C7 Mutation PDF

TOPIC 7:MUTATION TOPIC 7: MUTATION SUBTOPIC 7.1: OVERVIEW THE CLASSIFICATION AND TYPES OF MUTATION LEARNING OUTCOMES: a) Define mutation. (CLO 1) b) Classify mutation into (CLO...

TOPIC 7:MUTATION TOPIC 7: MUTATION SUBTOPIC 7.1: OVERVIEW THE CLASSIFICATION AND TYPES OF MUTATION LEARNING OUTCOMES: a) Define mutation. (CLO 1) b) Classify mutation into (CLO 1) i. spontaneous mutation ii. induced mutation (e.g. exposure to mutagens) c) State two types of mutation: (CLO 1) i. gene/ point mutation ii. chromosomal mutation 7.1 (a) Mutation DEFINITION MUTATION A change in the nucleotide sequence of an organism’s DNA or in the DNA or RNA virus. (ref: Campbell 12th ed.) Occurs randomly at gene or chromosome. Mutations create genetic diversity (variation) among individuals. Mutation leads to change in genotype & phenotype, that is different from its parent. Can be passed from generation to generation (inheritable) if it occurs in gamete cells. Mutation in somatic cells is passed on to daughter cell by mitosis. 7.1 (b) Classification of mutation CLASSIFICATION OF MUTATION 1. Spontaneous mutation o Mutation happens spontaneously during DNA replication in cell division. o Occurs naturally (a normal mistake) about one in every million to one in every billion divisions. o Due to low level natural mutagens. o The most common mechanism for spontaneous mutation is point mutation (gene mutation). o Example: nondisjunction 2. Induced mutation o Occur when organism exposed to mutagens such as chemical (colchicine) and radiation (X-rays). o Can create new mutations by treating organism with mutagens. 144  TOPIC 7:MUTATION 7.1 (c) Types of mutation SUBTOPIC 7.2: GENE MUTATION LEARNING OUTCOMES: a) Define gene mutation (CLO 1) b) State the three types of gene mutation. (CLO 1) c) Explain three types of gene mutation: (CLO 2) i. base substitution ii. base insertion iii. base deletion d) Explain base substitution (e.g. sickle cell anaemia as missense mutation) (CLO 2) e) State the effect of base substitution (missense, nonsense and silent mutation) and base insertion and base deletion (frameshift mutation). (CLO 1) f) Explain base insertion and base deletion as frameshift mutation. (CLO 2) 7.2 (a) Gene mutation DEFINITION GENE MUTATION The changes in the nucleotide sequence of genetic material (DNA) that represents a gene. Gene mutation can cause mistakes in base pairing during DNA replication or misreading of the genetic code during translation phase of protein synthesis Lead to the change in amino acid sequences, thus may change the proteins/enzymes produced. Effect of mutation; protein not functioning as normal// unable to function. When the gene Figure 7.2.1: Example of Gene Mutation mutation involves only a single base pair, it is called a point mutation. 145  TOPIC 7:MUTATION 7.2 (b-d) Types of gene mutation. Figure 7.2.2: Types of Gene Mutation 7.2 (d-e) Effect of base substitution 1. Missense mutation A changes in the base sequence will result in changes of codon. Changes in the codon lead to changes in the amino acid sequence. Example effect is sickle cell anaemia. WILD TYPE MISSENSE MUTATION Figure 7.2.3 : Effect of base substitution (Missense mutation) 146  TOPIC 7:MUTATION Sickle cell anaemia (defective in erythrocyte) Normal people have normal haemoglobin that consist of chains. The replacement of base thymine (T) to base adenine (A) at the 17th nucleotide DNA for the -chain of haemoglobin/ CTC to CAC. changes the codon GAG into GUG. Glutamic acid is replaced with valine in both -polypeptide chains. Caused abnormal haemoglobin allele (Hb-S) in erythrocyte. Erythrocyte with Hb-S are sickle-shape/ deformed shape of red blood cell That shape is not efficient for transporting oxygen throughout the cell. Caused blood to clot in small blood vessel. Figure 7.2.4 : Example effect of missense mutation-Sickle cell anemia Symptom of sickle cell anaemia The person suffers physical weakness/fatigue/headache, pale skin, chest pain, short breath. Fatal form of anaemia. Insufficient supply of oxygen to the organs. Organ damage. Physical weakness / fatigue. Periodic pain occurs in the chest, abdomen, bones and joints due to blockage of tiny blood vessels by sickle-shaped RBC. 147  TOPIC 7:MUTATION 2. Nonsense mutation Occurs when base substitution results in changing a codon into stop codon. It causes translation to be terminated prematurely (stop codon; UAA, UAG, UGA). The earlier in the gene sequence that this mutation occurs, the more truncated (made shorter) the polypeptide/protein product becomes & more likely that it will be unable to function. WILD TYPE NONSENSE MUTATION Figure 7.2.5 : Effect of base substitution (Nonsense mutation) 3. Silent mutation A change in base sequence transforms one codon to another codon that still codes/translates the same amino acid. Called silent; no effect on amino acid sequence. WILD TYPE SILENT MUTATION Figure 7.2.6 : Effect of base substitution (Silent mutation) 148  TOPIC 7:MUTATION 7.2 (e-f) Effect of base insertion and base deletion (frameshift mutation). EFFECT OF BASE INSERTION AND BASE DELETION – FRAMESHIFT MUTATION Frameshift mutation is a changes/shifts the reading frame of the codons during translation. In gene mutation; inserts or deletes one or more nucleotides (that are not multiples of threes) at the DNA nucleotide sequence change mRNA strand (transcription). Gene will be transcribed in the wrong three base groups (codon). Codons will be translated differently & will abrupt the coding sequence of amino acids. Thus, codons will code different amino acids. This will change all amino acids at and after the point of mutation. Many of these deletions/insertions start in the middle of a codon. Originally, the stop codons (UAA, UAG, UGA) will not be read or may be created at an earlier site. Because of frameshift mutation, the protein produced may be abnormally short, abnormally long, or contain the wrong amino acids. It will be most likely not functional. Effect of frameshift mutation ~ usually harmful to humans. E.g.: Thalassaemia WILD TYPE BASE INSERTION Polypeptide chain become shorten BASE DELETION Frameshift mutation change all amino acids at and after the point of mutation. Figure 7.2.6 : Effect of base insertion and deletion (Frameshift mutation) 149  TOPIC 7:MUTATION SUBTOPIC 7.3: CHROMOSOMAL MUTATION LEARNING OUTCOMES: a) Define chromosomal mutation. (CLO 1) b) State two types of chromosomal mutation: (CLO 1) i. changes in chromosomal structure/chromosomal aberration ii. changes in chromosomal number. c) Explain changes in chromosomal structure/chromosomal aberration. (CLO 2) d) Explain types of chromosomal aberration. (CLO 2) e) Explain alteration of chromosome number. (CLO 2) f) State the types of the alteration: (CLO 1) i. aneuploidy ii. euploidy/ polyploidy g) Explain aneuploidy. (CLO 2) h) State aneuploidy effect on autosomal chromosome (Monosomy 21 and Trisomy 21) and sex chromosome (Klinefelter syndrome and Turner syndrome). (CLO 1) i) Explain autosomal abnormalities and their effects: (CLO 2) i. Monosomy (Monosomy 21) ii. Trisomy (Down syndrome/ Trisomy 21) j) Explain sex chromosomal abnormalities: (CLO 2) i. Klinefelter syndrome (47, XXY) ii. Turner syndrome (45, XO) k) Explain euploidy/polyploidy: (CLO 2) i. autopolyploidy ii. allopolyploidy 7.3 (a) Chromosomal mutation. (b) Types of chromosomal mutation DEFINITION CHROMOSOMAL MUTATION Changes in chromosomal structure and changes in chromosome number Figure 7.3.1: Types of Chromosomal Mutation Figure 7.3.1 : Types of chromosomal mutation 150  TOPIC 7:MUTATION 7.3 (c-d) Chromosomal Mutation : Chromosomal structure/chromosomal aberration. 1. CHROMOSOMAL STRUCTURE / ABERRATION Changes to chromosomal structure result in abnormalities in the structure of chromosomes. The breakage and re-joining of chromosome parts result in four structural changes within or between chromosomes. Four types of chromosomal structure/ aberration i. translocation ii. deletion (segmental deletion) (e.g. cri du chat) iii. inversion iv. duplication i. Translocation Occurs when a chromosomal segment breaks off and attach/ rejoining another region; either the same chromosome or another nonhomologous chromosome. Chromosomal material is maintained, but in different arrangements after a translocation. 2 types of translocation: o Intrachromosomal translocation – A chromosomal fragment breaks off and joins within the same chromosome. o Interchromosomal translocation – A chromosomal fragment breaks off and joins to a nonhomologous chromosome. Figure 7.3.2: Types of Translocation 151  TOPIC 7:MUTATION Two types for interchromosomal translocation: o Reciprocal translocation Chromosomal segments are exchanged between two nonhomologous chromosomes. The results are one chromosome becomes extra-long and other one becomes extra-short. Changes in position of the genes involved. Chromosomal translocations have been implicated in certain diseases. E.g: Chronic Myelogenous Leukemia (CML) In CML a portion of chromosome 22 has switched places with a small fragment from a tip of chromosome 9. Figure 7.3.3: A reciprocal translocation produces a short chromosome 22, (Philadelphia chromosome), and a long chromosome 9, leading blood cells to escape control of the cell cycle, becoming cancerous and causing leukemia. O Nonreciprocal translocation Fragment rearrangement between two nonhomologous chromosomes, that result from the fusion of the entire long arms of two acrocentric chromosomes (chromosomes with centromere near their ends). acrocentric chromosomes Nonreciprocal translocation The chromosomes stick together. The remaining short arm loses. Figure 7.3.4: Nonreciprocal translocation 152  TOPIC 7:MUTATION ii. Deletion (segmental deletion) Removal/loss of one segment of chromosome, containing one or more genes when the chromosome breaks at two points. The remaining segments of the chromosomes will join again and become shorter. This results in the loss of certain genes and can cause abnormalities and serious genetic diseases. Figure 7.3.5: Chromosomal Abberation : Deletion Figure 7.3.6: Cri-du chat chromosome 5 pairs An example in humans, the deletion of a small part of the short arm of chromosome 5 causes cri du chat syndrome (‘cry of the cat syndrome’). Characteristics of cri du chat syndrome individual: o mental retardation. o small head. o unusual facial features. Figure 7.3.5: Children o a cry like the mewing of a distressed cat. with Cri-du chat o fatal in infancy and early childhood (short lifespan). iii. Inversion A rearrangement of a chromosome segment, where a segment of chromosome is break off, inverted (rotated) 180o and rejoined within a chromosome. Usually do not cause any abnormalities, as long as the rearrangement is balanced with no extra/missing genetic information. 2 types of inversion: - o pericentric – include the centromere. o paracentric – does not include centromere. No change in the genotype but phenotype may change. Figure 7.3.7: Chromosomal Mutation: Inversion 153  TOPIC 7:MUTATION iv. Duplication Repetition of one or more segments of chromosome; giving the additional sets of genes. Chromosomes becomes longer due to duplication. Figure 7.3.8: Chromosomal Mutation: Duplication 7.3 (e-f) Chromosomal Mutation : Alteration of chromosome number. 2. ALTERATIONS OF CHROMOSOME NUMBER Changes in the number of chromosomes. Alterations of chromosome number cause some genetic disorders. Figure 7.3.9: Types of Alteration NORMAL ANEUPLOIDY EUPLOIDY/POLYPLOIDY (2n= 4) (2n +1 = 5) (3n) 154  TOPIC 7:MUTATION 7.3 (g) Aneuploidy. Aneuploidy Condition where the cell of diploid organism (2n) gains or loses 1 or more individual chromosomes. (2n + 1) or (2n -1). The most common cause of aneuploidy is nondisjunction during meiosis I and II. It may occur: in autosomes. in sex chromosome - give effect to sex chromosomal abnormalities. WHAT IS NONDISJUNCTION? Homologous chromosomes fail to separate and move properly to opposite poles during anaphase meiosis I or sister chromatids fail to separate and move properly to opposite poles during anaphase meiosis II. Occur due to spindle fibres cannot form during cell division. This process can affect production of gametes: Some gametes produced have an extra chromosome (n+1) and other gametes have a chromosome missing (n-1). If nondisjunction occurs during meiosis I: Two gametes produced have an extra chromosome (n+1) while the other half/ two gametes have a chromosome missing (n-1). If nondisjunction occurs during meiosis II: One gamete produced have an extra chromosome (n+1), while the other one gamete has a chromosome missing (n-1) and two gametes are normal (n). Figure 7.3.10: Nondisjunction 155  TOPIC 7:MUTATION Offspring results from fertilization of a normal gamete with one of these gametes will have an abnormal chromosome number or aneuploidy. 7.3 (h-i) Effect aneuploidy on autosomal chromosome ANEUPLOIDY ON AUTOSOMAL CHROMOSOME During fertilization the fusion of gametes occur between: Meiosis I Nondisjunction meiosis I Meiosis II Nondisjunction meiosis II Gametes FERTILIZATION WITH NORMAL GAMETE n+1 n+1 n- 1 n- 1 n n n+1 n- 1 n 2n+1 2n+1 2n -1 2n -1 2n 2n 2n+1 2n -1 Trisomic Trisomic Monosomic Monosomic Normal Normal Trisomic Monosomic Figure 7.3.11 : Monosomic and Trisomic 1. Gametes with chromosome (n+1) and normal gamete (n), Produced embryo with chromosome (2n+1). Example: o Autosome (e.g.: Trisomy 21/ Down syndrome). o Sex chromosome (e.g.: Klinefelter syndrome) Trisomy: refers to the gain of an extra chromosome to a diploid chromosome set. Individuals are called trisomic. 2. Gametes with chromosome (n-1) and normal gamete (n), Produced embryo with chromosome (2n-1). Example: o Autosome (e.g.: Monosomy 21). o Sex chromosome (e.g.: Turner syndrome) Monosomy: refers to the loss of one chromosome from a diploid chromosome set. Individuals are called monosomic 156  TOPIC 7:MUTATION EXAMPLES OF AUTOSOMAL ABNORMALITIES 1. Monosomy (Monosomy 21): 2n-1/ 45 chromosomes A condition of monosomy 21 – lack of one chromosome at chromosome 21. Occurs due to nondisjunction of chromosome 21 during anaphase of meiosis I or anaphase of meiosis II. Produce abnormal gametes contain 22 chromosomes with no chromosome 21 (n-1). Fusion of normal gamete (n) with 23 chromosomes and a gamete with a lack of one chromosome number 21 (n-1). Producing individuals with chromosome number 2n – 1 (45 chromosome) known as monosomy 21 Figure 7.3.11 : Individu with monosomy Figure 7.3.12 : Karyotype monosomy 21 21 Symptom of monosomy 21: Short distance between eyes Large ears Contracted muscle. Small head and jaw. Asymmetric face. 157  TOPIC 7:MUTATION 2. Trisomy (Down syndrome/ Trisomy 21) : (2n+1/ 47 chromosome) Figure 7.3.13: Karyotype trisomy 21 A condition of trisomy 21 – extra of one chromosome 21. Occurs due to nondisjunction of chromosome 21 during anaphase of meiosis I or anaphase of meiosis II. Produce abnormal gametes contain 24 chromosomes (n+1) with extra chromosome 21. Fusion of normal gamete (n)/ gamete with 23 chromosomes and a gamete with an extra of one chromosome number 21 (n+1). Producing individuals with chromosome number 2n + 1/ 47 chromosomes known as trisomy 21. Characteristics of Down syndrome such as : Mentally retarded Protruding furrowed tongue Flat and rounded face Flattened nose Slanted eyes Wide/broad forehead Limbs/hands are often short and stubby Most infertile/sterile/sexually underdeveloped Usually short life span At higher risk for infections/disease such as leukaemia and Alzheimer’s diseases Heart defect Figure 7.3.14 : Individu with Down Respiratory problems syndrome/ trisomy 21 158  TOPIC 7:MUTATION 7.3 (i-j) Effect aneuploidy on sex chromosome. ANEUPLOIDY ON SEX CHROMOSOME Abnormalities in the sex chromosome number. Causes by nondisjunction during spermatogenesis or oogenesis at meiosis I or meiosis II. Any extra copies of the sex chromosome can cause developmental errors. Nondisjunction during oogenesis: Women carry two sex chromosome (XX chromosome). If nondisjunction happened during meiosis I: Some gametes might not carry any X chromosome(O), others might carry two X chromosomes (XX). If nondisjunction happened during meiosis II: Some gametes might not carry any X chromosome (O), others might carry two X chromosomes (XX) and others might carry one X chromosome (X). Figure 7.3.16: Figure 7.3.17: Nondisjunction during meiosis I oogenesis Nondisjunction during meiosis II oogenesis Nondisjunction during spermatogenesis: Men carry XY sex chromosome, normal sperm have chromosome X or Y. If nondisjunction occur during meiosis I, some gametes might not carry any chromosome(O), others might carry XY chromosomes Nondisjunction in first XY meiotic division XY O O Figure 7.3.18: Nondisjunction of sex chromosome during meiosis I 159  TOPIC 7:MUTATION If nondisjunction during meiosis II, sperm will have the abnormal sex chromosome: XX, YY or O (not have X or Y chromosome) Figure 7.3.19: Nondisjunction of sex chromosome during meiosis II spermatogenesis EXAMPLES SEX CHROMOSOMAL ABNORMALITIES 1. Klinefelter syndrome (47 chromosomes, XXY) Causes by nondisjunction at: Meiosis I or Meiosis II during oogenesis. If nondisjunction happens during meiosis I or meiosis II of oogenesis, an abnormal gamete with two X chromosomes (XX) is produced. When this abnormal egg (XX) fuse with normal sperm with Y chromosome during fertilization, XXY zygote is formed. Meiosis I during spermatogenesis. If nondisjunction happens during meiosis I of spermatogenesis, an abnormal gamete with XY chromosome is produced. When this abnormal sperm (XY) fuse with a normal egg with X chromosome gamete during fertilization, XXY zygote is formed. Male individual with Klinefelter syndrome has extra copies of the sex chromosome, X can cause developmental errors. 160  TOPIC 7:MUTATION The number of chromosomes for this individual is 44 + XXY. Figure 7.3.20: Physical appearance and karyotype of individual with Klinefelter syndrome Characteristics of Klinefelter syndrome (47 chromosomes, XXY) Sterile. Testes and prostate glands are abnormally small, produce small amounts of testosterone, Have breast enlargement. Have long arms and legs. They may have feminine characteristics such as soft voice, and may have subnormal intelligence. Others have a mild mental retardation or learning disability. 2. Turner syndrome (45, XO) Causes by nondisjunction at: Meiosis I or Meiosis II during oogenesis. If nondisjunction happened during meiosis I or meiosis II of oogenesis, an abnormal gamete without sex chromosome is produced (O). When this abnormal egg without sex chromosome fuse with normal sperm with X chromosome during fertilization, XO zygote is formed. Meiosis I during spermatogenesis. If nondisjunction happened during meiosis I or II of spermatogenesis, an abnormal gamete without sex chromosome is produced. When this abnormal sperm without sex chromosome (O) fuse with a normal egg with X chromosome during fertilization, XO zygote is formed. This condition is called Turner syndrome. 161  TOPIC 7:MUTATION Female individual with Turner syndrome has lost a copy of the sex chromosome, X can cause developmental errors. The number of chromosomes for this individual is 44 + XO. Figure 7.3.21: Physical appearance and karyotype of individual with Turner syndrome Characteristics of Turner syndrome; They are females who are usually short. Broad-necked (webbed neck). Sterile because lack of menstruation and sex organ does not mature, that do not undergo changes during puberty. Most have normal intelligence 7.3 (k) Euploidy/polyploidy EUPLOIDY/ POLYPLOIDY Condition where the cell of diploid organism (2n) having more than two complete sets of chromosomes (3n, 4n, 5n) Polyploid organism is naming based on the total sets of chromosomes present. WHAT IS PLOIDY? Ploidy = The number of sets of chromosomes in a cell or an organism. Example: Haploid : a set of chromosomes without their pair, n. Diploid : 2 sets of homologous chromosomes, 2n. Polyploid : multiple sets of chromosome pairs, 3n, 4n,….. 162  TOPIC 7:MUTATION Occur as a result of nondisjunction of all chromosome pairs, producing gametes with two sets of chromosomes (2n). Two types of polyploidy: o Autopolyploidy. o Allopolyploidy. TYPES OF EUPLOIDY/POLYPLOIDY 1. Autopolyploidy Increasing the genome (complete set of chromosomes) more than two chromosome sets derived from the same species. Occur due to nondisjunction of all chromosomes during meiosis. Can arise from: a spontaneous, naturally occurring or induced genome doubling of a single species (by using chemicals like colchicine). Important in economic value is that autopolyploid plants produce flower and fruit bigger than normal diploid plants. This autopolyploid mutant can reproduce with itself (self-pollination) or with other tetraploids. Figure 7.3.22: Autopolyploidy 2. Allopolyploidy Allopolyploidy is the increasing genome (complete set of chromosomes) of more than two chromosomes sets derived from a different species through hybridization and doubling of genomes of different species. F1 hybrids produced from different species are usually sterile. The haploid set of chromosomes from one species cannot pair during meiosis with the haploid set of chromosomes from the other species because no homologous chromosome. Meiosis cannot occur and no gamete produce. However, the hybrids may be able to reproduce asexually (vegetative propagation) to colonize an area. 163  TOPIC 7:MUTATION Importance of allopolyploidy: Producing new species with desired qualities. Economic value such as producing flowers and fruits bigger, more resistant compared to normal diploid plant. Various mechanisms can transform a sterile hybrid into a fertile polyploidy. i. Hybrids undergo chromosome doubling. ii. Or hybrids can interbreed with either parent species. MECHANISM 1- CHROMOSOME DOUBLING EXAMPLE 1 EXAMPLE 2 EXAMPLE 3 Figure 7.3.23: Allopolyploidy- sterile hybrids undergo chromosome doubling (naturally occurs in plants) 164  TOPIC 7:MUTATION MECHANISM 2- INTERBREED WITH EITHER PARENT SPECIES Unreduced (diploid) gametes fuse with normal haploid gametes to form triploids. Triploids are normally sterile, but can contribute to fertile hybrid. Unreduced triploid gametes that can back-cross with a normal haploid gamete to form fertile hybrids (new species). EXAMPLE 1 EXAMPLE 2 Figure 7.3.24: Allopolyploidy- sterile hybrids interbreed with either parent species (occurs usually in cell culture) 165