Gene Mutation

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  • All cancers result from changes in the DNA sequence of our genome. These changes occur throughout life because the genome within our cells is exposed to mutagens like UV radiation and accumulates mistakes during replication. These changes result in a progressive, subtle divergence of the DNA sequence from the original copy from the fertilised egg. Occasionally, one of these mutations alters the function of a critical gene, providing a growth advantage to the cell in which it has occurred. This means that this cell and its offspring divide at a faster rate than that of their neighbours. The result is tumour formation, invasion of surrounding tissue and eventually ‘metastasis’, or spread of the cancer to other parts of the body. The image in the slide shows a human melanoma cell undergoing cell division. The chromosomes (blue) have separated and the two daughter cells have almost split apart – only a small bridge of cytoplasm remains. The green staining labels the endoplasmic reticulum and the red labels the mitochondria.
  • Proto-oncogenes code for proteins that drive cell division. When these genes acquire mutations that result in continually active proteins they become oncogenes and cause uncontrolled cell growth and division.  The “cell as a car” analogy: If you are using the car analogy, oncogenes can be seen as the accelerator. When one healthy copy of the proto-oncogene is altered it is the equivalent of the accelerator pedal being stuck – speeding up cell growth and division. Notice in the case of oncogenes that it only takes one copy of the gene to undergo changes to lead to cancer, rather than both copies as is the case with TSGs.
  • Tumour suppressor genes (TSG) code for proteins that slow down cell growth. They can halt the cell growth cycle to stop unnecessary division or promote apoptosis (cell death) if the cell’s DNA is damaged.Different tumour suppressor proteins carry out the following functions: Repression of genes which are essential to the cell cycle, therefore inhibiting cell division. Linking the cell cycle to DNA damage; if there is damage to the cell it will not allow it to divide. Identifying where the DNA damage is irreparable and initiating apoptosis (cell suicide).The animated chromosome diagram illustrates that both copies of the TSG have to be inactivated by mutation or other alteration for there to be a loss of cell cycle control. If one functional copy remains, there is still a “brake” on the cell’s growth. The “cell as a car” analogy: One way to think about TSGs is to see them as the brakes of a car. There is a gene on both chromosomes so in a sense there are two brakes. If one gene is mutated and its protein loses its function, the cell can still halt and prevent unregulated cell growth as the other copy of the gene (or brake) is still functioning. However if that back up copy also changes and no longer codes for a functioning protein, the cell cycle is no longer under control and this can lead to cancer.
  • An example of germline cancer mutations inherited from parents are mutations in the BRCA1 and BRCA2 genes. These are breast cancer susceptibility cancer genes. They are rare and the risk of cancer is high.Women who have inherited a mutation in one of these genes from a parent will have a life time risk of breast cancer of approximately 70% , compared to 10% in the rest of the population. However, even in those cases where someone has inherited a susceptibility, additional somatic mutations are required.
  • Gene Mutation

    1. 1. GENE MUTATIONGeneticsBy: Jaycris C. Agnes
    2. 2. The genetic code is the set of rules bywhich information encoded withingenetic material(DNA or mRNA sequences)is translated into proteins (aminoacid sequences) by living cells.Genetic Code•Introduction:
    3. 3. • The Codons in mRNA arenucleotide bases, “read” in blocksof three.• There are 64 codons, 61 of thesebase triplets correspond to specificamino acids. Three other serve assignal to stop translation.Codons
    4. 4. A gene mutation is defined as analteration in the sequence ofnucleotides in DNA a polymer ofnucleotides joined together.Gene Mutation
    5. 5. • During protein synthesis, DNAis transcribed into RNA andthen translated to produce proteins.• Altering nucleotide sequences mostoften results in nonfunctioning proteins.• Mutations cause changes in the geneticcode that lead to genetic variation andthe potential to develop disease.
    6. 6. Kinds of Gene Mutation
    7. 7. Point mutations are the most common type ofgene mutation. Also called a base-pairsubstitution, this type of mutation changes asingle nucleotide base pair. Point mutations canbe categorized into three types:1. Point MutationSILENT MISSENSENONSENSE
    8. 8. SILENT MUTATIONAlthough a change in the DNA sequenceoccurs, this type of mutation does not changethe protein that is to be produced.
    9. 9. MISSENSE MUTATION
    10. 10. TYPES OF MISSENSE MUTATIONConservativeNon-conservativeResult in an amino acid change. However,the properties of the amino acid remain thesame (e.g., hydrophobic, hydrophilic, etc).Result in an amino acid change that hasdifferent properties than the wild type. Theprotein may lose its function, which canresult in a disease in the organism.
    11. 11. DNA sequence Amino acid sequenceType ofmutationATG CAG GTG ACC TCA GTG M Q V T S V NoneATG CAG CTG ACC TCA GTG M Q L T S V ConservativeATG CCG GTG ACC TCA GTG M P V T S VNon-conservativeConservative vs. Non-conservative
    12. 12. Non-conservative MutationDiseases• Sickle Cell Anemia (loss-of-function)Sequence for normal hemoglobinATG GTG CAC CTG ACT CCT GAG GAG AAG TCT GCC GTT ACTSTART Val His Leu Thr Pro Glu Glu Lys Ser Ala Val ThrSequence for Sickle Cell AnemiaATG GTG CAC CTG ACT CCT GTG GAG AAG TCT GCC GTT ACTSTART Val His Leu Thr Pro Val Glu Lys Ser Ala Val Thr
    13. 13. • CancerValine Glutamic AcidMutation changing a valine to glutamic acid inthe braf gene; this leads to an activation of theRAF protein which causes unlimited proliferativesignalling in cancer cells.
    14. 14. All cancers derive fromsingle cells that haveacquired thecharacteristics ofcontinually dividing in anunrestrained mannerand invadingsurrounding tissues.•What is cancer?Human melanoma cellundergoing cell divisionCredit: Paul Smith & Rachel Errington, WellcomeImages
    15. 15. • Cancer cells behave in thisabnormal manner because ofchanges in the DNA sequence ofkey genes, which are known ascancer genes. Therefore allcancers are genetic diseases.•What is cancer?
    16. 16. Oncogene(gain-of-function)CancerRasGenes which normally function to PROMOTE cellgrowth/division in a controlled manner
    17. 17. Tumour suppressor gene (loss-of-function)TSCancerThese genes normally function to PREVENTcell growth/division
    18. 18. •Importance of somatic DNAchanges in human cancerSomaticInheritedBothOnly 5 –10% of cancer cases have a clear hereditarycomponent,e.g. BRCA1 and BRCA2 in breast cancerEven in those cases where susceptibility is clearly inherited,somatic changes are required for cancer to develop
    19. 19. NONSENSE MUTATION
    20. 20. 2. Frameshift Mutation
    21. 21. 3. Repeat Expansion Mutation
    22. 22. END.
    23. 23. 1. Causes thick, sticky mucus andvery salty sweat.2. Bacteria colonize in the mucuscausing infections.3. Eventually fatal.• Cause by Deletion of a base in Phenylalaninein chromosome number 7. X-Linked recessive.•Cystic Fibrosis
    24. 24. 1. Myotonic dystrophy isa chronic, slowlyprogressing, highlyvariable, inheritedmultisystemic disease.2. It is characterized bywasting of the muscles(musculardystrophy), cataracts,heart conductiondefects, endocrine changes, and myotonia.•Myotonic DystrophyCaused by trinucleotide repeat of CUG (Leucine).X-linked Dominant.
    25. 25. • Large, protruding ears (one or both)• Long face (vertical maxillary excess)• High-arched palate (related to theabove)• Hyperextensible finger joints• Hyperextensible (Double-jointed)thumbs• Flat feet• Soft skin• Postpubescent macroorchidism (Large testes in men after puberty)• Hypotonia (low muscle tone)• single palm crease (crease goesacross entire palm)•Fragile X SyndromeCaused by trinucleotide repeat of CGG(Arginine) in X-Chromosome. X-linked Dominant.
    26. 26. • Autism/ ADHD/ Mental Retardation.• Strabismus (lazy eye)• Obsessive-Compulsive Disorder (OCD) [some]• Speech may be cluttered or nervous.• Stereotypic movements (e.g., hand-flapping)and atypical social development, particularlyshyness, limited eye contact, memoryproblems, and difficulty with face encoding.People inflicted by FXS have:•Fragile X Syndrome
    27. 27. • Afflicted person suffered fromsevere anemia.Caused by Nonsense mutation ofCAG(glutamine) to UAG (STOP). AutosomalRecessive.•B-Thalassemia

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