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  • 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. 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. 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. MUTATION1.1. DefinitionTypes of mutation Gene mutation Chromosomal mutation 5 Slide 5 of 10
  • 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. 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. 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. 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. 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. 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. MUTATION1.2.1 Types of gene mutation 12 Slide 12 of 10
  • 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. MUTATION1.2.1 Types of gene mutation 14 Slide 14 of 10
  • 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. 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. MUTATION 1.2.1 Types of gene mutation Insertion & Deletion 17 Slide 17 of 10
  • 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. 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. 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. MUTATION1.3. Chromosomal MutationChromosomal mutation Duplication Deletion Translocation Inversion 21 Slide 21 of 10
  • 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. 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. 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. 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. 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. MUTATION1.3.1 Types of chromosomal mutation 4. Translocation 27 Slide 27 of 10
  • 28. MUTATION1.3.1 Types of chromosomal mutationReciprocal translocations Two non-homologous chromosomes break and exchange fragments 28 Slide 28 of 10
  • 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. MUTATION1.3.1 Types of chromosomal mutation 30 Slide 30 of 10
  • 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. 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. 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. 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. MUTATION1.1.3 Classfication 35 Slide 35 of 10
  • 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. 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. MUTATION1.1.4 Normal Karyotype 38 Slide 38 of 10
  • 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. MUTATION1.1.4 Normal Karyotype Human Female 40 Slide 40 of 10
  • 41. MUTATION1.1.4 Normal KaryotypeHuman Male 41 Slide 41 of 10
  • 42. MUTATION1.1.4 Normal Karyotype 42 Slide 42 of 10
  • 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. 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. 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. MUTATION1.2.1 Clinical applicationDown Syndrome karyotype 11/16/2011 46 Slide 46 of 10
  • 47. MUTATION1.2.1 Clinical applicationDown Syndrome 47 Slide 47 of 10
  • 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. 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. MUTATION1.2.1 Clinical applicationTurner Syndrome 50 Slide 50 of 10
  • 51. MUTATION1.2.1 Clinical applicationTurner Syndrome Karyotype 51 Slide 51 of 10
  • 52. MUTATION1.2.1 Clinical application Klinefelter Syndrome Men inherit an extra X chromosome ) 52 Slide 52 of 10
  • 53. MUTATION1.2.1 Clinical application 53 Slide 53 of 10
  • 54. MUTATION Slide 54 of 10 Topics