Mutations and Mutants* - Biology

Mutations and Mutants* - Biology

We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.


Errors occurring during DNA replication are not the only way by which mutations can arise in DNA. Induced mutations are those that result from an exposure to chemicals, UV rays, x-rays, or some other environmental agent. Spontaneous mutations occur without any exposure to any environmental agent; they are a result of spontaneous biochemical reactions taking place within the cell.

Mutations may have a wide range of effects. Some mutations are not expressed; these are known as silent mutations. Point mutations are those mutations that affect a single base pair. The most common nucleotide mutations are substitutions, in which one base is replaced by another. These can be of two types, either transitions or transversions. Transition substitution refers to a purine or pyrimidine being replaced by a base of the same kind; for example, a purine such as adenine may be replaced by the purine guanine. Transversion substitution refers to a purine being replaced by a pyrimidine, or vice versa; for example, cytosine, a pyrimidine, is replaced by adenine, a purine. Mutations can also be the result of the addition of a nucleotide, known as an insertion, or the removal of a base, also known as deletion. Sometimes a piece of DNA from one chromosome may get translocated to another chromosome or to another region of the same chromosome; this is known as translocation.

As we will visit later, when a mutation occurs in a protein coding region it may have several effects. Transition or transversion mutants may lead to no change in the protein sequence (known as silent mutations), change the amino acid sequence (known as missense mutations), or create what is known as a stop codon (known as a nonsense mutation). Insertions and deletions in protein coding sequences lead to what are known as frameshift mutations. Missense mutations that lead to conservative changes results in the substitution of similar but not identical amino acids. For example, the acidic amino acid glutamate being substituted for the acidic amino acid aspartate would be considered conservative. In general we do not expect these types of missense mutations to be as severe as a non-conservative amino acid change; such as a glutamate substituted for a valine. Drawing from our understanding of functional group chemistry we can correctly infer that this type of substitution may lead to severe functional consequences, depending upon location of the mutation.

Note: Vocabulary Watch

Note that the preceding paragraph had a lot of potentially new vocabulary - it would be a good idea to learn these terms.

Figure 1. Mutations can lead to changes in the protein sequence encoded by the DNA.

Suggested discussion

Based on your understanding of protein structure, which regions of a protein would you think are more sensitive to substitutions, even conserved amino acid substitutions? Why?

Suggested discussion

A insertion mutation that results in the insertion of three nucleotides is often less deleterious than a mutation that results in the insertion of one nucleotide. Why?

Mutations: Some nomenclature and considerations


Etymologically speaking, the term mutation simply means a change or alteration. In genetics, a mutation is a change in the genetic material - DNA sequence - of an organism. By extension, a mutant is the organism in which a mutation has occurred. But what is the change compared to? The answer to this question, is that it depends. The comparison can be made with the direct progenitor (cell or organism) or to patterns seen in a population of the organism in question. It mostly depends on the specific context of the discussion. Since genetic studies often look at a population (or key subpopulations) of individuals we begin by describing the term "wild-type".

Wild Type vs Mutant

What do we mean by "wild type"? Since the definition can depend on context, this concept is not entirely straightforward. Here are a few examples of definitions you may run into:

Possible meanings of "wild-type"

  1. An organism having an appearance that is characteristic of the species in a natural breeding population (i.e. a cheetah's spots and tear-like dark streaks that extend from the eyes to the mouth).
  2. The form or forms of a gene most commonly occurring in nature in a given species.
  3. A phenotype, genotype, or gene that predominates in a natural population of organisms or strain of organisms in contrast to that of natural or laboratory mutant forms.
  4. The normal, as opposed to the mutant, gene or allele.

The common thread to all of the definitions listed above is based on the "norm" for a set of characteristics with respect to a specific trait compared to the overall population. In the "Pre-DNA sequencing Age" species were classified based on common phenotypes (what they looked like, where they lived, how they behaved, etc.). A "norm" was established for the species in question. For example, Crows display a common set of characteristics, they are large, black birds that live in specific regions, eat certain types of food and behave in a certain characteristic way. If we see one, we know its a crow based on these characteristics. If we saw one with a white head, we would think that either it is a different bird (not a crow) or a mutant, a crow that has some alteration from the norm or wild type.

In this class we take what is common about those varying definitions and adopt the idea that "wild type" is simply a reference standard against which we can compare members of a population.

Suggested discussion

If you were assigning wild type traits to describe a dog, what would they be? What is the difference between a mutant trait and variation of a trait in a population of dogs? Is there a wild type for a dog that we could use as a standard? How would we begin to think about this concept with respect to dogs?

Figure 2. Mutations can lead to changes in the protein sequence encoded by the DNA that then impact the outward appearance of the organism.

Mutations are simply changes from the "wild type", reference or parental sequence for an organism. While the term "mutation" has colloquially negative connotations we must remember that change is neither inherently "bad". Indeed, mutations (changes in sequences) should not primarily be thought of as "bad" or "good", but rather simply as changes and a source of genetic and phenotypic diversity on which evolution by natural selection can occur. Natural selection ultimately determines the long-term fate of mutations. If the mutation confers a selective advantage to the organism, the mutation will be selected and may eventually become very common in the population. Conversely, if the mutation is deleterious, natural selection will ensure that the mutation will be lost from the population. If the mutation is neutral, that is it neither provides a selective advantage or disadvantage, then it may persist in the population. Different forms of a gene, including those associated with "wild type" and respective mutants, in a population are termed alleles.

Consequences of Mutations

For an individual, the consequence of mutations may mean little or it may mean life or death. Some deleterious mutations are null or knock-out mutations which result in a loss of function of the gene product. These mutations can arise by a deletion of the either the entire gene, a portion of the gene, or by a point mutation in a critical region of the gene that renders the gene product non-functional. These types of mutations are also referred to as loss-of-function mutations. Alternatively, mutations may lead to a modification of an existing function (i.e. the mutation may change the catalytic efficiency of an enzyme, a change in substrate specificity, or a change in structure). In rare cases a mutation may create a new or enhanced function for a gene product; this is often referred to as a gain-of-function mutation. Lastly, mutations may occur in non-coding regions of DNA. These mutations can have a variety of outcomes including altered regulation of gene expression, changes in replication rates or structural properties of DNA and other non-protein associated factors.

Suggested discussion

In the discussion above what types of scenarios would allow such a gain-of-function mutant the ability to out compete a wild type individual within the population? How do you think mutations relate to evolution?

Mutations and cancer

Mutations can affect either somatic cells or germ cells. Sometimes mutations occur in DNA repair genes, in effect compromising the cell's ability to fix other mutations that may arise. If, as a result of mutations in DNA repair genes, many mutations accumulate in a somatic cell, they may lead to problems such as the uncontrolled cell division observed in cancer. Cancers, including forms of pancreatic cancer, colon cancer, and colorectal cancer have been associated with mutations like these in DNA repair genes. If, by contrast, a mutation in DNA repair occurs in germ cells (sex cells), the mutation will be passed on to the next generation, as in the case of diseases like hemophilia and xeroderma pigmentosa. In the case of xeroderma pigmentoas individuals with compromised DNA repair processes become very sensitive to UV radiation. In severe cases these individuals may get severe sun burns with just minutes of exposure to the sun. Nearly half of all children with this condition develop their first skin cancers by age 10.

Consequences of errors in replication, transcription and translation

Something key to think about:

Cells have evolved a variety of ways to make sure DNA errors are both detected and corrected, rom proof reading by the various DNA-dependent DNA polymerases, to more complex repair systems. Why did so many different mechanisms evolve to repair errors in DNA? By contrast, similar proof-reading mechanisms did NOT evolve for errors in transcription or translation. Why might this be? What would be the consequences of an error in transcription? Would such an error effect the offspring? Would it be lethal to the cell? What about translation? Ask the same questions about the process of translation. What would happen if the wrong amino acid was accidentally put into the growing polypeptide during the translation of a protein? Contrast this with DNA replication.

Mutations as instruments of change

Mutations are how populations can adapt to changing environmental pressures.

Mutations are randomly created in the genome of every organism, and this in turn creates genetic diversity and a plethora of different alleles per gene per organism in every population on the planet. If mutations did not occur, and chromosomes were replicated and transmitted with 100% fidelity, how would cells and organisms adapt? Whether mutations are retained by evolution in a population depends largely on whether the mutation provides selective advantage, poses some selective cost or is at the very least, not harmful. Indeed, mutations that appear neutral may persist in the population for many generations and only be meaningful when a population is challenged with a new environmental challenge. At this point the apparently previously neutral mutations may provide a selective advantage.

Example: Antibiotic resistance

The bacterium E. coli is sensitive to an antibiotic called streptomycin, which inhibits protein synthesis by binding to the ribosome. The ribosomal protein L12 can be mutated such that streptomycin no longer binds to the ribosome and inhibits protein synthesis. Wild type and L12 mutants grow equally well and the mutation appears to be neutral in the absence of the antibiotic. In the presence of the antibiotic wild type cells die and L12 mutants survive. This example shows how genetic diversity is important for the population to survive. If mutations did not randomly occur, when the population is challenged by an environmental event, such as the exposure to streptomycin, the entire population would die. For most populations this becomes a numbers game. If the mutation rate is 10-6 then a population of 107 cells would have 10 mutants; a population of 108 would have 100 mutants, etc.

Uncorrected errors in DNA replication lead to mutation. In this example, an uncorrected error was passed onto a bacterial daughter cell. This error is in a gene that encodes for part of the ribosome. The mutation results in a different final 3D structure of the ribosome protein. While the wildtype ribosome can bind to streptomycin (an antibiotic that will kill the bacterial cell by inhibiting the ribosome function) the mutant ribosome cannot bind to streptomycin. This bacteria is now resistant to streptomycin.
Source: Bis2A Team original image

Suggested discussion

Based on our example, if you were to grow up a culture of E. coli to population density of 109 cells/ml; would you expect the entire population to be identical? How many mutants would you expect to see in 1 ml of culture?

An example: Lactate dehydrogenase

Lactate Dehydrogenase (LDH), the enzyme that catalyzes the reduction of pyruvate into lactic acid in fermentation, while virtually every organism has this activity, the corresponding enzyme and therefore gene differs immensely between humans and bacteria. The proteins are clearly related, they perform the same basic function but have a variety of differences, from substrate binding affinities and reaction rates to optimal salt and pH requirements. Each of these attributes have been evolutionarily tuned for each specific organism through multiple rounds of mutation and selection.

Suggested discussion

We can use comparative DNA sequence analysis to generate hypotheses about the evolutionary relationships between three or more organisms. One way to accomplish this is to compare the DNA or protein sequences of proteins found in each of the organisms we wish to compare. Let us, for example, imagine that we were to compare the sequences of LDH from three different organisms, Organism A, Organism B and Organism C. If we compare the LDH protein sequence from Organism A to that from Organism B we find a single amino acid difference. If we now look at Organism C, we find 2 amino acid differences between its LDH protein and the one in Organism A and one amino acid difference when the enzyme from Organism C is compared to the one in Organism B. Both organisms B and C share a common change compared to organism A.

Schematic depicting the primary structures of LDH proteins from Organism A, Organism B, and Organism C. The letters in the center of the proteins line diagram represent amino acids at a unique position and the proposed differences in each sequence. The N and C termini are also noted H2N and COOH, respectively.
Attribution: Marc T. Facciotti (original work)

Question: Is Organism C more closely related to Organism A or B? The simplest explanation is that Organism A is the earliest form, a mutation occurred giving rise to Organism B. Over time a second mutation arose in the B lineage to give rise to the enzyme found in Organism C. This is the simplest explanation, however we can not rule out other possibilities. Can you think of other ways the different forms of the LDH enzyme arose these three organisms?


induced mutation:

mutation that results from exposure to chemicals or environmental agents


variation in the nucleotide sequence of a genome

mismatch repair:

type of repair mechanism in which mismatched bases are removed after replication

nucleotide excision repair:

type of DNA repair mechanism in which the wrong base, along with a few nucleotides upstream or downstream, are removed


function of DNA pol in which it reads the newly added base before adding the next one

point mutation:

mutation that affects a single base

silent mutation:

mutation that is not expressed

spontaneous mutation:

mutation that takes place in the cells as a result of chemical reactions taking place naturally without exposure to any external agent

transition substitution:

when a purine is replaced with a purine or a pyrimidine is replaced with another pyrimidine

transversion substitution:

when a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine

Mutation: Meaning, Kinds and Frequency

The credit of discovery of mutation goes to Wright (1791) when he observed it in male sheep. Any permanent or stable hereditary change other than one due to Mendelian segregation and recombination may be termed in its broader sense as mutation. Thus, the term ‘mutation’ in this sense ‘a sudden heritable change in a characteristic of an organism’ was primarily introduced by Hugo de Vries in 1900.

Mutation may be defined as an abrupt or sudden or discontinuous chromosomal change with genetic effect. —Mayer

“A mutation is a change in gene potentially capable of being transmitted”. —Synder

“A mutation is a sudden and discontinuous change in a gene occurring rarely for any particular gene and capable of producing a change great or small in some part of body.” —Collins

Mutation in the broad sense include all the changes in the hereditary material which can alter the character of any individual.

The word mutation is derived from Latin word mutate, meaning to change. Thus, mutations are the permanent changes in the genes. Mutant genes do not become expressed immediately because most of them are recessive.

Its phenotypic effects are seen only after one or more generations when the mutant gene is able to recombine with another similar recessive gene. Thus, mutation may be defined as an event that gives rise to a heritable alternation in the genotype. A sudden appearance of new hereditary character in a population is said to be due to mutation.

The mutation can be classified as follows:

2. Changes in chromosomal number (polyploidy, haploidy, heteroploidy)

3. Changes in the arrangement of the chromosomal segments due to

(а) Intra-chromosomal segmental rearrangements (Inversions)

(b) Inter-chromosomal segmental rearrangements (Translocations)

(c) Losses and duplication of chromosomal segments (Deletions and Deficiency)

Kinds of Mutations:

According to the phenotypic expression the mutation may be classified in the following types:

When changes in genes occur in the somatic or vegetative cells of the individuals, these are referred to as somatic mutation. Hugo de-Vries termed it as sports are saltation’s. It has been found by Emerson in endosperm of maize and in many tissues of plants. Chimeras have been developed of such nature.

(ii) Spontaneous Mutations:

These spontaneous or gene mutation generally are developed by natural agencies like light, temperature etc. There are various characters which are gene mutation. In mice spontaneous gene mutations determine coat colour which may be variously coloured like black, brown, spotted etc. In Drosophila there are many wild or normal type genes and their mutants like white eyes, pink eyes, yellow or black body colour and vestigial wing etc. Likewise, there are other gene affecting characters.

(iii) Germinal Mutations:

If the mutation occurs in the reproductive cells of gonads, then these are said as germinal mutation. Such type of mutation may be genetic occurring in the gametes of individuals or zygotic originating in the fused diploid gamete. Different sex linked mutations are of these types and pass from generation to generation.

(iv) Biochemical Mutation:

Such mutants influence the production of chemicals within an organism or causes the prevention of some enzymatic formation thus constituting biochemical mutation. Beadle and Tatum have studied in detail in Neurospora. Alcaptonuria and phenyl ketonuria described under gene nature are also biochemical mutations.

(v) Spurious Mutations:

These are hidden mutations appearing in the generation as a result of crossing over or other means. For example, in Drosophila, the gene for pink eyes remain usually hidden but it comes to light after crossing over. The appearance of recessive genes produced by crossing-over constitute spurious mutation.

(vi) Anomozygous Mutations:

These changes have developed due to structural (chromosomal aberrations) or numerical (polyploids) variations in the chromosomes.

(vii) Reverse Mutations:

It has been found in certain bacteria that are not capable to produce vitamins and other nutrients for their growth which normal type of bacteria can do efficiently. Sometimes such deficient mutants revert or change to normal condition is termed as reverse mutation. The chief cause of reverse mutation is radiation. Even then these reverse mutations as a rule occur rare.

(viii) Induced Mutations:

When gene changes are artificially produced or induced by means of experiments, such change constitutes induced mutation. The agent which cause these induced mutations are called mutagenic agents which may be x- ray’s radiation, various chemicals etc. Various chromosomal breaks make these changes.

Mutations have certain general characteristics which are summarised as below:

(i) Mutations are random i.e., they may come in a gene. However, some gene show higher mutation rates than others.

(ii) Mutations are generally lethal or harmful to the organism, a small proportion (0.1%) of all the induced mutations are useful.

(iii) Mutations are recurrent, i.e., the same mutation may occur repeatedly or again and again.

(iv) Induced mutations generally show pleiotropy (single gene affecting two or more different characters) often due to mutations in closely linked genes.

(v) Mutations provide the raw material for evolution.

(vi) Origin of mutation is unpredictable and haphazard.

(vii) Mutations are reversible i.e., an allele that arose through mutations of a gene can in turn mutate back to the original form of the gene. This is known as back mutation.

This can be represented as follows:

(viii) A number of different mutational possibilities exists for any particular gene. Different mutations at the same locus give rise to multiple allelic series. For example, in Drosophila, the sex-linked white-eye locus (w) is represented by a large number of different alleles. These include eosin and apricot as well as white and the wild type allele.

(ix) Some genes increase the spontaneous mutations rates of some other genes of the genome, such genes are called mutator genes. Some genes are termed as anti-mutator genes which suppress or prevent the mutation of other genes.

(x) Many agents, both physical and chemical increase the frequency of mutations, they are said as mutagenic agents.

(xi) Some mutant alleles do not mutate back. They do not exhibit reverse mutation. Such mutant alleles are believed to be formed by deletions.

Generally mutation have harmful effect on organisms. The individuals which carry them, reduce their viability.

Depending upon their effect on their viability of the individuals, it may be classified in to four groups:

Muller (1927) firstly produced mutation successfully in Drosophila by x-ray treatment.

Lethal mutations kill each and every organisms which carry them. Dominant lethals, therefore, cannot be studied because they can not survive even in the heterozygous state. Thus, we have to consider only recessive lethals. Recessive lethals would kill the individuals that carry them in homozygous state, e.g., albina chlorophyll mutation.

(ii) and (iii) Sub-lethal and Sub-vital.

It reduces the viability but do not kill the individuals carrying them. Sub-lethals will kill more than 50% individuals, where as sub-vitals less than 50%. A large majority of mutations are sub-lethals and sub-vitals, thus are of no value in crop improvement.

Vital mutations do not reduce the viability of the individuals carrying them. Practically, crop improvement needs only such mutations. It occurs in very low frequency as compared to the other types.

Stages at which Mutations Occur:

Mutations may occur at any stage in the development of the organism. If mutation comes in the primordial germ cells, all the gametes derived from these primordial germ cells will be carrying the mutant character.

If it happens in one of the gamete, this leads a mutant individual in the progeny. If mutation takes place in one of the daughter chromosomes of the dividing zygote, one part of the body of the individual will be carrying the mutation.

The later it appears, smaller will be the part of the body carrying the mutation. This type of individual is called Mosaic, for example, in Drosophila normal red eye with a speck of white or with one white and one red eye. Mutations also take place in the somatic tissue of any part of the body.

Mutation appears suddenly and never occurs gradually in a single individual and transmits to its progeny. Mutations have been observed in Oenothera, maize, man and other plant and animal species like Drosophila. In recent years, micro-organisms have been found to be the most favourable material to study this phenomenon.

Frequency of Mutations:

Different genes have different rates of mutability. Mutation rate may be defined as the number of changes at one special locus from one allele to another, measured in a biological unit of time, i.e., generation in a given population.

The rate of mutation varies from one organism to another and even from one variety to another in the same organism. The mutation rate varies considerably from one locus to another in the same variety.

(a) Mutations in Drosophila:

In 1909, T.H. Morgan found in his normal red eyed strain of Drosophila culture, an exceptional male with white-eyes. He observed that the gene for eye colour is located in the sex chromosome and the character is transmitted as a sex-linked one. In the white-eyed flies, mutation occurred in the gene located in the sex chromosome and as a result the eye colour becomes white.

Thereafter, the eye colour remained as white generation after generation. So change in eye colour of Drosophila is due to sudden change in the gene which is located in the sex-chromosome. This sudden change is known as gene or point mutation.

Mutation may occur during at any developmental stage of organisms, but certain stages of cell division e.g., S phase may yield mutations at a higher rate with mutagens than those during other phases of cell-cycle.

(b) Mutation in Oenothera:

The Oenothera Lamarckian (evening primrose) is a native of America, de-Vries found it growing as a weed in Holland. In de Vries garden it produced a number of striking mutants. Of these a mutant called gigas differed from the parental form in its large size another mutant called nanella was a small one and still other different in colour, size and shape of various parts.

Now it has been traced out that what de-Vries had described as mutations are really changes in the chromosomal number. It has been proved that the parental forms have 14 chromosomes, and the mutant gigas have 28 chromosomes. So it is clear that the appearance of gigas is due to the change in the number of chromosomes only and not in the number of genes.

(c) Mutations in Bacteria:

Due to mutations bacteria may undergo the following changes:

(i) Bacteria may become resistant to the antibiotics such as Penicillin or they may become susceptible to it.

(ii) When Bacteriophages are introduced in a Bacteria culture, most of them die. But some of them become resistant to Bacteriophages. This resistance might have occurred in two ways (i) before the introduction of bacteriophages, mutations might have occurred and they would have become resistant or (ii) after the introduction of Bacteriophages mutation might have occurred in genes and they would have become resistant.

(d) Mutation in Man:

Biochemical Mutations:

Enzymes have a significant role in metabolism of every organism. But many of the enzymes are not present in the fertilized egg but gradually develop during the course of development under the influence of genes.

Chemical substances in the body are often of a complicated nature and are built up or broken down in a series of steps. Each enzyme is responsible just for one step and the following step would be taken in care of a totally different enzyme.

In the absence of enzyme 𔃱’ A will not be converted in to B and in the absence of B, there will be no C and D. Each gene influences or is responsible for one particular enzyme and in the event of mutation in that gene the specific enzyme that influences is absent, and there would be a chemical block.

For example, if 𔃱’ enzyme is in the chemicals produced by an organism or which prevent their production are called Biochemical mutations. These are known to occur both in man and other organisms.

Biochemical Mutations in Man:

The first recorded biochemical mutation in man is Alcaptonuria, described by Garrod in 1909. This is characterised by the fact that the urine of the patient turns black on exposure to air. Alcaptonuria is inherited as an autosomal recessive character. Garrod found that people who suffer from this disorder can not break down a certain chemical substance known as homogenetisic acid.

In normal people, homogenetisic acid is converted in to an intermediate substance known as acetoacetic acid which then is broken down in to CO2 and H2O. But in alcaptonurics, the step from homogenetisic acid to acetoacetic acid does not occur, with the result that the homogenetisic acid accumulates in the urine and gives black colour when exposed to air.

The normal reaction takes place under the influence of an enzyme present in the blood serum of normal persons, but seems to be absent in the sera of alcaptonurics.

Garrod was able to show that the chemical block, here was due to a recessive mutation.

2. Phenylketonuria:

It is a metabolic disorder more serious than Alcaptonuria, but chemically related to it. Children suffering from this disorder are mentally defective and are called phenyl pyruvic idiots. They have also a variety of other defects of a serious nature and die at an early age.

On the chemical side, they are unable to break down a certain chemical substance, known as phenyl pyruvic acid, in to another substance called hydroxy-phenyl-pyruvic acid which in turn would usually be broken down in to simple waste products, CO2 and H2O. Here again, the chemical block is due to a mutation.

Albinism in man is due to a mutation which interferes with a step in the building up of melanin pigment. All the three defects mentioned above are chemically related, in that they involve breaks in a metabolic chain which can be traced back to a substance known as phenylalanine.

Gout is another disease in man. Biochemically it results from a defect of nucleic acid metabolism. This results in accumulation of uric acid in the blood. If the amount of uric acid exceeds too much, gouty arthritis may occur because of uric acid crystals forming in the joints.

5. Diabetes mellitus:

This is a well-known and important disease characterised by excretion of sugar in the urine. It is caused by failure of the pancreatic inlets to secrete insulin, a hormone which is essential to carbohydrate metabolism. The symptom of the disease is sugar in the urine, which in turn results from elevation of the blood sugar level above 180 milligrams percent.

Induced Mutations:

Mutations produced artificially due to the chemical or a physical agents (mainly radiations) are said as induced mutation. The agents capable of inducing mutations are called as mutagens and their capacity for inducing mutation is termed as mutagenic property. The process of inducing mutations through treatment of mutagen is called as mutagenesis, while use of induced mutations for improvement of crops is referred to as mutation breeding’s.

Detection of Mutation, CIB Method:

H.J.Muller (1927) showed that mutations could be artificially produced in Drosophila by X-rays. These mutations caused visible changes as from red-eye colour to white or lethal effects causing death. X-rays produce lethals in all the chromosomes of Drosophila, but here the discussion will be confined to X- chromosome.

There is a standard technique for the detection of new lethals in the X-chromosomes in Drosophila devised by Muller and known as CIB method. In the females (XX) one X-chromosome contains three genes: a dominant C is the cross-over suppressor a recessive lethal gene and the dominant gene B for bar eyes.

All the three genes CIB are in one X-chromosome and the other X- chromosome is normal. Such flies are known as CIB females. These bar eyed female (CIB) are mated with normal males (XY) that have been X-rayed.

As a result of mating, barred females were produced containing CIB (derived from their mother) and X-chromosome from father being treated with X-rays. This female (CIB X’) when mated with any normal male (XY), then in F2 half of their sons receive the CIB chromosome and die.

The other half receive the treated X-chromosome, and these also die if the treated X- chromosome contains a lethal. But all the F2 daughters will survive since they receive a normal X-chromosome from their father. Thus it is concluded that if F1 CIB female produces only daughters and not sons, it means that she has received a lethal from treated father.

Some times a special technique ‘attached X method’ is used to detect visible mutation. In this female carrying attached X and Y chromosomes are mated with the males radiated by X-rays. Sons which will have two different X-chromosomes may be identified and mutation can be detected.

Evolution of Mutation:

It has been observed that Mendelian variation may arise by the recombination of the existing genes through hybridization. Therefore, fundamental change is provided for by the mutation. Mutations are not losses of genes but are only changes in genie structure. Mutations are almost recessive. Baur in Antirrhinum majus found only 9 to 10 dominants out of 300 mutations and the others proved to be recessive to the wild types.

The rate and direction of mutation vary in different genes. Mutations cause a large disturbance in the normal development, functioning and living of any body. Therefore, mutations are of great importance in evolution with small effects. These are some times said as micro mutations and their effects are often not observable. If these small variations prove to be of advantage to the organisms, the later have greater value in evolution.

The hereditary variations by mutations are directive and non-purposive. The mutation are not directed by the environment and these do not develop to fulfill any specified purpose for the organism.

As examples for mutation providing chances for evolution of new forms, varieties or species may be mentioned, Cicer gigas and Arachis hypogea var. gigantea. The very popular improved variety in paddy G.E.B. 24 is believed to be arisen by mutation in Kona Mani. Similarly, in ragi (Eleusine coracana) E.C. 3735 arose by mutation in E.C. 593. The former is earlier in duration than the latter.

Mutation in both quantitative and qualitative characters has been exploited for development of over 300 varieties of various crops. Some mutations are useful in crop improvement and have beneficial effects. Mutations have allowed the analysis of genes as well as the determination of relationship between genes and proteins as well as some features of the genetic code.

Induced mutations are being applied for analysis of the effects of the various types of known alternations in DNA or genes on the expression of the concerned characters. Such an analysis is often called reverse genetics as opposed to the classical genetics.

Fundamentally mutation in a gene allows that gene to be identified and studied. For example, white eye locus was observed only after the white eyed mutant of the Drosophila was discovered, the same holds true for other eye colour genes.

Role of Mutation in Plant Breeding:

It has been used for improving qualitative and quantitative characters including disease resistance and yielding ability of various crops.

The various applications of mutation breeding may be given as below:

(i) F1 hybrids produced from hybridization may be treated with various mutagens to increase genetic variability and to facilitate recombination among linked genes. This method has not been extensively used.

(ii) Various mutagens have been used to improve different quantitative characters specially yield. By this technique various varieties have been developed so far which have shown high yielding performance.

(iii) In the case of clonal crops which are highly heterozygous in nature, mutagenesis is only the best method to bring about improved specific characteristic of clones without modifying their genetic make up. e.g., ‘red sports’ in apple etc. In other words, it is useful to improve specific characteristics of a well adopted high yielding variety.

(iv) Mutation breeding serves as a useful supplement to the available germplasm. It should be well understood that mutation breeding cannot minimise the necessity of collection of germplasm.

(v) Mutation have been found useful in certain specific characters like seed setting. Much more work has been done in Sweden by Gustafson 1954, 1960, Nybora 1954, Mackey, 1956, Smith 1951, where mutagenic agents are applied over many cultivated crop plants including garden trees.

Likewise, a huge amount of work has been done in east Germany on soya bean and barley by Scholz 1960, Zacharias 1956, Stubbe 1959 and in U.S.A. on Arachis hypogea. (pea-unit) by Gregory (1956). A variety of barely named Pallas and of pea named Stral has been developed by X-ray irradiation The mutant variety of barley is different in quality than its parent in following ways- (a) Early maturity (b) hard stem (c) more diastase activity (d) bold seeds and (e) disease resistance etc.

(vi) Irradiation of distant hybrids has been done to produce translocations. This is done to transfer a segment of chromosome having a desirable gene from the alien chromosome to the chromosome of a cultivated species of crop.

(vii) As a result of mutagenesis more than 335 varieties have been produced in different countries of the world. Such mutant varieties may be exemplified as in cereals, vegetables, millets, oil seeds, pulses, fruit trees etc. but paddy, barley, wheat account for 50% of the mutant varieties in all the crops. These crop varieties belong to diploid and polyploid, sexually and asexually reproducing species.

In India the work on inducing mutation has been started from ICAR, New Delhi. ‘Gamma garden’ has been developed for the same. Since 1930, a number of crop varieties have been developed through mutagenesis e.g., G.E.B. 24, Jagannath paddy, CO8152, CO8153 (sugarcane), wheat NP836, cotton Indore 2, Jute JRO 412 and 514, Gram T87 etc. Jagannath paddy is a gamma-ray induced semi-dwarf mutant from the tall variety T141. Jagannath has various qualities like resistance to lodging, higher yielding ability and more responsible to fertilizer application in comparison of parent variety.

Sugarcane variety CO8152 is a gamma-ray induced mutant from CO527. It was observed that CO8152 gave 40 percent higher yield than the parent variety. The mutant variety CO8152 has two chromosomes less than the parent variety CO527. This is an example of a change in chromosome number which has already produced a desirable mutant phenotype.

The mutant varieties (about 94%) developed till 1982 were due to following treatments like physical mutagens through chemical mutagenesis (about 5%) and 1% through combined treatment (physical & chemical mutagens both). It was observed that physical mutagens were more effective in asexually propagated crops than the sexually reproducing ones as shown below-

Apsara in Bhabha atomic research centre, Trombe is now underutilization for inducing mutation since 1956. By application of neutron in Apsara various crop varieties have been produced for example, Pt B 10 and G.E.B. 24, Inbred lines like D4, N6, D65 & ITe 701 in maize etc.

Limitations of Mutation:

(1) Induction of mutation artificially is very costly. Therefore, this technique is not so useful.

(2) Mutations are not stable.

(3) Most of the mutations are lethal.

(4) The main target of the mutation is to develop variation but India is lucky where natural variation is in plenty.


Mutations can involve the duplication of large sections of DNA, usually through genetic recombination. [9] These duplications are a major source of raw material for evolving new genes, with tens to hundreds of genes duplicated in animal genomes every million years. [10] Most genes belong to larger gene families of shared ancestry, detectable by their sequence homology. [11] Novel genes are produced by several methods, commonly through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions. [12] [13]

Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties. [14] For example, the human eye uses four genes to make structures that sense light: three for cone cell or color vision and one for rod cell or night vision all four arose from a single ancestral gene. [15] Another advantage of duplicating a gene (or even an entire genome) is that this increases engineering redundancy this allows one gene in the pair to acquire a new function while the other copy performs the original function. [16] [17] Other types of mutation occasionally create new genes from previously noncoding DNA. [18] [19]

Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2 this fusion did not occur in the lineage of the other apes, and they retain these separate chromosomes. [20] In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into new species by making populations less likely to interbreed, thereby preserving genetic differences between these populations. [21]

Sequences of DNA that can move about the genome, such as transposons, make up a major fraction of the genetic material of plants and animals, and may have been important in the evolution of genomes. [22] For example, more than a million copies of the Alu sequence are present in the human genome, and these sequences have now been recruited to perform functions such as regulating gene expression. [23] Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity. [6]

Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation. [24] The abundance of some genetic changes within the gene pool can be reduced by natural selection, while other "more favorable" mutations may accumulate and result in adaptive changes.

For example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population.

Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can increase in frequency over time due to genetic drift. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness. [25] [26] Also, DNA repair mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise-permanently mutated somatic cells.

Beneficial mutations can improve reproductive success. [27] [28]

Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens. Scientists may also deliberately introduce mutant sequences through DNA manipulation for the sake of scientific experimentation.

One 2017 study claimed that 66% of cancer-causing mutations are random, 29% are due to the environment (the studied population spanned 69 countries), and 5% are inherited. [29]

Humans on average pass 60 new mutations to their children but fathers pass more mutations depending on their age with every year adding two new mutations to a child. [30]

Spontaneous mutation Edit

Spontaneous mutations occur with non-zero probability even given a healthy, uncontaminated cell. Naturally occurring oxidative DNA damage is estimated to occur 10,000 times per cell per day in humans and 100,000 times per cell per day in rats. [31] Spontaneous mutations can be characterized by the specific change: [32]

    – A base is changed by the repositioning of a hydrogen atom, altering the hydrogen bonding pattern of that base, resulting in incorrect base pairing during replication. [33] – Loss of a purine base (A or G) to form an apurinic site (AP site). – Hydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can be corrected by DNA repair mechanisms and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA base. – Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.

Error-prone replication bypass Edit

There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA damage in the template strand. In mice, the majority of mutations are caused by translesion synthesis. [34] Likewise, in yeast, Kunz et al. [35] found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translesion synthesis.

Errors introduced during DNA repair Edit

Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation. Non-homologous end joining (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps. As a consequence, NHEJ often introduces mutations. [36]

Induced mutation Edit

Induced mutations are alterations in the gene after it has come in contact with mutagens and environmental causes.

Induced mutations on the molecular level can be caused by:

  • Chemicals (e.g., Bromodeoxyuridine (BrdU)) (e.g., N-ethyl-N-nitrosourea (ENU). These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can mutate the DNA only when the analog is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions.
  • Agents that form DNA adducts (e.g., ochratoxin A) [38]
  • DNA intercalating agents (e.g., ethidium bromide) converts amine groups on A and C to diazo groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication.
    light (UV) (including non-ionizing radiation). Two nucleotide bases in DNA—cytosine and thymine—are most vulnerable to radiation that can change their properties. UV light can induce adjacent pyrimidine bases in a DNA strand to become covalently joined as a pyrimidine dimer. UV radiation, in particular longer-wave UVA, can also cause oxidative damage to DNA. [39] . Exposure to ionizing radiation, such as gamma radiation, can result in mutation, possibly resulting in cancer or death.

Whereas in former times mutations were assumed to occur by chance, or induced by mutagens, molecular mechanisms of mutation have been discovered in bacteria and across the tree of life. As S. Rosenberg states, "These mechanisms reveal a picture of highly regulated mutagenesis, up-regulated temporally by stress responses and activated when cells/organisms are maladapted to their environments—when stressed—potentially accelerating adaptation." [40] Since they are self-induced mutagenic mechanisms that increase the adaptation rate of organisms, they have some times been named as adaptive mutagenesis mechanisms, and include the SOS response in bacteria, [41] ectopic intrachromosomal recombination [42] and other chromosomal events such as duplications. [40]

By effect on structure Edit

The sequence of a gene can be altered in a number of ways. [44] Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins. Mutations in the structure of genes can be classified into several types.

Large-scale mutations Edit

Large-scale mutations in chromosomal structure include:

  • Amplifications (or gene duplications) or repetition of a chromosomal segment or presence of extra piece of a chromosome broken piece of a chromosome may become attached to a homologous or non-homologous chromosome so that some of the genes are present in more than two doses leading to multiple copies of all chromosomal regions, increasing the dosage of the genes located within them.
  • Deletions of large chromosomal regions, leading to loss of the genes within those regions.
  • Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct fusion genes (e.g., bcr-abl).
  • Large scale changes to the structure of chromosomes called chromosomal rearrangement that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include:
      : interchange of genetic parts from nonhomologous chromosomes. : reversing the orientation of a chromosomal segment.
  • Non-homologous chromosomal crossover.
  • Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the Fused in Glioblastoma (FIG) gene and the receptor tyrosine kinase (ROS), producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes oncogenic transformation (a transformation from normal cells to cancer cells).
  • Small-scale mutations Edit

    Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called point mutations.) Small-scale mutations include:

      add one or more extra nucleotides into the DNA. They are usually caused by transposable elements, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter splicing of the mRNA (splice site mutation), or cause a shift in the reading frame (frameshift), both of which can significantly alter the gene product. Insertions can be reversed by excision of the transposable element. remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the reading frame of the gene. In general, they are irreversible: Though exactly the same sequence might, in theory, be restored by an insertion, transposable elements able to revert a very short deletion (say 1–2 bases) in any location either are highly unlikely to exist or do not exist at all. , often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another. [45] These changes are classified as transitions or transversions. [46] Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid, base mispairing, or mutagenic base analogs such as BrdU. Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is the conversion of adenine (A) into a cytosine (C). Point mutations are modifications of single base pairs of DNA or other small base pairs within a gene. A point mutation can be reversed by another point mutation, in which the nucleotide is changed back to its original state (true reversion) or by second-site reversion (a complementary mutation elsewhere that results in regained gene functionality). As discussed below, point mutations that occur within the protein coding region of a gene may be classified as synonymous or nonsynonymous substitutions, the latter of which in turn can be divided into missense or nonsense mutations.

    By impact on protein sequence Edit

    The effect of a mutation on protein sequence depends in part on where in the genome it occurs, especially whether it is in a coding or non-coding region. Mutations in the non-coding regulatory sequences of a gene, such as promoters, enhancers, and silencers, can alter levels of gene expression, but are less likely to alter the protein sequence. Mutations within introns and in regions with no known biological function (e.g. pseudogenes, retrotransposons) are generally neutral, having no effect on phenotype – though intron mutations could alter the protein product if they affect mRNA splicing.

    Mutations that occur in coding regions of the genome are more likely to alter the protein product, and can be categorized by their effect on amino acid sequence:

    • A frameshift mutation is caused by insertion or deletion of a number of nucleotides that is not evenly divisible by three from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can disrupt the reading frame, or the grouping of the codons, resulting in a completely different translation from the original. [47] The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is. (For example, the code CCU GAC UAC CUA codes for the amino acids proline, aspartic acid, tyrosine, and leucine. If the U in CCU was deleted, the resulting sequence would be CCG ACU ACC UAx, which would instead code for proline, threonine, threonine, and part of another amino acid or perhaps a stop codon (where the x stands for the following nucleotide).) By contrast, any insertion or deletion that is evenly divisible by three is termed an in-frame mutation.
    • A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous.
      • A synonymous substitution replaces a codon with another codon that codes for the same amino acid, so that the produced amino acid sequence is not modified. Synonymous mutations occur due to the degenerate nature of the genetic code. If this mutation does not result in any phenotypic effects, then it is called silent, but not all synonymous substitutions are silent. (There can also be silent mutations in nucleotides outside of the coding regions, such as the introns, because the exact nucleotide sequence is not as crucial as it is in the coding regions, but these are not considered synonymous substitutions.)
      • A nonsynonymous substitution replaces a codon with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. Nonsynonymous substitutions can be classified as nonsense or missense mutations:
        • A missense mutation changes a nucleotide to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. Such mutations are responsible for diseases such as Epidermolysis bullosa, sickle-cell disease, and SOD1-mediated ALS. [48] On the other hand, if a missense mutation occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid, then sometimes little or no change is rendered in the protein. For example, a change from AAA to AGA will encode arginine, a chemically similar molecule to the intended lysine. In this latter case the mutation will have little or no effect on phenotype and therefore be neutral.
        • A nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. This sort of mutation has been linked to different diseases, such as congenital adrenal hyperplasia. (See Stop codon.)

        By effect on function Edit

        • Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function (being partially or wholly inactivated). When the allele has a complete loss of function (null allele), it is often called an amorph or amorphic mutation in the Muller's morphs schema. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called haploinsufficiency). mutations, also called activating mutations, change the gene product such that its effect gets stronger (enhanced activation) or even is superseded by a different and abnormal function. When the new allele is created, a heterozygote containing the newly created allele as well as the original will express the new allele genetically this defines the mutations as dominant phenotypes. Several of Muller's morphs correspond to gain of function, including hypermorph (increased gene expression) and neomorph (novel function). In December 2017, the U.S. government lifted a temporary ban implemented in 2014 that banned federal funding for any new "gain-of-function" experiments that enhance pathogens "such as Avian influenza, SARS and the Middle East Respiratory Syndrome or MERS viruses." [49][50]
        • Dominant negative mutations (also called antimorphic mutations) have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or semi-dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes p53, [51]ATM, [52]CEBPA[53] and PPARgamma[54] ). Marfan syndrome is caused by mutations in the FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix. [55] Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency. [56][57] , after Mullerian classification, are characterized by altered gene products that acts with decreased gene expression compared to the wild type allele. Usually, hypomorphic mutations are recessive, but haploinsufficiency causes some alleles to be dominant. are characterized by the control of new protein product synthesis. are mutations that lead to the death of the organisms that carry the mutations.
        • A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype. [58]

        By effect on fitness (harmful, beneficial, neutral mutations) Edit

        In genetics, it is sometimes useful to classify mutations as either harmful or beneficial (or neutral):

        • A harmful, or deleterious, mutation decreases the fitness of the organism. Many, but not all mutations in essential genes are harmful (if a mutation does not change the amino acid sequence in an essential protein, it is harmless in most cases).
        • A beneficial, or advantageous mutation increases the fitness of the organism. Examples are mutations that lead to antibiotic resistance in bacteria (which are beneficial for bacteria but usually not for humans).
        • A neutral mutation has no harmful or beneficial effect on the organism. Such mutations occur at a steady rate, forming the basis for the molecular clock. In the neutral theory of molecular evolution, neutral mutations provide genetic drift as the basis for most variation at the molecular level. In animals or plants, most mutations are neutral, given that the vast majority of their genomes is either non-coding or consists of repetitive sequences that have no obvious function ("junk DNA"). [59]

        Large-scale quantitative mutagenesis screens, in which thousands of millions of mutations are tested, invariably find that a larger fraction of mutations has harmful effects but always returns a number of beneficial mutations as well. For instance, in a screen of all gene deletions in E. coli, 80% of mutations were negative, but 20% were positive, even though many had a very small effect on growth (depending on condition). [60] Note that gene deletions involve removal of whole genes, so that point mutations almost always have a much smaller effect. In a similar screen in Streptococcus pneumoniae, but this time with transposon insertions, 76% of insertion mutants were classified as neutral, 16% had a significantly reduced fitness, but 6% were advantageous. [61]

        This classification is obviously relative and somewhat artificial: a harmful mutation can quickly turn into a beneficial mutations when conditions change. For example, the mutations that led to lighter skin in caucasians, are beneficial in regions that are less exposed to sunshine but harmful in regions near the equator. Also, there is a gradient from harmful/beneficial to neutral, as many mutations may have small and mostly neglectable effects but under certain conditions will become relevant. Also, many traits are determined by hundreds of genes (or loci), so that each locus has only a minor effect. For instance, human height is determined by hundreds of genetic variants ("mutations") but each of them has a very minor effect on height, [62] apart from the impact of nutrition. Height (or size) itself may be more or less beneficial as the huge range of sizes in animal or plant groups shows.

        Distribution of fitness effects (DFE) Edit

        Attempts have been made to infer the distribution of fitness effects (DFE) using mutagenesis experiments and theoretical models applied to molecular sequence data. DFE, as used to determine the relative abundance of different types of mutations (i.e., strongly deleterious, nearly neutral or advantageous), is relevant to many evolutionary questions, such as the maintenance of genetic variation, [63] the rate of genomic decay, [64] the maintenance of outcrossing sexual reproduction as opposed to inbreeding [65] and the evolution of sex and genetic recombination. [66] DFE can also be tracked by tracking the skewness of the distribution of mutations with putatively severe effects as compared to the distribution of mutations with putatively mild or absent effect. [67] In summary, the DFE plays an important role in predicting evolutionary dynamics. [68] [69] A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods.

        • Mutagenesis experiment: The direct method to investigate the DFE is to induce mutations and then measure the mutational fitness effects, which has already been done in viruses, bacteria, yeast, and Drosophila. For example, most studies of the DFE in viruses used site-directed mutagenesis to create point mutations and measure relative fitness of each mutant. [70][71][72][73] In Escherichia coli, one study used transposon mutagenesis to directly measure the fitness of a random insertion of a derivative of Tn10. [74] In yeast, a combined mutagenesis and deep sequencing approach has been developed to generate high-quality systematic mutant libraries and measure fitness in high throughput. [75] However, given that many mutations have effects too small to be detected [76] and that mutagenesis experiments can detect only mutations of moderately large effect DNA sequence data analysis can provide valuable information about these mutations.
        • Molecular sequence analysis: With rapid development of DNA sequencing technology, an enormous amount of DNA sequence data is available and even more is forthcoming in the future. Various methods have been developed to infer the DFE from DNA sequence data. [77][78][79][80] By examining DNA sequence differences within and between species, we are able to infer various characteristics of the DFE for neutral, deleterious and advantageous mutations. [24] To be specific, the DNA sequence analysis approach allows us to estimate the effects of mutations with very small effects, which are hardly detectable through mutagenesis experiments.

        One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral. [81] [25] Hiroshi Akashi more recently proposed a bimodal model for the DFE, with modes centered around highly deleterious and neutral mutations. [82] Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the DFE of random mutations in vesicular stomatitis virus. [70] Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast. [75] In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations.

        Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes. [83] Like neutral mutations, weakly selected advantageous mutations can be lost due to random genetic drift, but strongly selected advantageous mutations are more likely to be fixed. Knowing the DFE of advantageous mutations may lead to increased ability to predict the evolutionary dynamics. Theoretical work on the DFE for advantageous mutations has been done by John H. Gillespie [84] and H. Allen Orr. [85] They proposed that the distribution for advantageous mutations should be exponential under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations. [86] [87] [88]

        In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on effective population size second, the average effect of deleterious mutations varies dramatically between species. [24] In addition, the DFE also differs between coding regions and noncoding regions, with the DFE of noncoding DNA containing more weakly selected mutations. [24]

        By inheritance Edit

        In multicellular organisms with dedicated reproductive cells, mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations (also called acquired mutations), [89] which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.

        Diploid organisms (e.g., humans) contain two copies of each gene—a paternal and a maternal allele. Based on the occurrence of mutation on each chromosome, we may classify mutations into three types. A wild type or homozygous non-mutated organism is one in which neither allele is mutated.

        • A heterozygous mutation is a mutation of only one allele.
        • A homozygous mutation is an identical mutation of both the paternal and maternal alleles. mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles. [90]

        Germline mutation Edit

        A germline mutation in the reproductive cells of an individual gives rise to a constitutional mutation in the offspring, that is, a mutation that is present in every cell. A constitutional mutation can also occur very soon after fertilisation, or continue from a previous constitutional mutation in a parent. [91] A germline mutation can be passed down through subsequent generations of organisms.

        The distinction between germline and somatic mutations is important in animals that have a dedicated germline to produce reproductive cells. However, it is of little value in understanding the effects of mutations in plants, which lack a dedicated germline. The distinction is also blurred in those animals that reproduce asexually through mechanisms such as budding, because the cells that give rise to the daughter organisms also give rise to that organism's germline.

        A new germline mutation not inherited from either parent is called a de novo mutation.

        Somatic mutation Edit

        A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic mutation. [89] Somatic mutations are not inherited by an organism's offspring because they do not affect the germline. However, they are passed down to all the progeny of a mutated cell within the same organism during mitosis. A major section of an organism therefore might carry the same mutation. These types of mutations are usually prompted by environmental causes, such as ultraviolet radiation or any exposure to certain harmful chemicals, and can cause diseases including cancer. [92]

        With plants, some somatic mutations can be propagated without the need for seed production, for example, by grafting and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious" apple and the "Washington" navel orange. [93]

        Human and mouse somatic cells have a mutation rate more than ten times higher than the germline mutation rate for both species mice have a higher rate of both somatic and germline mutations per cell division than humans. The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of genome maintenance in the germline than in the soma. [94]

        Special classes Edit

        • Conditional mutation is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition). [95] These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously. [96] The permissive conditions may be temperature, [97] certain chemicals, [98] light [98] or mutations in other parts of the genome. [96]Invivo mechanisms like transcriptional switches can create conditional mutations. For instance, association of Steroid Binding Domain can create a transcriptional switch that can change the expression of a gene based on the presence of a steroid ligand. [99] Conditional mutations have applications in research as they allow control over gene expression. This is especially useful studying diseases in adults by allowing expression after a certain period of growth, thus eliminating the deleterious effect of gene expression seen during stages of development in model organisms. [98] DNA Recombinase systems like Cre-Lox recombination used in association with promoters that are activated under certain conditions can generate conditional mutations. Dual Recombinase technology can be used to induce multiple conditional mutations to study the diseases which manifest as a result of simultaneous mutations in multiple genes. [98] Certain inteins have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss-of-function mutations at other temperatures. [100] Conditional mutations may also be used in genetic studies associated with ageing, as the expression can be changed after a certain time period in the organism's lifespan. [97]
        • Replication timing quantitative trait loci affects DNA replication.

        Nomenclature Edit

        In order to categorize a mutation as such, the "normal" sequence must be obtained from the DNA of a "normal" or "healthy" organism (as opposed to a "mutant" or "sick" one), it should be identified and reported ideally, it should be made publicly available for a straightforward nucleotide-by-nucleotide comparison, and agreed upon by the scientific community or by a group of expert geneticists and biologists, who have the responsibility of establishing the standard or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature, [101] which should be used by researchers and DNA diagnostic centers to generate unambiguous mutation descriptions. In principle, this nomenclature can also be used to describe mutations in other organisms. The nomenclature specifies the type of mutation and base or amino acid changes.

        • Nucleotide substitution (e.g., 76A>T) – The number is the position of the nucleotide from the 5' end the first letter represents the wild-type nucleotide, and the second letter represents the nucleotide that replaced the wild type. In the given example, the adenine at the 76th position was replaced by a thymine.
          • If it becomes necessary to differentiate between mutations in genomic DNA, mitochondrial DNA, and RNA, a simple convention is used. For example, if the 100th base of a nucleotide sequence mutated from G to C, then it would be written as g.100G>C if the mutation occurred in genomic DNA, m.100G>C if the mutation occurred in mitochondrial DNA, or r.100g>c if the mutation occurred in RNA. Note that, for mutations in RNA, the nucleotide code is written in lower case.

          Mutation rates vary substantially across species, and the evolutionary forces that generally determine mutation are the subject of ongoing investigation.

          In humans, the mutation rate is about 50-90 de novo mutations per genome per generation, that is, each human accumulates about 50-90 novel mutations that were not present in his or her parents. This number has been established by sequencing thousands of human trios, that is, two parents and at least one child. [102]

          The genomes of RNA viruses are based on RNA rather than DNA. The RNA viral genome can be double-stranded (as in DNA) or single-stranded. In some of these viruses (such as the single-stranded human immunodeficiency virus), replication occurs quickly, and there are no mechanisms to check the genome for accuracy. This error-prone process often results in mutations.

          Changes in DNA caused by mutation in a coding region of DNA can cause errors in protein sequence that may result in partially or completely non-functional proteins. Each cell, in order to function correctly, depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. One study on the comparison of genes between different species of Drosophila suggests that if a mutation does change a protein, the mutation will most likely be harmful, with an estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial. [8] Some mutations alter a gene's DNA base sequence but do not change the protein made by the gene. Studies have shown that only 7% of point mutations in noncoding DNA of yeast are deleterious and 12% in coding DNA are deleterious. The rest of the mutations are either neutral or slightly beneficial. [103]

          Inherited disorders Edit

          If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases. In particular, if there is a mutation in a DNA repair gene within a germ cell, humans carrying such germline mutations may have an increased risk of cancer. A list of 34 such germline mutations is given in the article DNA repair-deficiency disorder. An example of one is albinism, a mutation that occurs in the OCA1 or OCA2 gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision.

          DNA damage can cause an error when the DNA is replicated, and this error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. DNA damages are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair damages in DNA. Because DNA can be damaged in many ways, the process of DNA repair is an important way in which the body protects itself from disease. Once DNA damage has given rise to a mutation, the mutation cannot be repaired.

          Role in carcinogenesis Edit

          On the other hand, a mutation may occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell within the same organism. The accumulation of certain mutations over generations of somatic cells is part of cause of malignant transformation, from normal cell to cancer cell. [104]

          Cells with heterozygous loss-of-function mutations (one good copy of gene and one mutated copy) may function normally with the unmutated copy until the good copy has been spontaneously somatically mutated. This kind of mutation happens often in living organisms, but it is difficult to measure the rate. Measuring this rate is important in predicting the rate at which people may develop cancer. [105]

          Point mutations may arise from spontaneous mutations that occur during DNA replication. The rate of mutation may be increased by mutagens. Mutagens can be physical, such as radiation from UV rays, X-rays or extreme heat, or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA). Mutagens associated with cancers are often studied to learn about cancer and its prevention.

          Prion mutations Edit

          Prions are proteins and do not contain genetic material. However, prion replication has been shown to be subject to mutation and natural selection just like other forms of replication. [106] The human gene PRNP codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions.

          Although mutations that cause changes in protein sequences can be harmful to an organism, on occasions the effect may be positive in a given environment. In this case, the mutation may enable the mutant organism to withstand particular environmental stresses better than wild-type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection. Examples include the following:

          HIV resistance: a specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes. [107] One possible explanation of the etiology of the relatively high frequency of CCR5-Δ32 in the European population is that it conferred resistance to the bubonic plague in mid-14th century Europe. People with this mutation were more likely to survive infection thus its frequency in the population increased. [108] This theory could explain why this mutation is not found in Southern Africa, which remained untouched by bubonic plague. A newer theory suggests that the selective pressure on the CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague. [109]

          Malaria resistance: An example of a harmful mutation is sickle-cell disease, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance hemoglobin in the red blood cells. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the allele, because, in areas where malaria is common, there is a survival value in carrying only a single sickle-cell allele (sickle cell trait). [110] Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria Plasmodium is halted by the sickling of the cells that it infests.

          Antibiotic resistance: Practically all bacteria develop antibiotic resistance when exposed to antibiotics. In fact, bacterial populations already have such mutations that get selected under antibiotic selection. [111] Obviously, such mutations are only beneficial for the bacteria but not for those infected.

          Lactase persistence. A mutation allowed humans to express the enzyme lactase after they are naturally weaned from breast milk, allowing adults to digest lactose, which is likely one of the most beneficial mutations in recent human evolution. [112]

          Mutationism is one of several alternatives to evolution by natural selection that have existed both before and after the publication of Charles Darwin's 1859 book, On the Origin of Species. In the theory, mutation was the source of novelty, creating new forms and new species, potentially instantaneously, [113] in a sudden jump. [114] This was envisaged as driving evolution, which was limited by the supply of mutations.

          Before Darwin, biologists commonly believed in saltationism, the possibility of large evolutionary jumps, including immediate speciation. For example, in 1822 Étienne Geoffroy Saint-Hilaire argued that species could be formed by sudden transformations, or what would later be called macromutation. [115] Darwin opposed saltation, insisting on gradualism in evolution as in geology. In 1864, Albert von Kölliker revived Geoffroy's theory. [116] In 1901 the geneticist Hugo de Vries gave the name "mutation" to seemingly new forms that suddenly arose in his experiments on the evening primrose Oenothera lamarckiana, and in the first decade of the 20th century, mutationism, or as de Vries named it mutationstheorie, [117] [113] became a rival to Darwinism supported for a while by geneticists including William Bateson, [118] Thomas Hunt Morgan, and Reginald Punnett. [119] [113]

          Understanding of mutationism is clouded by the mid-20th century portrayal of the early mutationists by supporters of the modern synthesis as opponents of Darwinian evolution and rivals of the biometrics school who argued that selection operated on continuous variation. In this portrayal, mutationism was defeated by a synthesis of genetics and natural selection that supposedly started later, around 1918, with work by the mathematician Ronald Fisher. [120] [121] [122] [123] However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by Udny Yule, [124] and built up with theoretical and experimental work in Europe and America. Despite the controversy, the early mutationists had by 1918 already accepted natural selection and explained continuous variation as the result of multiple genes acting on the same characteristic, such as height. [121] [122]

          Mutationism, along with other alternatives to Darwinism like Lamarckism and orthogenesis, was discarded by most biologists as they came to see that Mendelian genetics and natural selection could readily work together mutation took its place as a source of the genetic variation essential for natural selection to work on. However, mutationism did not entirely vanish. In 1940, Richard Goldschmidt again argued for single-step speciation by macromutation, describing the organisms thus produced as "hopeful monsters", earning widespread ridicule. [125] [126] In 1987, Masatoshi Nei argued controversially that evolution was often mutation-limited. [127] Modern biologists such as Douglas J. Futuyma conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution. [128]

          Variation & Mutation

          During replication , an organism’s genetic make-up (DNA) can change or mutate. Changes to genes are called mutations . Mutations can be spontaneous (they just happen). They can also happen because of:

          If mutation is large then the organism will probably not survive to reproduce

          If mutation is small then change might be beneficial. Offspring will flourish, doing better than others in that species. Many more offspring will inherit this beneficial mutation and will be better suited to that environment

          Thus continues natural selection

          Mutations may have no effect. For example, the protein that a mutated gene produces may work just as well as the protein from the non-mutated gene.

          Mutations may sometimes be helpful but they are often harmful. For example, haemophilia is an inherited disorder that stops blood from clotting properly. It is caused by a mutated gene.

          Genes can be switched on and off. In any one cell, only some of the full set of available genes are used. Different types of cells produce different ranges of proteins. This affects the functions they can carry out. For example, only pancreas cells switch on the gene for making the hormone insulin.

          Mutations to genes can alter the production of certain proteins, or even prevent them being made by a cell.

          Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease

          Isocitrate dehydrogenases (IDHs) are critical metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG), NAD(P)H, and CO2. IDHs epigenetically control gene expression through effects on αKG-dependent dioxygenases, maintain redox balance and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis, and regulate respiration and energy production through generation of NADH. Cancer-associated mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effect. Mutant enzymes produce (R)-2-hydroxyglutarate, which in turn inhibits αKG-dependent dioxygenase function, resulting in a global hypermethylation phenotype, increased tumor cell multipotency, and malignancy. Recent studies identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down-regulated, as contributing to cancer and neurodegeneration, respectively. We describe how mutant and wild-type enzymes contribute on molecular levels to disease pathogenesis, and discuss efforts to pharmacologically target IDH-controlled metabolic rewiring.


          Fig. 1. Subcellular localization and chemical reactions…

          Fig. 1. Subcellular localization and chemical reactions catalyzed by wild-type IDH and tumor-derived IDH mutant…

          Fig. 2. Deregulation of IDH enzymatic activity…

          Fig. 2. Deregulation of IDH enzymatic activity is associated with human disease.

          Fig. 3. Compensation for wild-type IDH1 loss…

          Fig. 3. Compensation for wild-type IDH1 loss of function in GBM tumors characterized by high…

          Becoming molecular and cellular

          Genetics is generally rather abstract in the ways in which it reveals how things work. Biological phenomena and processes are described in terms of gene names, but do not provide mechanistic explanations that describe the nature of the molecules and the biochemical processes involved. To move from abstract explanations to biochemical mechanisms requires cloning the relevant genes. This is possible by genetically mapping the genes and determining their position within the genome followed by sequencing of the region, a methodology greatly helped by the availability of whole-genome sequences. Another approach can be used when efficient DNA transformation procedures are available. Gene libraries can be constructed and transformed into mutant cells to select for clones that rescue the mutant function. This is cloning by complementation (Fig. 4), and was the approach used to clone genes in the yeasts (Beach et al. 1982 Nasmyth and Reed 1980). (Box 5—Is it a contaminant?).

          A cdc2 ts mutant is able to grow at the restrictive temperature when cells carry the human CDC2 gene on a plasmid. This gene is able to complement the yeast cdc2 ts mutant function and cells can grow and divide to form colonies (white arrow heads). Cells that lose the plasmid are no longer able to divide, but continue to grow and form elongated cells (black arrow heads)

          In fission yeast complementation, cloning was combined with whole genome sequencing and positional mapping to generate the sequences of the majority of cell cycle genes (Kohli et al. 1977 Wood et al. 2002) (Box 6—Cottage Industry). With the availability of gene sequences, it is possible to predict their putative molecular functions. Biochemical investigations of these molecular functions are facilitated by purification of the gene products for example, through tagging the genes or raising antibodies via protein expression in bacteria and protein purification, or by peptide synthesis. With gene product purification, comes the ability to perform biochemical assays, providing the link between genetics and molecular mechanism. Using tagged genes or specific antibodies against gene products also allows the cellular locations and behaviour of gene products of interest to be determined. Many cell cycle genes in different organisms have been tagged, and the locations and levels of the tagged proteins have been monitored as cells proceed through the cell cycle. Combining molecular and cellular information leads to the development of mechanistic explanations of biological processes, linking molecules to phenotypes.

          One of the advantages of toggling between genetic, cellular and molecular data is that it increases the robustness of explanations. Each of these spheres of investigation have strengths and weaknesses that can complement each other, generating different types of explanations both abstract and mechanistic, thus strengthening the understanding of biological phenomena and processes. This is considered further in the next section.

          Box 5 Is it a contaminant?

          The ability to transform fission yeast with exogenous DNA was needed to clone cell cycle genes by complementation (Beach and Nurse 1981). It was developed in the laboratory about a year or two after the technique had been shown to work for budding yeast (Beggs 1978). Initial trials were based on making protoplasts, which had to be plated after suspension in an osmoticum contained within soft agar. Unfortunately, the wrong soft agar was used by PN, which led to partial solidification in the tubes before plating. Only by shaking out the setting agar and squashing it down in the plate with the plate lid could the experiment be completed. The outcome was a complete mess prone to contamination, and the whole experiment should have been thrown away. However, the plates were put in the incubator ‘just in case’. Amazingly colonies grew up within the shattered agar lumps although they could not be examined microscopically. It was assumed that these were contaminants, but in fact they were transformed fission yeast, the first ever to have been made.

          Box 6 Cottage industry

          Fission yeast was never on the ‘hot-list’ for the genomic sequencing community, unlike budding yeast, the worm, and the fly, for example, and no funding could be raised to get the organism sequenced. Luckily, PN met Bart Barrell who had worked with Fred Sanger, and Bart had resources from a funding agency to contribute to the sequencing of budding yeast. BB had rather too much support for the budding yeast sequencing, so he and PN cooked up the idea of using the excess funding to sequence fission yeast. Would the funding agency notice? Unfortunately they did! About half the genome sequence was done in 6 months but when we went to the funding agency to get the rest of the money to make fission yeast the second eukaryote to be fully sequenced the agency was not amused, and did not provide the extra resources. This meant we had to go to the EU and fund about a dozen laboratories around Europe as a cottage industry to finish the sequence. This took over a year more, but the sequence was completed and completed to a high standard, which was not surprisingly given BB’s high standards and pedigree. Fission yeast ended up being the 4th free-living eukaryote to be fully sequenced.

          The Genetic Code

          All our genetic information is stored and passed on in the simple arrangement of 4 basic nitrogenous bases &ndash Adenine (A), Guanine (G), Thymine (T) and Cytosine (C). In RNA, the Thymine is replaced by Uracil (U). Adenine and Guanine are called purines, while thymine, cytosine and uracil are pyrimidines.

          The arrangement of these 4 bases in various combinations eventually gives rise to proteins. The nitrogen bases are read in sets of 3, called codons. The codons determine the order of arrangement of the amino acids which undergo folding and more folding to create proteins.

          (Photo Credit : Wikimedia Commons)

          There a total of 64 codons &ndash 4 3 = 64 (four bases read in sets of three). Of these, there is one START codon and 3 STOP codons.

          Consider the following sequence : AUGCCAGCA

          If the reading starts from A, the codons will look like this : AUG CCA GCA

          If the reading starts from U, the codons will look like this : A UGC CAG CA

          If the reading starts from G, the codons will look like this : AU GCC AGC A

          The same arrangement of bases gives rise to different amino acids. Therefore, the START codon is a universal codon from where reading begins. Similarly, the STOP codon does the reverse, i.e. it determines where the reading for a protein will stop, and the next one will begin. The START codon is AUG, and the STOP codons are UAG, UAA, UGA.

          Deleterious Mutations

          As mentioned earlier, these mutations reduce the fitness of an individual. But what is meant by fitness? It refers to the capacity and ability of an individual to carry out normal life activities, to live a relatively disease-free existence, and to pass on their genetic material to the next generation by reproducing. This is applicable to all living beings, from plants to animals, from microorganisms to birds, and from insects to humans. The fitness of the individual enables it to reach maturity, where its healthy constitution is conducive to reproduction, via which its genetic legacy is passed on to the next generation.

          However, in case of deleterious mutation, any one or all of these stages may be compromised, causing the individual to be unfit. The mutation may cause health problems, reproductive failure, and even premature death, depending on the gene in which it occurs. With respect to humans, these three effects can be explained by the following examples.

          Health Problem

          A mutation in the LMNA gene that produces laminin, a protein that provides support to the cellular nucleus, gives rise to a condition called ‘progeria’. It is a disease that causes accelerated aging, and is characterized by sclerotic skin, baldness, bone abnormalities, growth impairment, etc. Almost all genetic disorders are caused due to the presence of deleterious mutations.

          Reproductive Failure

          A mutation in the AZF (azoospermia factor) or the SRY (sex-determining region Y) gene gives rise to a non-functional gene-product, resulting in infertility in case of men, thereby inhibiting that particular male to be able to pass his genes to the next generation.

          In case of animals like peacocks, who attract mates by the display of their bright tail feathers, any mutation that adversely affects this phenotype would result in the peacock’s failure to attract a mate (peahen) and reproduce.

          Premature Death

          Mutations that give rise to conditions like spina bifida, metabolic genetic disorders, and Marfan syndrome greatly reduce the quality and length of the affected individual’s lifespan, causing that person to die a premature death. Also, some mutations that occur in embryo development genes result in the premature death of the embryo, leading to miscarriages or still births.

          DNA Mutation Activity

          This activity uses a simulation from the Concord Consortium that shows how DNA is transcribed to RNA and then turned into a protein. It’s a very clear animation and can be used on its own as part of a lecture on protein synthesis.

          The simulation then allows you to edit the DNA which will then create a new protein. The worksheet asks students to review terms and label an image showing tRNA, mRNA, codons, amino acids, and ribosomes.

          Students then edit the DNA in a specific way so that they can observe the effects of a point mutation, a frameshift mutation, and a silent mutation. In the point mutation, a single base is changed which leads to a difference amino acid. Students do not need a codon chart to complete this activity.

          You can also do this activity with the class if you have a projector, this would also allow more discussion on why some point mutations change the output protein and why some are silent.

          Time Required: 15-20 minutes

          HS-LS1-1 Construct an explanation based on evidence for how the structure of DNA determines the structure of proteins which carry out the essential functions of life through systems of specialized cells

          HS-LS3-1 Ask questions to clarify relationships about the role of DNA and chromosomes in coding the instructions for characteristic traits passed from parents to offspring.

          Mutations and Mutants* - Biology

          Over a lifetime, our DNA can undergo changes or mutations in the sequence of bases: A, C, G and T. This results in changes in the proteins that are made. This can be a bad or a good thing.

          A mutation is a change that occurs in our DNA sequence, either due to mistakes when the DNA is copied or as the result of environmental factors such as UV light and cigarette smoke. Mutations can occur during DNA replication if errors are made and not corrected in time. Mutations can also occur as the result of exposure to environmental factors such as smoking, sunlight and radiation. Often cells can recognize any potentially mutation-causing damage and repair it before it becomes a fixed mutation.

          Mutations contribute to genetic variation within species. Mutations can also be inherited, particularly if they have a positive effect. For example, the disorder sickle cell anaemia is caused by a mutation in the gene that instructs the building of a protein called hemoglobin. This causes the red blood cells to become an abnormal, rigid, sickle shape. However, in African populations, having this mutation also protects against malaria.

          However, mutation can also disrupt normal gene activity and cause diseases, like cancer. Cancer is the most common human genetic disease it is caused by mutations occurring in a number of growth-controlling genes. Sometimes faulty, cancer-causing genes can exist from birth, increasing a person’s chance of getting cancer.

          An illustration to show an example of a DNA mutation. Image credit: Genome Research Limited