Mutation - BIOC0010 Chapter 5 - PDF

# MUTATION ## 5.1 Mutation Classification and Types - Mutation refers to any changes in the amount or arrangement of genes or nucleotide sequence of a DNA encoding a gene or chromosomes in a cell of an organism. - Mutation can take place in any cell of an organism. - Mutation may produce a new cha...

# MUTATION ## 5.1 Mutation Classification and Types - Mutation refers to any changes in the amount or arrangement of genes or nucleotide sequence of a DNA encoding a gene or chromosomes in a cell of an organism. - Mutation can take place in any cell of an organism. - Mutation may produce a new characteristic that can be inherited, if it occurs in a gamete. - Mutations can lead to the loss of a gene function or produce a new function. - Most of these mutations are recognized as mutants because the phenotype of the organism has changed. - Mutation can be classified as - gene/point mutation - chromosomal mutation - There are 2 types of mutation: - Spontaneous mutations are mutations that occur randomly and spontaneously. - Induced mutations are mutations induced by factors called mutagens. - A spontaneous mutation is a mutation that occurs naturally. - The environmental influences that cause this type of mutation is not known. - The most common mechanism for spontaneous mutation is point mutation (gene mutation). - Usually, humans exhibit a spontaneous gene mutation rate of 10-10 to 10-8 mutations per gamete per gene. - Induced mutation is mutation caused by mutagens such as chemical and radiation. - Scientists create new mutations by treating an organism with mutagens. - Mutagens are substances or agents that can cause a much higher rate of mutation. - The process itself is known as mutagenesis. - There are 2 types of mutagens: - physical mutagens - chemical mutagens - Radiations such as ultraviolet and ionizing radiation can function as mutagens. - Ultraviolet (UV) radiation will induce dimer formation between adjacent pyrimidine bases on the DNA chain through covalent bonding. - Ionizing radiation such as X-rays and gamma rays have more energy than UV. It ionizes water and other molecules to form radicals. This can break DNA strands and alter the purine and pyrimidine bases. This in turn can induce point mutations (changes in a single nucleotide) or deletions (loss of a chromosomal segment). - Chemical mutagens include mustard gas, nitrous acid, ethyl methane sulphonate (EMS), diethyl sulphate (DES), ethyl inamine (EI), ethyl ethane sulphonate (EES), colchichine and ethidium bromide. - Chemical mutagens induce mostly point mutations. - Point mutations occur when a single base pair of a gene is changed. These changes are classified as transitions or transversions. - Transitions occur when a purine base is converted into another purine (A to Gor Gto A) or a pyrimidine is converted into another pyrimidine (T to C or C to T). - Transversion occur when a purine is converted into a pyrimidine or a pyrimidine is converted into a purine. - There are 2 major classes of chemical mutagens: alkylating agents and base analogues. - Alkylating agents such as ethyl methane sulphonate (EMS), ethyl ethane sulphonate (EES) and mustard gas can mutate both replicating and non-replicating DNAs. - Base analogues such as 5-bromouracil and 2-aminopurine can only mutate a DNA when the analog is incorporated into the replicating DNA. ## 5.2 Gene Mutation - Gene mutations are defined as changes in the nucleotide base sequence of a gene. - When the gene mutation involves only a single base, it is called a point mutation. - There are 4 types of genetic point mutation: base substitution, base insertion, base deletion and base inversion. ### Base Substitution - In base substitution, one nucleotide is exchanged with another nucleotide that has a different base. For example, ATT is exchanged with ATC, or CTT is exchanged with CAT. - This can lead to a different DNA sequence, which will be transcribed into a different mRNA. Later, the altered mRNA will be translated into a polypeptide with a different amino acid sequence from the normal one. - This mutation is also referred as a missense mutation. Missense mutation mostly codes for a different amino acid. - As a result, the activity of an enzyme or hormone might decrease or be destroyed. This will take place if the mutation occurs at an active site of a DNA sequence that codes for an enzyme or hormone. - Silent mutation sometimes occurs when a change in a base sequence may transform one codon into another that is translated into the same amino acid. - For example, if TCA is mutated to TCG, the codon in mRNA that is supposed to be AGU becomes AGC. However, the same acid amino serine will be inserted because both codons code for serine. - Silence mutations are said to be silent because they cause no change in their product and cannot be detected without sequencing the gene (or its mRNA). - Nonsense mutation occurs when a base substitution results in changing a codon into a termination codon (stop codons UAA, UAG, or UGA). Usually, this mutation will destroy the function of the gene product. - The earlier in the gene sequence that this mutation occurs, the more truncated (made shorter) the protein product becomes and the more likely that it will be unable to function. - The most common example of a base substitution effect is sickle-cell anaemia. ### Base Insertion - Base insertion is the insertion or addition of nucleotides into a DNA nucleotide sequence. For example, the sequence ATT-CTT- is inserted with a nucleotide with base C and becomes ATC-TCT-T. - Base insertion can cause a shift of the reading frame. This type of mutation is also called as frameshift mutation. - Frameshift mutation will alter the gene product and produce an entirely new sequence of amino acids. - For example, if base insertion occurs in a gene coding for an enzyme, the new coding will destroy the activity of the new enzyme. ### Base Deletion - Base deletion is the loss or removal of one or more nucleotides from a DNA nucleotide sequence. - This mutation may cause nonsense mutation or produce a new sequence of amino acids depending on the nucleotides that are lost from the sequence. - If a new sequence of amino acids occurs, these mutations can alter the reading frame of the gene. Base deletion is also considered as a frameshift mutation. ### Frameshift Mutation - Base additions or deletions are also known as frameshift mutation. - A frameshift mutation is a gene mutation that inserts or deletes a number of nucleotides (that are not multiples of threes) from a DNA nucleotide sequence. - These insertions or deletions can disrupt the reading frame, or the grouping of the codons. - Therefore, codons after the mutation (with a few exceptions due to redundancy) will code for different amino acids. - Furthermore, the stop codons (UAA, UGA, or UAG) will not be read, or a stop codon may be created at an earlier site. - The protein created may be abnormally short, abnormally long, and/or contain the wrong amino acids. It will be most likely not functional. - Figure 5.5 shows how by shifting the reading frame of one nucleotide to the right, the same sequence of nucleotides encodes a different sequence of amino acids. ### Base Inversion - Base inversion is a mutation that reverses a portion of a nucleotide sequence. - The connection between genes break and the sequence of these genes are reversed. - For example, purine is exchanged for a pyrimidine or a pyrimidine for a purine (C/TA/G). - The new sequence may not be viable to produce a gene product, depending on which genes are reversed. ## 5.3 Chromosomal Mutation - Chromosomal mutations are defined as alterations in the numbers or structure of the chromosome. - Changes in the chromosome structure or chromosome number are likely to cause changes in the characteristics of the particular organism. - The characteristics that have been changed in that organism can be passed on to its offspring if the mutations occur in the cells that become gametes. This will increase variation among the offspring. - Chromosomal mutations can occur during the following events. - Condensation and separation of chromosomes in mitosis and meiosis - Replication of DNA in interphase - Crossing over in prophase I in meiosis - There are 2 types of chromosomal mutations: - chromosomal aberration (change in structure) - chromosomal number alteration (change in number) ### Chromosomal Aberration - Changes in the chromosome structure are also known as chromosomal aberration. - This type of mutation occurs due to structural changes that take place during meiosis, resulting in abnormalities in the affected chromosome. - Normally, when the chromosome breaks at a certain point, the broken ends will reunite to produce the same sequence of genes. However, in this case (chromosomal aberration), the broken ends may not rejoin in the same pattern, causing changes in the chromosome structure and resulting in various chromosomal mutations. - There are 4 main categories of chromosomal mutations: translocations, deletions, inversions, and duplications. #### Translocation - Translocation occurs when a chromosomal segment shifts to another region within the same chromosome or to another chromosome. - Chromosomal material is maintained, but in a different arrangement after a translocation. - Intrachromosomal translocation involves the movement of a chromosome segment from one location in a chromosome to another location within the same chromosome. - Interchromosomal translocation involves the movement of chromosome segment(s) between chromosomes. - Reciprocal translocation (non-Robertsonian translocation) occurs when chromosomal segments are exchanged between two nonhomologous chromosomes. For example, a type of Down's syndrome involves translocations between chromosome 14 and chromosome 21. This is between nonhomologous chromosomes. - Nonreciprocal (Robertsonian) translocation are a one-way transfer of a chromosome segment from one chromosome to another. Intrachromosomal translocations are also considered nonreciprocal. #### Deletion - A deletion is a mutation whereby a chromosomal fragment is missing. - Deletion happens when a gene is mistakenly removed from a chromosome. It is a loss of genetic material and can cause abnormalities and serious genetic diseases. - An example is the cri du chat syndrome also known as 'cry of the cat' syndrome. It is found in approximately 1 in 50 000 live births. - The individual with this syndrome has a small head, facial abnormalities, and severe mental retardation. The structure of the glottis and larynx results in crying that resembles that of a cat. The surviving infants have a shortened lifespan. - Other examples include some cases of male infertility and two thirds of Duchenne muscular dystrophy cases. - Deletion can be caused by errors in chromosomal crossover within an inversion during meiosis, losses from translocations, unequal crossing over or fragments breaking away without rejoining back to chromosomes. - There are 2 types of deletions. - Terminal deletion is deletion that occurs towards the end of a chromosome. - Intercalary deletion is deletion that occurs from the interior of a chromosome. #### Inversion - Inversion is the rearrangement of a chromosome segment, in which a segment is cut out, inverted 180° and rejoined to the same chromosome. - Inversion can increase variation without losing genetic material. - There are 2 types of inversions (depending on whether or not the centromere is a portion of the inverted segment): paracentric and pericentric. - Paracentric inversion does not include the centromere and both breaks occur in the same one arm of the chromosome. - Pericentric inversion includes the centromere and there is a break point in each arm. - In general, inversions do not cause any abnormalities in carriers as long as the rearrangement is balanced with no extra or missing genetic information. Families that can be carriers of inversions may be offered genetic testing and counseling. - The most common inversion seen in humans is on chromosome 9, where this inversion is generally considered to have no deleterious or harmful effects. However, there is some evidence it leads to an increased risk of miscarriage for about 30% of the affected couples. #### Duplication - Duplication is the doubling of one or several chromosome fragments of the genome. - It involves the insertion of an extra copy of a region of the chromosome into a neighbouring position. - Duplication of an entire chromosome can lead to the duplication of a region of DNA containing a gene. - Zygotes produced from gametes that have had duplications are often viable and may or may not have any serious problems. - The duplicated gene may either (a) acquire mutations that lead to a gene with a new function or (b) acquire deleterious mutations and become a pseudogene. Pseudogene resembles a functional gene but is not transcribed. - An example of this type of mutation is thalassemia which is a form of anaemia involving abnormal haemoglobin. - Plants are the most prolific genome duplicators. For example, wheat, is an hexaploid organism, meaning it has six duplicate copies of its genome (normally called a polyploid organism). ## 5.3 Chromosomal Number Alteration - Changes in the number of chromosomes are usually the result of errors that occur during meiosis but the errors can also occur during mitosis. - There are 2 types of changes in the number of chromosomes in a genome (a complete haploid set of genes or a complete chromosome set): - Aneuploidy - Euploidy (Polyploidy) ### Aneuploidy - Aneuploidy is the abnormal condition where one or more chromosomes from a normal set of chromosomes are missing or are present in an unusual number of copies (2n + 1, 2n +2, 2n -1, 2n-2, ......). - Aneuploidy occurs when diploid organisms lose or gain one or more individual chromosomes, thus exceeding the normal 2n number. - This alteration of chromosome number is common in humans and may result in abnormalities or chromosomal disorders. Aneuploidy is common in cancerous cells too. - The types of aneuploidy commonly seen are shown in the table below. - Aneuploidy happens when homologous chromosomes fail to segregate during either meiosis I or meiosis II. This process is called non-disjunction. - The homologous chromosomes fail to separate during anaphase I of meiosis I or anaphase II of meiosis II. As a result of this, gametes that are produced either have too few or too many chromosomes. - During anaphase I, both sets of chromosomes move to the same pole of the cell. Later, during anaphase II, the gamete cells that are formed will contain either no or more than one chromosomes (Figure 5.11). - When these gametes fuse with normal haploid gametes, the zygotes that are produced from this fusion will have an odd number of chromosomes. - Normally, zygotes that contain chromosome numbers that are less than the usual diploid chromosome number will fail to develop. - In contrast, zygotes with extra chromosome numbers may develop. ### Autosome Abnormalities - The effect of aneuploidy abnormalities can be found in autosome and sex chromosomal abnormalities. - In autosomal abnormalities, the most common examples of aneuploidy are monosomy and trisomy. - In monosomy, the individual will lack one chromosome from a certain pair of homologous chromosomes. - A common example of monosomy is monosomy 21. The person born with this syndrome is missing one chromosome of the diploid chromosome 21 (45,-21). - The syndrome is characterized by growth, motor and mental retardation. The syndrome is generally lethal and very few cases of living newborns are reported. Of these, most die between 3 weeks and 20 months of living but some do survive into childhood. - In trisomy, the individual will have three copies of a particular chromosome. In animals, trisomy cases will produce severe abnormalities. - The most common example of trisomy in humans is Down's syndrome (Mongolism) also known as trisomy 21. - A person with Down's syndrome has three copies of chromosome 21, rather than the usual two. The ratio of this syndrome is about 1 in 800 live births. Individuals with Down's syndrome usually have multiple physical malformations, mental retardation, and relatively short lives. - They typically have short, stocky bodies with thick hands and feet. They also commonly have broad, short heads with small low-set ears, small concave saddle-shaped or flattened noses, relatively large-ridged tongues that roll over a protruding lower lip, low muscle tone, and loose joints. - The probabilities a zygote acquiring this syndrome varies markedly with the age of the mother when conception takes place. - Most trisomies in humans result in spontaneous abortions and the most common types that do survive are trisomy 21 (Down's syndrome), trisomy 18 (Edward's syndrome), trisomy 13 (Patau syndrome), trisomy 8 (Warkany syndrome) and trisomy 9. ### Sex Chromosomal Abnormalities - Sex chromosomal abnormalities involves sex chromosomes. Any extra copies of the sex chromosome can cause developmental errors. Most of the sex chromosomal abnormalities are gender-specific, either female or male. - Female abnormalities are the result of variations in the number of X chromosomes. - Male abnormalities are the result of irregular numbers of either the X or the Y chromosome or both. - The irregular numbers of either X or Y chromosomes are carried by abnormal gametes produced as a result of non-disjunctions during spermatogenesis or oogenesis (Figure 5.13). - The most common examples of sex chromosomal abnormalities in aneuploidy are Turner's syndrome, Klinefelter's syndrome, XYY syndrome and triple X syndrome. These are the most common trisomies involving sex chromosomes in humans. - Turner's syndrome occurs when females have only one X-chromosome. Therefore, their genotype is XO (45, ΧΟ) (Figure 5.13). - This syndrome is relatively rare and it is about 1:2500 live births. Turner's syndrome is a chromosomal condition that exclusively affects girls and women. - Turner's syndrome is characterised by short stature, webbed neck, triangular face, amenorrhea (lack of menstruation), underdeveloped secondary sexual characteristics and infertility. - Klinefelter's syndrome occurs when an individual, normally male, has two X and one Y chromosomes. Therefore, his genotype is XXY (47, XXY) (Figure 5.13). - The individual will have a relatively high-pitched voice, gynecomastia (increased breast tissue) and comparatively little facial and body hair. They are normally sterile or subfertile. Their testes and prostate glands are small, therefore, they produce small amounts of testosterone. They are mostly likely to be overweight, have difficulties in learning, especially with language, and have short-term memory. - The frequency of Klinefelter's syndrome has been reported to be between 1 in 500 and 1 in 1000 male births. - In the XYY syndrome, the individual will have an extra copy of the Y chromosome. The genotype is XYY (47, XYY) and normally is male. This individual is also referred as a 'super-male. - During adolescence, they are often slender, have severe facial acne, and are poorly coordinated. They are usually fertile and lead ordinary lives as adults. As adults, these 'super-males' will grow above 6 feet tall and generally appear and act normal. However, they produce high levels of testosterone. - The rate of birth for these 'super-males' may be as common as 1 in 900 male births to as rare as 1 in 2000. - In the XXX syndrome, the individual will have three X chromosomes, the genotype is XXX (47, XXX) and must be female. These individuals are also referred as 'super-females' because they are usually an inch or so taller than average. - They have long legs and slender torsos. Their sexual characteristics are normal but they may have slight learning difficulties and are usually in the lower range of normal intelligence. - The frequency of birth is approximately 1 in 1000 female infants and it occurs more commonly when the mother is older. ### Euploidy (Polyploidy) - Euploidy is the form of polyploidy in which an entire set of chromosomes of a biological cell or organism is duplicated once or several times (2n, 3n, 4n, ...). The diploid organism contains more than two homologous sets of chromosomes. - Polyploidy occurs as a result of non-disjunction on all the chromosome pairs, producing gametes with two sets of chromosomes (2n) and gametes without any chromosome. The non-disjunction happens when spindle fibers fail to segregate chromosomes into their separate groups in mitosis or meiosis. - When fertilisation takes place between diploid (2n) and normal (n) gametes, a triploid (3n) organism will be produced. - If fertilisation happens between two diploid (2n) gametes, then the zygotes produced will be tetraploid (4n). - Polyploids are usually found in plants, but rarely in animals. One reason is that sex balance is important in animals and variations from the diploid number results in sterility. - Polyploid types are termed according to the number of chromosome sets in the nucleus as follows. - Triploid: 3n - Tetraploid: 4n - Pentaploid: 5n - Hexaploid: 6n - Octaploid: 8n - Decaploid: 10n - Polyploidy occurs in animals such as goldfish, salmon and salamanders. Lower group animals like flatworms, leeches and brine shrimps are also common examples of polyploidy in animals. - Polyploid animals are often sterile, so they often reproduce by parthenogenesis. - Polyploidy occurs in plants such as ferns and flowering plants, including both wild and cultivated species. - For example, there are two types of polyploid wheat. One is a tetraploid plant with the common name durum or macaroni wheat, and another, a hexaploid plant with the common name bread wheat. - Brassica spesies is also an example of a tetraploid plant. - Polyploidy can be induced in a cell culture by certain chemicals; the best known is colchicine which inhibits chromosome segregation during meiosis. - In plant breeding, the induction of polyploids is a common technique to overcome the sterility of a hybrid species. - Triticale is a hybrid of wheat (Triticum turgidum) and rye (Secale cereale). It combines valuable characteristics of the parents, but the initial hybrids are sterile. - After polyploidisation, the hybrid becomes fertile and can thus be further propagated. - There are two kinds of polyploid: - Autopolyploid - Autopolyploids are polyploids that have additional sets of chromosomes that are identical to the parent species. - This species usually originates from a single species. - It can arise from a spontaneous, naturally-occurring or induced genome doubling of a single species. - The genomes are very identical or very similar. For example: AA AAA, AAAAAA, or BB → BBB, BB BBBB. - Allopolyploid - Allopolyploids are polyploids that have additional sets of chromosomes but are derived from a different species. - They may originate from hybridisation and doubling of genomes of different species. - Allopolyploids contain two or more diploid genomes. - Examples are AABBAAABBB, or CCDD - CCCDDD. #### Autopolyploid - The most common autopolyploid in plants are autotriploids and autotetraploids. - An autotriploid would have the chromosomal composition of AAA and an autotetraploid would be AAAA. - Autotriploids can occur through the following number of ways. - Failure of chromosome segregation during meiosis may produce diploid gametes. When a diploid (2n) gamete is fertilised by a normal haploid (n) gamete, a triploid zygote (3n) is formed. - When two sperms fertilise a single ovum and produce a triploid zygote. - When a gamete from a tetraploid organism fertilises a gamete from a diploid organism. - Organisms of autopolyploid with an even number of chromosome sets are healthier than those with an odd number of chromosome sets. - Triploid plants are usually sterile with big flowers and leaves; and can reproduce asexually. Examples include roses, chrysanthemums, bananas, guava, apples, pineapples, sugar beet and watermelons. - Tetraploid plants are usually vigorous, big-sized, longer-living and disease-resistant. Examples include cabbage, tomatoes and wheat. - Most autopolyploid plants have a higher economic value. - The following are some examples of common cultivated plants that are autopolyploids. - Wild potato (2n=24) - Wild cotton (2n=26) - Dahlia (2n=32) - Wild tobacco (2n=24) - Cultivated potato (2n=48) - Cultivated cotton (2n=52) - Garden dahlia (2n=64) - Cultivated tobacco (2n=48) #### Allopolyploid - Allopolyploids are made up of different genomes from different species. - It may contain two copies of genome A and two copies of genome B. - Allopolyploids are common among cultivated plants (wheat, cotton, coffee, sugar cane, tobacco and soybean) and wild plants (Arabidopsis suecica). - Most allopolyploids originate from hybridisation between two species. - If both species have the same number of chromosomes, then the derived species would be an allotetraploid. - Amphidiploid is another word for an allopolyploid. - The giant tree, Sequoia sempervirens or coast redwood has a hexaploid (6n) genome, and is also thought to be an autoallopolyploid (AAAABB).