gene mutation


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GENE MUTATION Dr. R. K Pillai, Dept of Zoology, Hindu College, Moradabad [email protected]

Gene Mutation : 

Gene Mutation Organic evolution is dependent on hereditary variations such mutation and recombination. Mutation provides the raw material for the evolution. Recombination permits new combinations in the gene pool. The characters are transmitted from parents to offspring through the genes. The offspring will not have the same genes as those of the parents, rather they have copies of them. During reproduction, parental genes produce copies of themselves to be passed on to the offspring. Gene copying or gene reproduction is a precise process and generally there are no mistakes.

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Occasionally mistakes may occur while copying. The newly formed gene may get an altered structure. The modified gene then goes on multiplying and produces its own copies like the original gene. The alteration in the changed gene structure is called gene mutation. Mutation includes all phenotypic variations, which arise due to altered gene structure and are heritable. The term ‘gene mutation’ comprises, small and minute changes brought about by altered individual genes. Gene mutations are also called point mutations. They occur at a specific gene locus altering its molecular structure.

History : 

History The term ‘mutation’ was first coined by Hugo de Vries in 1900. de Vries was conducting breeding experiments on the plant Oenothera lamarckiana (commonly called the Evening primrose) . He noticed that some of the progenies possessed characters which were not to be found in either of the parental types. He further observed these changed types bred true. He therefore described these sudden changes as mutations. Charles Darwin knew mutations, even though he did not use the term (mutations). Darwin used the term 'sports' to sudden changes occurring in both plants and animals. Hugo de Vries

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The first recorded of mutation dates back to 1791. Seth Wright, an England farmer, reported a male sheep with short bowed legs. Wright reared this lamb with short legs called Ancon It was of great advantage as it could not jump even a low level fence. Ancon sheep

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The scientific study of mutations began with the work of American geneticist T.H. Morgan on Drosophila in 1910. Morgan observed that among a population of red eyed flies, some individuals with white eye appeared. He further found out that the white eyed gene is recessive to red eye and located on the X chromosome. T. H. Morgan

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The male individuals possessed only one X chromosome and the females had two X chromosomes. The recessive character appeared more frequently among males than among females. Later mutations have been reported in other organisms like maize, rodents, pea, snapdragons, poultry, man, etc. Even in microorganisms also mutations have been detected. Drosophila

Size or range of mutations : 

Size or range of mutations Size of mutation varies in different organisms and in different genes. These may be very minute and may not be detectable at all . In some microorganisms like Bacteria, Fungi (Neurospora), Blue green algae, etc., mutations may not bring out any morphological effect. But it may bring about some changes in their nutritional requirements. In some cases mutations may be so large as to even result in lethality to the individual.

Frequency of mutations : 

Frequency of mutations The frequency is generally less unless there is a drastic change of the surroundings. According to Muller, in Drosophila, the mutation rate for any gene is less than one in one million. It has also been calculated that a particular gene in Drosophila may mutate only once in every 40,000 years. The rate of mutation also varies between different individuals, organisms and sometimes even under different ages of the same organism. J. B. S. Haldane has estimated a comparison between man and Drosophila. Man has less chances of mutation as most of them are harmful so there is a selection pressure in man against mutations. As against the unaltered life expectancy of 40,000 years for a Drosophila gene, the human gene has a life expectancy of 25,000,00 years.

Mutational Unit : 

Mutational Unit Earlier it was not known as to what constitutes a mutation in a gene. But recent researches have shown that the smallest amount of DNA within which mutation can take place is called a muton. At the molecular level mutation involves alteration in the base pair sequence.

Mutator genes and mutable genes : 

Mutator genes and mutable genes It is difficult to assess (among plants and animals) as to which gene frequently mutates and which gene is comparatively stable. But in some of the organisms like maize (Emerson), it has been observed that some genes change quite frequently, while others are not so. Barbara McClintock has shown in maize that some genes are not only stable, but influence others to mutate. The genes that influence others (to mutate) are called mutator genes and the genes that are so influenced are called mutable genes. These genes, mutator and mutable are more frequent in plants than in animals.

Classification of mutations : 

Classification of mutations Visible mutations These are the mutations which bring about some striking, visible, phenotypic effects. Visible mutations are very rare constituting only a fraction of 1% of the mutations.

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Biochemical mutations They affect specific biochemical processes since the mutant organism has lost the ability to synthesize an essential metabolite such as vitamins or amino acids. Beadle and Tatum (1945) discovered nutritional mutations in the bread mold Neurospora crassa. Alkaptonuria and phenylketonuria are two common biochemical mutations in human beings. Beadle Tatum

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Lethal mutations Over 19% of the mutations cause the death of the organism. These mutations represent the loss of a function essential during the embryology of the organism. Biochemical mutations are lethal if the organism is not provided with the metabolite which it is not able to synthesize. About 80% of the mutations are termed as detrimentals which have no visible effect, but cause some decrease in viability and fertility. The expression of an individual detrimental gene may have only a slight effect, but the expression of a group of them in an organism can have a serious or lethal effect.

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Mutation: Somatic or Germinal A mutation may occur in any cell and at any stage in the development of a multicellular organism. Somatic mutations are those taking place in non-germ line cells. This mutation will not be transmitted through the gametes to the progeny. So the genetical and evolutionary consequences of somatic mutations are insignificant. Only single cell and their daughter cells are involved. If a somatic mutation occurs early in embryonic life, the mutant cells may constitute a large proportion of body cells. Cancer represents an uncontrolled growth of tissue and this disease may arise as a result of somatic mutation. Germinal mutations are those that occur in germ-line cells. This may be gametic or zygotic. Germinal mutations will be transmitted to the offsprings.

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Mutation: Spontaneous or Induced Spontaneous mutations are those that occur without a known cause. They suddenly occur in nature and are also called background mutations. These mutations have been reported in many organisms such as Oenothera, maize, bread molds, bacteria, viruses, fruitfles, mice, man, etc. Induced mutations are those resulting from exposure of organisms to physical and chemical agents that cause changes in DNA (or RNA in some viruses). Such agents are called mutagens. Mutagens include ionizing irradiation, ultraviolet light and a wide variety of chemicals. The induced mutations do not show any difference from natural mutations.

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Mutation: A Reversible Process A forward mutation in a wild-type gene can produce a mutant allele that results in an abnormal phenotype. Most mutations are forward type. When a second mutation restores the original phenotype the process is called reversion or reverse mutation.

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Mutation: Phenotypic effects The mutations having dominant phenotypic expressions are called dominant mutations. For example in man the mutation disease aniridia (absence of iris of eyes) occurs due to a dominant mutant gene. Majority of mutations are recessive lethals (resulting in death) Aniridia

Induced Mutations : 

Induced Mutations A mutation is a change in the genes or the base sequence of DNA. Any substance or agent inducing mutation is called a mutagen. The mutagens may be broadly grouped into two classes : physical mutagens and chemical mutagens.


PHYSICAL MUTAGENS Physical mutagens comprise mainly radiations. Following radiations induce mutations: Effective Radiations A. Ionizing (particulate) 1. a particles, 2. b rays 3. Protons 4. Neutrons B. Ionizing (Nonparticulate) 1. X-rays 2. g rays 3. Cosmic rays C. Nonionizing Ultraviolet rays

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Radiations can cause mutations by breaking DNA, chemically changing the structure of DNA or by forming unstable compound that physically alter DNA. Different wave lengths of radiations produce different types of mutations. Radiation has been used to induce mutations for the first time by H.J. Muller (1927) on animals and L.J. Stadler (1928) on plants. Radiation that can produce mutation is known as effective radiations. H.J. Muller

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Effective Radiations There are two types of effective radiations: ionizing radiations and non-ionizing radiations. Ionizing radiations produce directly or indirectly ion-clusters in the material exposed. Non-ionizing radiation do not make ionization. Important physical differences exist in the densities of ionization. X-rays and g rays produce less ionization per path of radiation. When radiation travels through the cell, ionizations are produced near tail of the energy path. But these radiations are much more penetrating than many other types of radiations. They are able to move through layers of tissues deep into the interior of an organism.

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X-rays and g rays cause DNA damage and mutations. The mechanism by which they cause mutation is less well understood. It is believed that they are involved in the formation of free radicals. Free radicals are chemicals that have an unshared electron and consequently are extremely reactive to molecules in the cell. They react with DNA to cause breaks, cause deletions and alter base pairing characteristics. High energy radiation like X-rays and g rays with a wave length between about 0.001 and 10 nm can easily penetrate deep with in the body. As a consequence its penetrating power, all cells in the body are subject to damage from high-energy radiation, including germ cells.

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Ultraviolet ray Ultraviolet ray has a wave length of about 10 to 300 nm. It is the most common type of radiation. UV is harmful only to cells on the surface because it has a low penetrating power. The mechanism of action of UV radiation is somewhat different from ionizing radiation. It can cause disruption of biological molecules as it produces excitation in molecules than ionization. Electrons are raised to a high energy state but are not ejected from the atoms. The principal effect is an instability in molecular structure. Ultraviolet light emits most of its energy between 240 and 280 nm. Because DNA absorbs light intensity at 250-260 nm, UV ray is very damaging to the DNA of all the cells it can penetrate.

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Fortunately, UV light has very limited penetrating power. In multicellular organisms such as humans, only the surface layer of cells are damaged by UV radiation. However, prolonged exposure to UV light will kill most microorganisms. UV ray has been very successfully used by scientists and medical personal to sterilize instruments. The sun is an excellent source of UV light. It can be extremely damaging to exterior cells of the body after repeated or prolonged exposure. The amount of solar UV light received at earth's surface varies with season, altitude, latitude and ozone levels. Most glass or clothing absorb UV rays completely.

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Mechanism of UV mutations Exposure to UV light produces mutation in the following manner. Ultraviolet radiation can cause two pyrimidines adjacent to each other on the same strand of DNA to form a dimer. Thymine dimers are most common form of pyrimidine dimers, although C:T and C:C dimers also form. The presence of pyrimidine dimer in the DNA affects base-pairing. The unpaired dimer disrupts the normal structure of DNA and bulges slightly from the double-stranded molecule. The dimer cannot act as a template during DNA replication. DNA polymerase stops before and restarts after dimer, creating a new sequence and a mutation.


CHEMICAL MUTAGENS Chemical Mutagens A. Base analogues 1. 5-bromodeoxyuridine (BrdU) 2. 2-amino purine (2-AP) B. Chemicals Modifying base-pairing 1. Hydroxylamine 2. Nitrous acid 3. Alkylating agents Nitrogen mustard Ethylmethane sulfonate (EMS) Methylmethane sulfonate (MMS) N-methyl-N'-nitro-nitroso-guanidine (NTG) C. Intercalating agents Proflavin Acridine organge

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Different classes of chemical mutagens have different modes of action. Some chemicals imitate bases (called base analogues) and replace them during replication. Others alter base structure and still others directly induce insertions and deletions during DNA replication. Base Analogues Base analogues have chemical structure that are similar to the nucleotides. When a base analogue is phosphorylated, it can be incorporated into the DNA.

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The base analogue 5-bromodeoxyuridine (BrdU) has a bromine at the 5 position of pyrimidine ring instead of a methyl group and resembles a thymine. As result BrdU is usually incorporated opposite adenine. However, BrdU can exist in either the enol or keto form. When it is in the enol form, it pairs with guanine. Consequently during replication, BrdU can produce frequent transitions of GC pairs to AT pairs and of AT pairs to GC pairs. Another common base analogue is 2-aminopurine (2-AP) 2-AP resembles with adenine but mispairs with cytosine. This base analogue causes many mutations because it is easily incorporated into DNA. When 2-AP is incorporated into DNA as adenine opposite thymine, it can generate A:T to G:C transitions

Chemicals modifying Base-pairing : 

Chemicals modifying Base-pairing A large number of chemicals react with the four nucleotides and modify their base-pairing capabilities. 1. Hydroxylamine (NH2OH) It is commonly used in industry and chemical laboratories. Treating DNA with hydroxylamine converts cytosine to N4-hydroxycytosine. This modified cytosine base-pairs with adenine and thus creates G:C to A:T transitions.

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2. Nitrous acid (NHO2) It is another common chemical that modifies nucleotides. Nitrous acid is a potent mutagen and causes deamination of cytosine, creating uracil. Uracil can then base-pair like thymine and gives a C:G to T:A. When adenine reacts with nitrous acid, it is converted into hypoxanthine and then base pairs with cytosine instead of thymine. Deamination of adenine gives A:T to GC.

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3. Alkylating agents These comprise an extremely large group of very potent mutagens. All these compound are highly reactive with DNA and yield many mutations at relatively low concentrations. These chemicals are used extensively in the industry in the synthesis of many products like plastics. They have been used in warfare as the poisonous gases known as mustard gases. They cause extremely painful death acting on skin, mucosal membranes and lungs.

Common alkylating agents causing mutations : 

Common alkylating agents causing mutations 1. Ethyleneimine 2. Nitrogen mustard 3. Sulphur mustard 4. Dimethyl nitrosamine 5. Nitrosomethyl urea 6. Ethylene oxide 7. Ethylmethane sulfonate (EMS) 8. Methylmethane sulfonate (MMS) 9. N-methyl-N'-nitro-nitroso-guanidine (NTG)

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Some alkylating agents can cross link the two DNA strands which cause the strands to break during replication. Alkylating agents cause mutations by transitions, transversions, deletions and frameshifts. Two laboratory alkylating agents used to mutagenize organisms such as bacteria and Drosophila are EMS and NTG. They are extremely potent mutagens that induce a high number of mutations into growing cells.

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Intercalating Agents Another group of potent mutagens are the acridine and acridine-like compound (proflavin and acridine orange). These heterocyclic compounds intercalate or sandwich themselves between the stacked base pairs in double helical DNA. The presence of acridine during replication of DNA causes frameshift mutations by adding or deleting one of two base pairs. Francis Crick used acridines to determine that a DNA code word is three nucleotides long.

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