Chapt 08


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Chapt 08

  2. 2. MUTATIONLearning Outcomes After completing this lecture, students will be able to: (a) Define gene mutation & chromosomal mutation (b) List the type of gene mutation & chromosomal mutation (c) Describe each type of gene & chromosomal mutation (d) Develop an understanding of the mutations in humans’ gene & chromosome Slide 2 of 10 Topics © 2010 Cosmopoint
  3. 3. MUTATIONTopic Outlines 1.1. Definition 1.2. Gene Mutation 1.2.1 Types of gene mutation 1.3. Chromosomal Mutation 1.3.1 Types of chromosomal mutation Slide 3 of 10 © 2010 Cosmopoint
  4. 4. MUTATION1.1. DefinitionIntroduction Mutation: changes in genes or chromosomes that is recorded durably & passed on to the offspring. Result in the change of the shape of a protein  protein cannot function well Mutation can be caused by (a) copying errors in the genetic material during cell division (spontaneous mutation) – point mutation + frameshift mutation (b) exposure to ultraviolet or ionizing radiation, chemical mutagens or viruses (induced mutation) 4 Slide 4 of 10
  5. 5. MUTATION1.1. DefinitionTypes of mutation Gene mutation Chromosomal mutation 5 Slide 5 of 10
  6. 6. MUTATION1.2. Gene MutationGene Mutation A permanent change in the DNA / nucleotide base sequence that makes up a gene. The change of a single nucleotide base pair is called point mutation. Types of point mutation: (a) base substitution (b) frameshift mutation ) 6 Slide 6 of 10
  7. 7. MUTATION1.2. Gene Mutation Gene mutations occur in two ways: (a) They can be inherited from a parent or acquired during a person’s lifetime (b) Mutations that are passed from parent to child are called hereditary mutations / germ line mutations (because they are present in the egg & sperm cells, which are also called germ cells) This type of mutation is present throughout a person’s life in virtually every cell in the body 7 Slide 7 of 10
  8. 8. MUTATION1.2. Gene Mutation Mutations that occur only in an egg / sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder 8 Slide 8 of 10
  9. 9. MUTATION1.2. Gene Mutation Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. These changes can be caused by environmental factors eg. ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm & egg cells) cannot be passed on to the next generation 9 Slide 9 of 10
  10. 10. MUTATION 1.2.1 Types of gene mutation When a mutation occurs within a gene, the protein encoded by the gene is often altered. This alteration may produce a visible change in the displayed characteristics (phenotype) of the organism studied. The actual mutation itself (genotype) is invisible to the naked eye. Structurally, mutations can be classified as (a) Small-scale / Gene mutations, eg affecting a small gene is one or a few nucleotides (b) Large-scale / chromosome mutations in chromosomal structure 10 Slide 10 of 10
  11. 11. MUTATION 1.2.1 Types of gene mutation 1. Point mutation Often caused by chemicals / malfunction of DNA replication, exchange a single nucleotide for another (base substitutions) Most common is (a) Transition that exchanges a purine for a purine (A G) or a pyrimidine for a pyrimidine (C  T) (b) Transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T  A/G) 11 Slide 11 of 10
  12. 12. MUTATION1.2.1 Types of gene mutation 12 Slide 12 of 10
  13. 13. MUTATION 1.2.1 Types of gene mutation Base substitutions occurring in protein-coding regions affect the expressed protein except when the change is in the 3rd base of a codon. Silent / synonymous mutation: gene mutation that may not cause any amino acid change in the expressed protein Non-synonymous mutation: (a) Missense mutation – modifies the affected codon, specifying an amino acid different from the one previously encoded (b) Nonsense mutation – changes a codon into one the three termination codon TAG, TAA or TGA 13 Slide 13 of 10
  14. 14. MUTATION1.2.1 Types of gene mutation 14 Slide 14 of 10
  15. 15. MUTATION 1.2.1 Types of gene mutation Example  Sickle cell anaemia  Autosomal recessive disease caused by a point mutation in the haemoglobin β gene (HBB) on the chromosome  Mutation results in the production of structurally abnormal haemoglobin, known as HbS  Amino acid glutamate is replaced by valine at position 6 of the β subunit  RBC distorted into sickle shape. 15 Slide 15 of 10
  16. 16. MUTATION 1.2.1 Types of gene mutation 2. Frameshift mutation Insertion - add one or more extra nucleotides into the DNA. - causing an alteration of the reading frame & producing an entirely new sequence of amino acid - if base insertion occurs in a gene coding for an enzyme, the resultant enzyme will lose its activity Deletion - remove one or more nucleotides from the DNA. - like insertions, these mutations can alter the reading frame of the gene. - they are generally irreversible 16 Slide 16 of 10
  17. 17. MUTATION 1.2.1 Types of gene mutation Insertion & Deletion 17 Slide 17 of 10
  18. 18. MUTATION1.2.1 Types of gene mutation 3(a): Protein that may not have normal activity 3(b): addition of a base produces a +1 frameshift, removing a pre-existing stop signal & giving rise to an elongated protein. 18 Slide 18 of 10
  19. 19. MUTATION1.2.1 Types of gene mutation Base inversion Involves the reversal of a portion of a nucleotide sequence ABCDEFGHI ABCFEDGHI 19 Slide 19 of 10
  20. 20. MUTATION1.3. Chromosomal Mutation Chromosomal mutation Definition: alterations in the number / structure of the chromosome It can be passed to the offsprings if they occur in cells that become gametes This can increase variation among the offspring Two kinds of chromosomal mutation (a) Chromosomal aberration (b) Chromosomal number alteration 20 Slide 20 of 10
  21. 21. MUTATION1.3. Chromosomal MutationChromosomal mutation Duplication Deletion Translocation Inversion 21 Slide 21 of 10
  22. 22. MUTATION1.3.1 Types of chromosomal mutation1. Duplication Leading to multiple copies of all chromosomal regions It involves the insertion of an extra copy of a region of the chromosome into a neighbouring position 22 Slide 22 of 10
  23. 23. MUTATION1.3.1 Types of chromosomal mutation2. Deletion 2 types (a) large chromosomal regions, leading to loss of the genes within those regions (b) intra-chromosomal deletion that removes a segment of DNA from a single chromosome 23 Slide 23 of 10
  24. 24. MUTATION1.3.1 Types of chromosomal mutation Chromosome breaks often heal spontaneously, but a break that fails to heal may cause the loss of an essential part of the gene complement This loss of genetic material is called gene deletion A germ cell thus affected may be capable of taking part in the fertilization process, but the resulting zygote may be incapable of full development & may therefore die in an embryonic state 24 Slide 24 of 10
  25. 25. MUTATION1.3.1 Types of chromosomal mutation3. Inversion A type of mutation where the structure of the chromosome is reversed, or inverted. It results from a segment that has broken out of the chromosome & rejoins at the same site but with inverted direction. 25 Slide 25 of 10
  26. 26. MUTATION1.3.1 Types of chromosomal mutation (a) a chromosomal inversion has a set of genes inverted. The letters represent genes along the chromosomes. (b) Recombination in a heterozygote can produce chromosomes that lack some genes and have others in double dose. These forms are probably selected against. 26 Slide 26 of 10
  27. 27. MUTATION1.3.1 Types of chromosomal mutation 4. Translocation 27 Slide 27 of 10
  28. 28. MUTATION1.3.1 Types of chromosomal mutationReciprocal translocations Two non-homologous chromosomes break and exchange fragments 28 Slide 28 of 10
  29. 29. MUTATION1.3.1 Types of chromosomal mutationCentric Fusions Translocation A centric fusion is a translocation in which the centromeres of two acrocentric chromosomes fuse to generate one large metacentric chromosome They are also often called Robertsonian translocations The karyotype of an individual carrying a centric fusion has one less than the normal number of chromosomes DML 202 General Biology & Human 11/16/2011 Genetics (Chapter 13: 29 Slide 29 of 10 Mutation)
  30. 30. MUTATION1.3.1 Types of chromosomal mutation 30 Slide 30 of 10
  31. 31. MUTATION1.1. Chromosome (definition)Introduction – Chromosome Organised structures of DNA & proteins that are found in cells Contain a single continuous piece of DNA, which contains many genes, regulatory elements & other nucleotide sequences. Each chromosome has one centromere, with one or two arms projecting from the centromere, although under most circumstances theses arms are not visible as such. 31 Slide 31 of 10
  32. 32. MUTATION1.1. Chromosome (definition) In the nuclear chromosomes of eukaryotes, the uncondensed DNA exists in a semi-ordered structure, where it is wrapped around histones (structural proteins), forming a composite material called chromatin. 32 Slide 32 of 10
  33. 33. MUTATION1.1.1 Structure of normal chromosomeStructure of Chromosome Each chromatid is made up of at least one molecule of DNA. This is the result of replication Each of the 2 identical molecules becomes a chromatid & they are attached together by a centromere During prophase, each DNA molecule wound around a group of 8 histone molecules forming a complex unit called nucleosome. During interphase, a certain amount of DNA does form nucleosomes called euchromatin, which contains genes that are activated 33 Slide 33 of 10
  34. 34. MUTATION1.1.2 Components of chromosome 6 such nucleosomes may coil regularly to form a secondary structure, which may be tertiary coiled to become the compact chromatid 34 Slide 34 of 10
  35. 35. MUTATION1.1.3 Classfication 35 Slide 35 of 10
  36. 36. MUTATION1.1.4 Normal KaryotypeKaryotype Pictures of chromosomes cut out from a microphotograph of a cell & rearranged into homologous pairs according to size & other physical characteristics. The standardized arrangement of karyotypes allows researchers to discover if an individual is a male or female & if he/she has any gross chromosomal abnormalities. 36 Slide 36 of 10
  37. 37. MUTATION1.1.4 Normal Karyotype Human have 46 chromosomes or 23 pairs in each cell The member of a pair have the same size, shape, location of centromere & banding pattern Sex chromosomes contain genes that determine sex The larger chromosome of this pair is X; smaller is Y Autosome: non-sex related chromosomes 37 Slide 37 of 10
  38. 38. MUTATION1.1.4 Normal Karyotype 38 Slide 38 of 10
  39. 39. MUTATION1.1.4 Normal Karyotype  Group A: chromosomes 1-3 are largest with median centromere  Group B: chromosomes 4-5 are large with sub-median centromere  Group C: chromosomes 6-12 are medium sized with sub-median centromere  Group D: chromosomes 13-15 are medium sized with acrocentric centromere  Group E: chromosomes 16-18 are short with median or sub-median centromere  Group F: chromosomes 19-20 are short with median centromere  Group G: chromosomes 21-22 are very short with acrocentric centromere; chromosome X is similar to group C & Y is similar to group G. 39 Slide 39 of 10
  40. 40. MUTATION1.1.4 Normal Karyotype Human Female 40 Slide 40 of 10
  41. 41. MUTATION1.1.4 Normal KaryotypeHuman Male 41 Slide 41 of 10
  42. 42. MUTATION1.1.4 Normal Karyotype 42 Slide 42 of 10
  43. 43. MUTATION1.2. Chromosomal abnormalityChromosomal abnormalities Usually occur when there is an error in cell division following meiosis or mitosis There are two major categories of chromosomal abnormalities: (a) irregular number of chromosomes (numerical) (b) structural modification in a chromosome (structural) 43 Slide 43 of 10
  44. 44. MUTATION1.2. Chromosomal abnormality Numerical abnormalities Aneuploidy: presence or absence of a single extra autosomal chromosome; describes a numerical change in part of the genome, usually a change in the dosage of a single chromosome. Polyploidy: a state where the number of set of chromosomes exceeds the diploid number by a multiple of n; happens due to the failure of the spindle fibers in mitosis/meoisis to segregate chromosomes into separate groups. 44 Slide 44 of 10
  45. 45. MUTATION1.2. Chromosomal abnormality Aneuploidy When an individual is missing either a chromosome from a pair (monosomy: 2n – 1) or has more than two chromosomes of a pair (trisomy: 2n + 1) Eg. Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two) Eg. of monosomy: Turner syndrome where the individual is born with only one sex chromosome, an X. Happens when homologous chromosomes fail to segregate properly during meiosis (non-disjunction) 45 Slide 45 of 10
  46. 46. MUTATION1.2.1 Clinical applicationDown Syndrome karyotype 11/16/2011 46 Slide 46 of 10
  47. 47. MUTATION1.2.1 Clinical applicationDown Syndrome 47 Slide 47 of 10
  48. 48. MUTATION1.2.1 Clinical application Down syndrome is associated with some impairment of cognitive ability & physical growth as well as facial appearance. Down syndrome can be identified during pregnancy or at birth. Symptoms: muscle hypotonia (poor muscle tone), a protruding tongue (due to small oral cavity, & an enlarged tongue near the tonsils), a short neck, white spots on the iris known as Brushfield spots 48 Slide 48 of 10
  49. 49. MUTATION1.2.1 Clinical applicationTurner Syndrome Instead of the normal XX sex chromosomes for a female, only one X chromosome is present & fully functional; in rarer cases a second X chromosome is present but abnormal. A normal female karyotype is labelled 46, XX; individuals with Turner syndrome are 45, X. In Turner syndrome, female sexual characteristics are present but generally underdeveloped. ) 49 Slide 49 of 10
  50. 50. MUTATION1.2.1 Clinical applicationTurner Syndrome 50 Slide 50 of 10
  51. 51. MUTATION1.2.1 Clinical applicationTurner Syndrome Karyotype 51 Slide 51 of 10
  52. 52. MUTATION1.2.1 Clinical application Klinefelter Syndrome Men inherit an extra X chromosome ) 52 Slide 52 of 10
  53. 53. MUTATION1.2.1 Clinical application 53 Slide 53 of 10
  54. 54. MUTATION Slide 54 of 10 Topics