Mutations. Section 6.3

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1 Section 6.3 Mutations Objectives Identify different changes to DNA within both genes and chromosomes Evaluate effects of changes to DNA on proteins produced and organisms overall survival New Vocabulary Gene mutation Insertion Deletion Substitution Chromosomal mutation Chromosomal deletion Amplification Inversion Chromosomal insertion Translocation Non-disjunction Silent mutation Missense mutation Nonsense mutation Frameshift mutation Overexpression Beneficial mutation Harmful mutation Neutral mutation Mutagen The nucleotides of DNA are often compared to letters in an alphabet. By using different combinations of letters, typographers can create different printed words. Similarly, by using different combinations of nucleotides, different proteins can be created. What happens to a word if a letter is copied incorrectly? Sometimes the reader can understand the word, but sometimes the word s meaning changes completely. Something similar can happen to strands of DNA: mutations.

2 Types of Mutations Gene Mutations A mutation that only affects one gene is a gene mutation. There are three different types of gene mutations: insertion, deletion, and substitution. An insertion occurs when one or more new nucleotides are added within a DNA sequence for a gene. A deletion occurs when one or more nucleotides are removed from a DNA sequence for a gene. A substitution (also called a point mutation) occurs when a nucleotide is replaced with a different nucleotide. The three types of gene mutations are summarized in Table Type Definition Example Insertion Deletion Substitution (point mutation) A new nucleotide is added A nucleotide is removed A nucleotide is replaced with a different nucleotide "...TAGCCAGATA... "...TAGCGCAGATA... "...TAGCCAGATA... "...TAGCAGATA... "...TAGCCAGATA... "...TAGCCAGTTA... Table There are three major types of gene mutations: insertions, deletions, and substitutions. The type of gene mutation occurring can be easily determined using the steps below. Step 1 Write the wild-type allele above the mutated allele so that the bases line up. " Reasoning: This will allow you to easily compare the two alleles. (Note: this step might already be done for you.) Step 2 Starting on the right, look along both strands and underline the first base that is different in the mutated allele. " Reasoning: This will allow you to identify where the change occurred. Step 3 Based on the difference between the two strands, identify the mutation that occurred. " Reasoning: The types of gene mutations are defined by the change that occurred. Step 4 If possible, use the overall lengths of the two strands to check your answer.! Reasoning: An insertion will increase the length, a deletion will decrease the length, and a substitution will keep the length the same. Chapter 6 - DNA & Genes 212 Section continues

3 Example problem Which of the three gene mutations occurred to change the sequence ACTAGATAGGCAT into ACTAGATAGCAGCAT? Step 1 Write the wild-type allele above the mutated allele so that the bases line up. " " " " " Wild-type" ACTAGATAGGCAT " " " " " Mutated" ACTAGATAGCAGCAT Step 2 Starting on the right, look along both strands and underline the first base that is different in the mutated allele. " " " " " Wild-type" ACTAGATAGGCAT " " " " " Mutated" ACTAGATAGCAGCAT Step 3 Based on the difference between the two strands, identify the mutation that occurred. " An insertion occurred (a cytosine and an adenine were inserted after the ninth nucleotide). Step 4 If possible, use the overall lengths of the two strands to check your answer. " The mutated strand is two bases longer than the wild-type. Longer mutated strands reflect an insertion. Does the answer make sense? Yes. This result makes sense because the mutated strand contains two extra bases, an insertion occurred. Chapter 6 - DNA & Genes 213 Section continues

4 Chromosomal Mutations A mutation that affects multiple genes is a chromosomal mutation. There are several different types of chromosomal mutations, including deletions, insertions, amplifications, translocations, non-disjunctions, and crossing over. The chromosomal mutation deletion is similar to the gene mutation deletion. Remember that in the gene mutation deletion, one or more nucleotides are removed. In a chromosomal deletion, a piece of the chromosome (many nucleotides) is lost. This mutation can remove one or more genes from the chromosome. In an amplification mutation (also called gene duplication), a large piece of the chromosome is repeated. This mutation causes two or more copies of one or more genes. In an inversion, a piece of a chromosome is removed and readded after being flipped, reversing its orientation. Chromosomal deletions, amplifications, and inversions are summarized in Figure Figure Chromosomal deletions, amplifications, and inversions each affect the genes in one part of a chromosome. Deletions remove these genes, amplifications multiply the genes, and inversions flip the orientation of bases within the genes. Segments of DNA can also move from chromosome to chromosome. In chromosomal insertions, a piece of one chromosome is removed and inserted into another chromosome. In translocation, two pieces of different chromosomes are interchanged. These two mutations are illustrated in Figure Some chromosomal mutations occur during meiosis. Remember that during meiosis, homologous chromosomes are separated so that one goes to each gamete. If they do not separate correctly and both chromosomes go to the same daughter cell, this is called non-disjunction. Jump to Meiosis Figure In an insertion, a segment of one chromosome is moved to another. In translocation, two pieces from different chromosomes are exchanged. Chapter 6 - DNA & Genes 214 Section continues

5 Effects of Mutations In the previous section, mutations were categorized by the change to nucleotides. Remember that through transcription and translation, these nucleotides will be used to form mrna codons that will be translated into a polypeptide chain. Because of this, mutations can also be categorized by their effect on the polypeptide chain made. In general, each type of change to the nucleotides causes a certain type of effect on the polypeptide. Jump to Translation Effects of Gene Mutations Gene mutations can affect a gene in multiple ways. Remember that in a substitution, one nucleotide is replaced by a different nucleotide, changing the mrna strand. Because of redundancies in the genetic code, a different codon does not always place a different amino acid during translation (Figure 6.3-3). If the substitution changes the mrna codon into a codon coding for the same amino acid, it is called a silent mutation because it has no outwardly visible affect. If the substitution changes the mrna codon into a codon coding for a different amino acid, it is called a missense mutation because one of the amino acids is now different. Depending on the location of the amino acids, this could change the protein created. If the substitution creates a stop codon, the amino acid terminates early. This can greatly affect the overall protein created and is therefore called a nonsense mutation. Figure The genetic code contains many redundancies, which allow silent mutations to occur. For example, leucine will be used if the codon is UUA, UUG, CUU, CUC, CUA, or CUG. Jump to Substitution Chapter 6 - DNA & Genes 215 Section continues

6 Insertions and deletions cause frameshift mutations. Since the codons are read in groups of three nucleotides, the addition or removal of a nucleotide changes the reading frame. Every codon past the mutation is affected, and a completely different polypeptide chain can be produced. Effects of gene mutations are summarized in (Figure 6.3-4). Figure As illustrated here, different mutations to the DNA can cause different effects to the polypeptide. Chapter 6 - DNA & Genes 216 Section continues

7 Effects of Chromosomal Mutations Since chromosomal mutations affect multiple genes, they can cause large impacts on an organism. Remember that in non-disjunction, the homologous chromosomes do not separate. This creates one gamete with an extra copy of a chromosome and one gamete with no information for that chromosome. If either of these gametes fuses with a normal gamete, the individual formed will not have the correct number of chromosomes. For example, in Down syndrome, a human has three copies of chromosome 21. This causes both physical and mental retardation (Figure 6.3-5). Jump to Non-Disjunction When a segment of a chromosome is duplicated in amplification, the organism might have an overexpression of those genes and create more copies of protein than normal. In contrast, if a segment of a chromosome is deleted or inversed, the organism might not be able to express any of these genes. Jump to Chromosomal Mutations Effects of Mutations on Fitness Any mutation can be categorized by its effect on fitness. A beneficial mutation increases an organism s fitness. For example, a mutation might cause an organism s fur color to be closer to the environment, allowing it to avoid predators. A harmful mutation decreases an organism s fitness. For example, a mutation might make the protein responsible for carrying oxygen in the blood less efficient. A neutral mutation does not affect an organism s fitness. For example, a mutation might not change the proteins created. All silent mutations are neutral mutations. Figure Caused by a non-disjunction event, Down syndrome causes both physical and mental retardation. One common trait is a wide gap between the large and second toe. Chapter 6 - DNA & Genes 217 Section continues

8 Lab DNA Mutations The effect of a gene mutation depends on the type and severity of change. The following virtual lab will provide you the opportunity to modify a gene and evaluate the effects. By creating different changes in the gene, you should have been able to create silent, missense, nonsense, and frameshift mutations. Chapter 6 - DNA & Genes 218 Section continues

9 Spotlight on Sickle-cell Anemia Sickle-cell disease is a generic name for a number of conditions resulting from a mutation in the genetic code. The most common of these conditions is sickle-cell anemia. As seen in Figure 6.3-6, the condition results in red blood cells with a hardened sickle shape instead of the normal flexible disk shape. Since healthy red blood cells carry oxygen to body tissues, sickle-cell anemia causes breathing problems, paleness, and fatigue. The abnormal blood cells also tend to clump together in the bloodstream. This can cause pain, infections, organ damage, and swelling. A primary component of red blood cells is hemoglobin, a specialized protein that can chemically bond to and transport oxygen and carbon dioxide through the bloodstream. As seen in Table 6.3-2, a single base substitution mutation causes a missense mutation in one of the polypeptide chains of hemoglobin. The substitution of the amino acid valine for glutamic acid causes a sticky spot in the hemoglobin beta polypeptide chain. This results in the sickle shape of the red blood cell. The mutant strain is HbS, and the wild-type is HbA. Figure This 3D rendering contrasts normal red blood cells with sickle-shaped red blood cells that result from sickle-cell disease. Jump to Globular Proteins Wild-Type DNA (HbA) CTG ACT CCT GAG GAG AAG TCT Leucine Threonine Proline Glutamic acid Glutamic acid Lysine Serine Substitution Mutation (HbS) CTG ACT CCT GTG GAG AAG TCT Leucine Threonine Proline Valine Glutamic acid Lysine Serine Table A mutation in the nucleotides for hemoglobin results in a different amino acid and misshapen red blood cells. Chapter 6 - DNA & Genes 219 Section continues

10 Remember that each person contains two copies of each gene, one from the mother and one from the father. Two copies of the mutant HbS gene, one from each parent, are needed to cause sickle-cell anemia. Only one copy of the HbS gene causes sickle-cell trait, in which the person is a carrier of the gene. However, the presence of only one HbS gene does not usually cause problems for carriers. Since this gene shows codominance, some red blood cells may contain some abnormal hemoglobin, but most red blood cells will be normally shaped because of the presence of the wild-type gene. Jump to Codominance In most parts of the world, the HbS gene is rare. However, the sickle-cell gene is found in those of Central African or Indian ancestry. These locations are also where the highest rates of a deadly form of malaria occur. This overlap is because carriers of the sickle-cell gene are more likely to survive malaria (the reasons are still being researched). Since these carriers are more likely to survive, they are more likely to have children. If two carriers have a child, this creates a monohybrid cross. In this cross, there is only a 25% chance that the child will be homozygous dominant and not have the sickle-cell gene to pass on. Jump to Dihybrid Cross Although some people with sickle-cell anemia can be cured through stem cell transplants, for most people, this disease is managed, not cured. Fortunately, a number of treatments and medications are available to lessen symptoms and complications of the disease. Chapter 6 - DNA & Genes 220 Section continues

11 Causes of Mutations Mutations have three primary causes. The first is mistakes that happen during DNA replication. Although cells have double-checking mechanisms during DNA replication, errors can still occur. The second cause is mutagens, environmental agents that can damage existing DNA. Examples of mutagens are ultraviolet radiation and chemical toxins. For example, UV radiation can damage a group of bases on one of the DNA strands (Figure 6.3-7). This damage causes the bases to pair with each other instead of with their complementary bases on the other DNA strand. The final primary cause of DNA mutations is spontaneous damage by molecules known as free radicals. Free radicals are reactive forms of molecules produced by normal metabolic processes. Free radicals cause damage directly to nitrogenous bases in DNA. Antioxidants, chemicals found in many healthy foods, are thought to neutralize free radicals and prevent damage. Figure UV radiation can cause bases on one strand to pair with one another instead of the other strand. Chapter 6 - DNA & Genes 221 Section continues

12 Repairing DNA Despite the various mutations possible, cells and tissues usually replicate their DNA without accumulating harmful mutations. This is because cells have several procedures to detect and repair mistakes. These procedures have been identified in both unicellular and multicellular organisms. Primarily, checkpoint procedures during the cell cycle prevent cell division if mistakes are found in DNA. Cells that do not pass the checkpoint may be marked for destruction by white blood cells or die naturally. Mutations can accumulate if the checkpoint system breaks down. If a mutation removes a checkpoint, cells with damaged DNA may undergo mitosis, as illustrated in Figure This causes damaged DNA to be passed on to daughter cells. Figure If the checkpoint system fails, damaged DNA is passed on. Jump Control of Cell Cycle Cells can also repair their own damage. UV radiation damage is detected because it causes a change in the shape of the DNA molecule. These changes are repaired through a complex method in which the damaged section is removed and the strand is repaired. Prokaryotes, fungi, plants, some insects, and even some vertebrates also use another system not present in humans. In these organisms, energy from light, enzymes, and other chemical molecules is used to change the DNA back into its original, undamaged shape. In another method of DNA repair, damage caused by free radicals and other cellular molecules is fixed. In this process, enzymes identify abnormal nitrogenous bases and chemically cut them out. Chapter 6 - DNA & Genes 222 Section continues

13 Sometimes the cell is unable to repair the damage. Some forms of ionizing radiation (such as that emitted from X-ray machines) cause physical breaks in one or both strands of DNA. In these mutations, pieces of the chromosome can be lost or become attached to other chromosomes. Although the cell attempts to repair these breaks, the damage is so great that the repairs themselves can cause even more damage. Ionizing radiation is very dangerous, and protection should be used when exposure is necessary (Figure 6.3-9). Special care should be given to babies and young children to avoid preventable causes of mutations. Their rapidly dividing cells are more susceptible to radiation, UV light, and even possibly the effects of free radicals. This is why pregnant women are cautioned against smoking tobacco, drinking alcohol, and even eating certain foods. Extra precautions are taken during medical testing if there is even a possibility of pregnancy. While it is true that damage from mutagens tends to accumulate as we age, there are some ways to avoid the damage. One is to avoid known mutagens, such as UV light. Recent research Figure A lead apron is used to protect body structures during an X-ray. has shown that a healthy lifestyle can prevent and, in some cases, even repair or reverse damage from mutations. Chapter 6 - DNA & Genes 223 Section complete

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