Mutations. A2 Biology For WJEC

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1 12. Mutation is a change in the amount, arrangement or structure in the DNA of an organism. 13. There are two types of mutations, chromosome mutations and gene mutations. Mutations A2 Biology For WJEC 14. Down's syndrome as an example of chromosome mutation (nondisjunction) and sickle cell anaemia as an example of gene mutation. 15. Mutations are spontaneous random events which may provide a source of material for natural selection pressures and therefore evolution. 16. Mutation rates are normally very low. In general, organisms with short life cycles and more frequent meiosis, show a greater rate of mutation. 17. Rates of mutation may be increased by mutagens, including ionising radiations, UV and X-rays, and certain chemicals, such as polycyclic hydrocarbons in cigarette smoke. A mutagen which causes cancer is a carcinogen. 18. Candidates should appreciate the consequences of mutation in relation to protein synthesis causing a change in phenotype. 19. Oncogenes allow cells to divide uncontrollably, and this can result in cancer. 1

2 1.0 What are mutations 1.1 Important definitions A mutation is any change that occurs in the genetic material of the DNA. If this change occurs in the germ cells (i.e. in the formation of gametes) then this change will be inherited if, however, the change occurs in somatic (body cells) then the change will not be inherited. Most mutations occur spontaneously which means they are statistically random. However, each gene has its own characteristic rate of mutation. So, what can increase the rate of a mutation occurring? Any substance that can cause an increase in the mutation rate is called mutagen. Occasionally, a mutation can occur that results in the formation of a cancer. A mutagen that can cause the formation of a cancer is called a carcinogen. 2

3 1.2 Types Of Mutations Mutations can occur by altering the basses in DNA in some way and also by affecting large sections of chromosomes or even whole chromosomes Mutations that effect DNA bases Point Mutations Mutations that effect Chromosomes These are mutation that occur in a gene and can affect the structure and function of a protein. A point mutation occurs when just one base pair is altered in DNA. These mutations can affect chromosomes in the following ways: 1. alteration of chromosome number 2. Alteration of number of sets of chromosomes 3. Alteration of chromosome structure. Point Mutations can occur by: 1. Substitutions 2. Insertions 3. Deletions The following sections will consider all the above mutations uses real life examples of diseases caused from the mutations. 3

4 2.0 Point Mutations Point mutations occur when there is a change in a single base pair of DNA. The mutations can be classed as nonsense, missense silent or frameshift all depending on the particular type of base change that occurs Base Substitution that gives rise to a missense mutation The case of Sickle cell anaemia. There are a number of genes that code for the haemoglobin. Remember that Haemoglobin is a quaternary protein and is made up of 4 polypeptide chains with two different globin proteins β Globin and α Globin polypeptide chains (See Figure 1). Figure 1. The quaternary structure of haemoglobin. 4

5 There are several genes that code for the haemoglobin protein. The genes are expressed at different stages of human development as shown in figure 2 below. Figure 2. Haemoglobin genes and the polypeptides that they code for. Each gene will be expressed at different stages of development. Prenatal means before birth while postnatal means after birth. 5

6 The Mutation that causes sickle cell anaemia. Sickle cell anaemia is a condition that effect the transport of oxygen around the body due to a mutation in the β Globin gene of adult haemoglobin. The mutation occurs in codon number 6 and involves the substitution of the Adenine base to the thymine base in DNA (see Figure 3 below). This substitution has resulted in a different co- don being produced. The codon will now code for the amino acid valine instead of glutamic acid. So, when the β globin gene is transcribed and then translated one wrong amino acid will be incorporated into the β globin polypeptide chain. Important concept A missense mutation normally occurs when the altered codon still codes for an amino acid and thus makes sense, although not necessarily the right sense, i.e. the wrong amino acid. Figure 3. The base substitution resulting in a missense mutation in the β globin gene. The polypeptide will have valine instead of glutamic acid resulting in the condition called sickle cell anaemia. Wild type means non-mutated DNA. The red blood cell images show normal cells in the wild type and the sickle shaped cells that result from the mutation. 6

7 2.0.2 Base Substitution that gives rise to a Nonsense mutation Important concept If a base in DNA is substituted for a base that changes the codon to a stop codon then a nonsense mutation has occurred. In Figure 4 below, the adenine base in the second codon has been substituted for a thymine base. This means the second codon has been change to a stop codon. One this happens then the rest of the protein cannot be translated Base Substitution that gives rise to a Silent mutation Important concept If a base in DNA is substituted for a base that changes the codon but does not change the amino acid that is coded for then a silent mutation has occurred. In Figure 5 below, the thymine base in the final codon has been substituted for a guanine base. This means the last codon has been altered but still codes for the glutamine amino acid. This type of mutation can occur due to the degenerate nature of the genetic code, i.e. more than one codon can code for the same amino acid. Figure 4. A nonsense mutation. Figure 5. A Silent mutation. 7

8 2.0.3 Genetic diseases caused by point mutations Several metabolic diseases can result from point mutations. These disease show nicely how mutations can effect protein function. In diseases below the proteins affected are all enzymes. There are several metabolic diseases that are affect by point mutations. These diseases are The tyrosine now becomes the substrate for the next enzyme in the metabolic pathway which is tyrosine aminotransferase. This enzymes converts tyrosine into hyroxyphenol pyruvic acid. And so the metabolic pathway continues. Mutations in any of the enzymes in this metabolic pathway will result in a genetic disease. The most serious of these disease is phenylketonuria as it effects the first enzyme in the metabolic pathway (phenylalanine hydroxylase). If this does not work then the whole metabolic pathway will not function. All these diseases effect the metabolism of the amino acids tyrosine and phenylalanine. The structure of tyrosine and phenylalanine are shown in figure 6. The 4 genetic diseases above all result in mutation in genes that code for enzymes. Phenylalanine and tyrosine are metabolised as shown in figure 6 on page 9. The metabolism of these amino acids occurs in a metabolic pathway where phenylalanine is converted to tyrosine by the enzyme phenylalanine hydroxylase. From figure 6 you can see that the only difference in phenylalanine and tyrosine is that tyrosine contains a hydroxyl group. This is what a hydroxylase enzymes does it adds an hydroxyl group. Figure 6. The structure of phenylalanine and tyrosine. 8

9 Figure 6. Mutations in the enzymes essential for the metabolism of phenylalanine and tyrosine and there diseases that results form these mutations. 9

10 2.0.4 Insertion and deletion of nucleotides giving rise to a frameshift mutation The genetic code is read as codons (see Figure 7) which is called the reading frame. If a mutation occurs when an insertion or deletion of nucleotides does not occur in multiples of three then a frameshift mutation will occur. Figure 7. The reading frame of a gene. Lets look at an example of a deletion occurring in a gene. Consider figure 8 where two nucleotides are being deleted from a gene. The wild type sequence is the same as that in figure 7, so the amino acids coded for by this nucleotide sequence is the same. As there are two nucleotides deleted the reading frame of the gene will have been altered as will have the codons after the point of the deletion. For example, the deletion has occurred in the first and second codon so the first codon has been altered to code for the amino acid isoleucine instead of methionine. Each subsequent codon has also been altered so the protein will have wrong amino acids incorporated. Figure 8. A deletion of two nucleotides resulting in a frameshift mutation. 10

11 2.0.5 An unusual frameshift mutation the case of muscular dystrophy There are two forms of muscular dystrophy: 1. Duchenne muscular dystrophy (DMD) 2. Becker muscular dystrophy (BMD) Both types of muscular dystrophy are X linked recessive disorders in which skeletal muscle and to some extent cardiac and smooth muscle waste away. DMD onset occurs early in childhood and is very severe. Suffers are in wheelchairs before the age of 11. Figure 9. Structure of the dystrophin protein. BMD onset is later and the condition is much milder than DMD and has a slower progression of muscular weakness. The dystrophin protein and its gene Dystophin is the largest human protein (figure 9) with 3685 amino acids. Dystrophin seems to stabilise the membrane of muscle cells and anchoring it to the cytoskeleton within the cytoplasm. Dystrophin is absent in DMD suffers and is greatly reduced (between 3-20% of the normal level) in BMD suffers. Figure 10. The dystrophin gene located on the X chromosome. 11

12 The dystrophin gene (figure 9) is the largest human gene. It has more than 75 exons (coding regions of a gene) with each exon having an average length of 200 nucleotides. The mutations giving rise to DMD and BMD Mutations that give rise to muscular dystrophy occur most frequently in exons 43 to 46 (figure 11). Figure 11. the most common mutated exon in the Dystophin gene. The following diagram explain how mutations give rise to the two forms of muscular dystrophy. 12

13 3.0 Chromosome Mutations Human Karyotypes. A karyotype shows the 46 chromosomes in the human nucleus. The chromosomes have been stained so that they can be seen. The chromosomes are arranged in and number in size order with the largest being first. Human male and female karyotypes are shown in figure Chromosome mutation resulting in a change in chromosome number Changes in chromosome number occurs by a process of nondisjunction. This is when chromosomes do not separate during anaphase. Mutations that result in a change in chromosome number occur due to non-disjunction occurring in anaphase II of meiosis. Changes in chromosome number are called aneuploidy and can result in an extra chromosome or a missing chromosome. Examples of aneuploidy are: 1. Down s Syndrome called trisomy 21. Figure 12. Male and female human karyotypes. Female is XX and the male is XY. From figure 12, you can see that the chromosomes are in pairs and are number from 1 to 23 with the sex chromosomes being shown last. Down s syndrome results in a person having 1 extra copy of the number 21 chromosome. Any mutation of this type is described as a trisomy mutation due to the extra third copy of the chromosome. Figure 13. karyotype of Downs syndrome 13

14 2. Trisomy 18. Figure 14. Karyotype of Trisomy 18. Trisomy 18 results in a person having 1 extra copy of the number 18 chromosome. Changes in chromosome number also occurs with the sex (XY) chromosomes. Some example of these mutation are: 1. Turners Syndrome XO Figure 16. Karyotype of Turners Syndrome. Turners Syndrome results in a person having a missing Y chromosome. This is called monosomy as there is only 1 sex chromosome. 3. Trisomy 13. Figure 15. Karyotype of Trisomy Klinfelter Syndrome XXY Figure 17. Karyotype of Klinfelter Syndrome. Trisomy 13 results in a person having 1 extra copy of the number 13 chromosome. Klinfelter Syndrome results in a person having a an Extra X chromosome. 14

15 The mechanism of non-disjunction resulting in aneuploidy. Cell 3 Cell 4 Cell 8 Cell 1 1 Cell 0 Cell 2 Meiosis I Meiosis I occurs normally and the homologous chromosome separate to opposite poles of the cell normally during anaphase I. The Two daughter cells (cell 1 and 2) formed are haploid because they do not contain homologous chromosomes. Cell 5 Cell 6 Meiosis II Meiosis II has not occurred normally, non disjunction has occurred in cell 2 and the small green chromosome has not had its sister chromatids separate to opposite poles but they have remained together and have entered cell 6. Cell 1 has undergone meiosis II normally and cells 3 and 4 are normal gametes (i.e. having haploid chromosomes that are also half the original number compared to cell 0). Cell 5 is missing a chromatid from the green chromosome so is describe as n-1 (i.e. haploid but with a missing chromosome). Cell 6 has both sister chromatids of the green chromosome plus the chromatid from the red chromosome, this cell is described as n+1 (i.e. haploid but with one extra chromosome). If cell six is fertilised by a sperm (cell 7) then the resulting zygote will have three copies of the smaller chromosome. If the smaller chromosome was number 21 then the resulting off spring would have trisomy 21. Cell 7 15

16 3.0.3 Chromosome mutation resulting in a change in whole sets of chromosome Chromosome mutation resulting in a change in structure of the chromosome. In plants it is common for them to have extra copies of all of their chromosomes. This is called polyploidy. Polyploidy does not occur in animals. Polyploidy occurs due to non-disjunction in both anaphase I and II. This results in all the chromosomes entering one gametes. If this gamete is then fertilised by a haploid gamete is can have three complete sets of chromosomes and would be described as n3 or triploid. if the gaetes was fertilised by another gamete that has undergone non-disjunction in both anaphase I and II then the organisms would have 4 complete copies of its chromosomes and wood be described as n4 or tetraploid. The structure of a chromosome can change based on a number of mutations. Figure 18 shows the structure of a normal replicated chromosome with it short and long arm and centromere. Figure 18. the structure of a normal replicated chromosome. 16

17 Changes in chromosome structure can occur by a: Translocation mutation An inversion mutation Duplication mutation A Deletion mutation Below are diagtrams describing each of these mutations. The numbered boxes in the chromosome represent large sections of chromosome and not individual genes or nucleotides. 1. A Translocation mutation 2. An inversion mutation 17

18 3. A duplication mutation 4. A Deletion mutation 18