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MUTATIONS

MUTATIONS. Defn: Permanent chagnes in nucleotide sequence. occur in somatic cells or germline cells. only germline cells inherited. somatic mutations believed responsible for many medical problems many cancers?. Heritable change in the nucleotide sequence of a chromosome .

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MUTATIONS

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  1. MUTATIONS

  2. Defn: Permanent chagnes in nucleotide sequence. • occur in somatic cells or germline cells. • only germline cells inherited. • somatic mutations believed responsible for many medical problems • many cancers?

  3. Heritable change in the nucleotide sequence of a chromosome. • Mutations can arise through exposure to mutagenic agents but the vast majority occur spontaneously through errors in DNA replication and repair.

  4. Although mutations can occur either in non-coding or coding sequences, it is only when they occur in the latter that they are recognised as an inherited disorder or disease. • A mutation arising in a somatic cell cannot be transmitted to offspring, whereas if it occurs in gonadal tissue or a gamete it can be transmitted to future generations.

  5. TYPES OF MUTATIONS • mutations can be considered in two main classes according to how they are transmitted. • mutations had been considered to be transmitted unaltered as what are termed fixed or stable mutations. • More recently a new class of mutations, known as dynamic or unstable mutations, have been demonstrated to undergo further alteration as they are transmitted in families.

  6. A- Fixed/stable mutations • Fixed/stable point mutations can be classified according to the specific molecular changes at the DNA level. • These include single base pair substitutions, insertions, deletions or duplications of part of a gene or DNA sequence.

  7. 1- Substitutions: • A substitution is the replacement of a single nucleotide by another. • If the substitution involves replacement by the same type of nucleotide, i.e. a pyrimidine for a pyrimidine (C for T or vice versa) or a purine for a purine (A for G or vice versa), this is termed a transition. • Substitution of a pyrimidine by a purine or vice versa is termed a transversion.

  8. Nucleotide Misincorporation -C-A-G-C-T- -G-T-C-G-A- CT substitution -C-A-G-C-T- -G-T-T-G-A- -C-A-G-C-T- -G-T-C-G-A- -C-A-G-C-T- -G-T-C-G-A- correctly copied

  9. 2- Deletions: • A deletion involves the loss of one or more nucleotides. • If it occurs in coding sequences and involves one, two or more nucleotides which are not a multiple of three, it will disrupt the reading frame.

  10. 3- Insertions: • An insertion involves the addition of one or more nucleotides into a gene. • Again, if an insertion occurs in a coding sequence and involves one, two or more nucleotides which are not a multiple of three, it will disrupt the reading frame.

  11. nucleotide added -C-A-G-C-T- -G-T-C G-A- -C-A-G-C-T- -G-T-C-G-A- A correctly copied Added Nucleotides -C-A-G-C-T- -G-T-C-G-A- -C-A-G-C-T- -G-T-C-G-A-

  12. B- Dynamic/unstable mutations • unstable or dynamic mutations consist of triplet repeat sequences which, in affected persons, occur in increased copy number when compared to the general population. • triplet amplification or expansion has been identified as the mutational basis for a number of different single gene disorders. • The mechanism by which amplification or expansion of the triplet repeat sequence occurs is not clear at present.

  13. Triplet Expansion in Fragile X No.triplets Affected Carrier Normal 200 60 6 FMR-1 3’ 5’ (CCG)n DNA

  14. STRUCTURAL EFFECTS OF MUTATIONS ON THE PROTEIN • Mutations can also be subdivided into two main groups according to the effect on the polypeptide sequence of the encoded protein, being either synonymous or non- synonymous.

  15. A- Synonymous/silent mutations • If a mutation does not alter the polypeptide product of the gene, this is termed a synonymous or silent mutation. • A single base pair substitution, particularly if it occurs in the third position of a codon, will often result in another triplet which codes for the same amino acid with no alteration in the properties of the resulting protein.

  16. B- Non-synonymous mutations • If a mutation leads to an alteration in the encoded polypeptide, it is known as a non-synonymous mutation. • Alteration of the amino acid sequence of the protein product of a gene is likely to result in abnormal function. • Non-synonymous mutations can occur in one of three main ways.

  17. 1- Missense • A single bp substitution can result in coding for a different amino acid and the synthesis of an altered protein, a so-called missense mutation.

  18. MIS-SENSE MUTATIONe.g. Sickle Cell Anaemia Cause: defective haemoglobin due to mutation in β-globin gene Symptoms: severe anaemia and death in homozygote

  19. Normal β-globin - 146 amino acids val - his - leu - thr - pro -glu - glu - --------- 1 2 3 4 5 6 7 Normal gene (aa 6) Mutant gene DNA CTC CAC mRNA GAG GUG Product Glu Valine Mutantβ-globin val - his - leu - thr - pro -val- glu - ---------

  20. 2- Nonsense • A substitution which leads to the generation of one of the stop codons will result in premature termination of translation of a peptide chain or what is termed a nonsense mutation.

  21. 1.Types of Mutationa) Substitution Codon amino acid Missense GAG glu AAG lys Nonsense GAG glu Change to termination UAG stop Silent GAG glu GAA glu

  22. 3- Frameshift If a mutation involves the insertion or deletion of nucleotides which are not a multiple of three, it will disrupt the reading frame and constitute what is known as a frameshift mutation.

  23. Frameshift RNAAUG UGU UAU CAU UGG Insertion AUGUUG UUA UCA UUG G Deletion AUG UGU UUC AUU GG A Note amino acids translated

  24. Mutations in non-coding DNA • Mutations in non-coding DNA, in general, would not be expected to have a phenotypic effect unless they occur in the DNA sequences involved in gene regulation, e.g. the TATA box, or in the splicing of introns, e.g. the highly conserved GT and AG dinucleotides at the end of introns. • Mutations in regulatory elements can affect the level of gene expression while mutations in splice junctions can result in coding sequences being lost or intronic sequences being added to the mRNA molecule.

  25. FUNCTIONAL EFFECTS OF MUTATIONS ON THE PROTEIN • The mutations effect can appear either through loss- or gain-of-function.

  26. 1- Loss-of-function: • These mutations can result in either reduced activity or complete loss of the gene product. • Loss-of-function mutations in the heterozygous state would be associated with half normal levels of the protein product.

  27. 2- Gain-of-function mutations • Gain-of-function mutations, as the name suggests, result in either increased levels of gene expression or the development of a new function(s) of the gene product.

  28. THE END

  29. MUTAGENS AND MUTAGENESIS

  30. Naturally occurring mutations are referred to as spontaneous mutations and are thought to arise through chance errors in chromosomal division or DNA replication. • Environmental agents which cause mutations are known as mutagens.

  31. MUTAGENS • These include natural or artificial ionizing radiation and chemical or physical mutagens.

  32. Ionizing radiation includes electromagnetic waves of very short wavelength (X-rays and gamma rays), and high energy particles (α particles, ß particles and neutrons).

  33. Causes of Mutations • radiation (nuclear accident or x-ray) • chemicals

  34. Mutagenesis “Process of producing a mutant” spontaneous induced Mutagen: physical agent or a chemical which causes or increases the rate of mutation

  35. Causes of Spontaneous mutations • error in DNA replication • faulty DNA repair e.g. mis-match • bases form tautomers which pair differently • natural mutagens

  36. T C G A C A G C T G T C A T C A G C T G T T C T A C C A T C A G AT G A G C T G DNA Mismatch Repair Normal DNA repair Base pair mismatch Mutation introduced by unrepaired DNA

  37. Mutagens PHYSICAL CHEMICAL BIOLOGICAL USE Research Disease Warfare

  38. Physical Mutagens Radiation • Non-ionising • Ultraviolet (UV) • Ionising • X-Rays

  39. Mutagenic chemicals in food contribute to 35% of cancers!

  40. THE END

  41. Biological Mutagens Insertion of a transposon within a gene • disrupts the reading frame • loss of function Jumping genes- transposable elements move to different positions in the chromosome. Transposon carries other genes with it. • (Antibiotic resistance)

  42. 1. UV (260nm) Absorbed by bases of DNA and RNA • forms pyrimidine dimers • 2 adjacent bases (CC or TT) are covalently joined • insertion of incorrect nucleotide at this point likely • during replication Skin cancer, sterilisation of equipment Poor penetration

  43. 2. Ionising radiation X-rays, cosmic rays, gamma rays More powerful than UV Penetrates glass Water etc ionises: mutagenic effect • free radicals e.g. OH- • inactivate DNA • cell death

  44. Chemical Mutagens 1.Base analogues Resemble DNA bases Faulty pairing properties Example 5-bromouracil • incorporated like T • faulty pairing with G

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