detect potential carcinogens has saved time, money and suffering for animals. Because the Ames mutagenicity test is rapid, accurate and relatively simple, many agencies and laboratories throughout the world have tested newly produced chemicals for their mutagenicity and potential carcinogenicity. In the European Union, the Ames test has thus become mandatory.

Carcinogens Leave No Definite Mutational Signatures

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading

In human cells, a gene called p53 expresses a protein that prevents the occurrence of cancers. Protein p53 is involved in the control of cell division and is thus an antioncogene. Strikingly, one finds a p53 mutation in more than half of all cancer types taken together, 90% of which are point mutations and two-thirds of them are transitions GC [RIGHTWARDS ARROW] AT. In contrast, in bronchial cancers one finds that 45% are GC [RIGHTWARDS ARROW] TA transversions. Benzopyrene, the main mutagen present in tobacco smoke, produces GC [RIGHTWARDS ARROW] TA transversions at low frequency. More generally, does the finding in cancercells of a GC [RIGHTWARDS ARROW] TA transversion in p53 prove that benzopyrene has caused the mutation? Since a large variety of carcinogens, including many pollutants, cause GC [RIGHTWARDS ARROW] TA transversions, the answer is negative. A point mutation is a prevalent and so minute DNA change that it cannot be taken alone as a mark left by a carcinogen.

In order to provide legal proof, a mutated DNA sequence must be long and varied enough to be exclusive. The probability of finding another identical copy of a given DNA fingerprint is below 10−8. DNA microsatellites, whose lengths are between 1000 and 20 000 bases, provide valid legal proof of identification.

Only a few chemicals are recognized legally as carcinogenic. For instance, asbestos, an oxidizing mineral, causes a unique type of tumour. Radioactive iodine ingested by children after the Chernobyl nuclear accident has been found to break a specific chromosome in thyroid cancer cells. Apart from a few exceptions, there is still a debatable causal relationship between mutation types induced by carcinogens and specific tumours. This reality undermines the concept that carcinogens might leave a ‘mutational signature’ on DNA.

Glossary
DNA-damaging agents

Physical or chemical agents that produce DNA lesions.

DNA repair

Designates the set of processes that restores DNA after it has sustained damage.

Gene

A segment of DNA whose expression results in the production of a messenger RNA that most often is translated into a protein.

Genetic

Qualifies what pertains to DNA, whereas ‘hereditary’ specifies what is transmitted from a parent to its progeny, from one generation to the following generation.

Genome

The DNA contained in the whole set of chromosomes present in a cell.

Hereditary

Specifies what is transmitted from a parent to its progeny, from one generation to the following generation.

Induced mutations

Mutations caused by DNA-damaging agents or by a defect in DNA replication.

Mutagenesis

The process by which mutations arise.

Mutagens

Physical or chemical agents that alter DNA, thus increasing the occurrence of mutations.

Mutation

A DNA change that is recorded durably and passed on to the offspring.

SOS mutagenic repair

A specific induced replication that places a base across a lesion.

Spontaneous mutations

Naturally occurring mutations that arise on DNA.

Further Reading

  1. Top of page
  2. Introduction
  3. Nature of Mutations
  4. Most Mutagens are DNA-damaging Agents
  5. DNA Lesions and Mutations
  6. Repair of DNA Lesions
  7. Mutation Types, Reversions and Location
  8. Synonymous Mutations are Neutral
  9. Mechanisms Generating Mutations
  10. A Majority of Mutagens are Carcinogens. The Ames Test
  11. Carcinogens Leave No Definite Mutational Signatures
  12. Further Reading