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Causes and Effects of mutation Gametic and somatic mutations • Gametic – affect testis of males or ovaries of females – can be inherited • Somatic – affect autosomes only – occur beyond zygote formation – are not heritable – affect the individual during their lifetime e.g. Chimaeras • mixture of cell types, some with the mutation and others without • can cause cancer, if gene regulation is disrupted What causes mutation? • Environmental Factors – Radiation (short wavelength EMWs, subatomic particles ) • Ionising radiation e.g. x-rays, γ-rays • Non-ionising radiation e.g. UV light – Chemicals such as benzene, formaldehyde, carbon tetrachloride, mustard gas, alkylating agents, base analogs, nitrous acid Ionising radiation - x-rays, γ rays —Cause deletions, insertions, inversions or translocations as a result of oxidative damage to DNA —Oxidative Damage • Occurs when IR interacts with water, causing an electron to be ejected from water • Irradiated water molecules become unstable and split into hydrogen ions and hydroxyl radicals • Hydrogen ions react with oxygen, forming hydroperoxyl (HO2)radicals • Both radicals are strong oxidizing agents • They cause the breakdown of the poly-sugar phosphate DNA backbone —Medical treatment associated with development of cancers (e.g. leukaemia, thyroid cancer and skin cancer) Non-Ionising radiation - UV radiation —Wavelength 1000 – 4000 Å, particularly longerwave UVA • UV light is absorbed by nucleic acids • Causes excitation of purines and pyrimidines • The excited molecules form dimers – formation of covalent bonds between adjacent purines/pyrimidines • Dimerization of thymine disrupts its base pairing with adenine • Thymine pairs with guanine instead • An AT pair is converted to a GC pair • Result: Substitution mutation Chemical Mutagens • Alkylating agents: molecules which replace amino or keto groups in nucleotides with an alkyl group, such as CH3 or Ch3CH2 • Base analogs: mutagenic molecules which can be substituted for purines or pyrimidines during nucleic acid synthesis, resulting in anomalous arrangements • Nitrous acid: changes the hydrogen bonding patterns of amine groups on A and C, leading to the formation of diazo groups Functional groups- basics Other Mutagens • Environmental poisons – Organic solvents such as formaldehyde, tobacco, coal tars, benzene, asbestos, some dyes • Alcohol– High alcohol intake increases the risk of some cancers • Diet high in lipids, especially fats and those containing burned or highly preserved meat Errors in Cell Division 1. DNA replication 2. Nondisjunction during Meiosis 3. Maternal Age • Human females are born with all the eggs they’ll need • The gametes are as old as an individual female is • Genetic errors in female gametes increase over time • Older females have a greater risk of chromosome abnormalities • Paternal age does not increase the risk of chromosome abnormalities as males produce new gametes throughout their lifetime The effect of mutations • Not all are harmful • Survival advantage • Most common among bacteria and viruses but also seen in insects • If no selective pressure may remain in population Harmful mutations...1 • Cystic fibrosis - three nucleotides are lost • Sickle cell anaemia - 1 base change, typically in the beta chain – Abnormal haemoglobin • Albinism – caused by mutation in gene enzyme pathway of melanin production Harmful Mutations...2 Haemoglobin • Haemoglobin is a tetramer – 2 chains, 2 -chains • The nucleotide sequences have been worked out • Several inherited diseases of abnormal haemoglobin occur on the -chain, which contains 146 amino acids • The genes for these polypeptides are found on different chromosomes – The -chain gene is found on chromosome-11 – The -chain gene is found on chromosome-16 Harmful mutations…3 Sickle cell anaemia • Caused by a point mutation in the βglobin chain of haemoglobin • The hydrophilic amino acid glutamic acid is replaced with the hydrophobic amino acid valine at the sixth position • This point mutation is a substitution Start: Third Term Point Mutations Point Mutations…1 • Structural abnormalities which involve changes in a very small segment of DNA molecule – Nucleotide or nucleotide pair – Result in deletions, insertions or substitutions • Deletion; loss of a single nucleotide or nucleotide pair in a codon or a gene • Insertion (addition); addition of one or more extra nucleotides to a gene or histone • Substitution; replacing a nucleotide with a different one in a specific codon Point Mutations…2 1. Deletion – One or more base pairs is lost from a sequence: Example: – CGATGG –– CATGG – GCTACC GTACC 2. Insertion – One or more base pairs is added to a sequence Example: – CGATGG –– CGAATGG – GCTACC GCTTACC 3. Substitution – One base-pair is replaced by another Example: – G to C or A to G – CG T C Point Mutation Comparison: Insertion/Deletion A point mutation can result in a frame-shift or in-frame mutation. Possible Results of a Mutation…1 The five possible results of a mutation are: 1. Silent mutation: • When a base pair is substituted the change still codes for the same amino acid in the sequence Example: • TCT and TCC both code for the amino acid Serine 2. Substitution: • When a base pair is substituted and the new codon codes for a different amino acid Example: • TCT codes for Serine and CCT codes for Proline Possible Results of a Mutation…2 3. Premature Stop: • When a substitution results in the formation of a STOP codon before all of the codons have been read and translated by the ribosome Example: • GTGGTCCGAAACACC –– GTGGTCTGAAACACC • Val-Val-Pro-Asn-Thr Val-Val-STOP 4. Codon Deletion or Insertion: • A whole new amino acid is added, or one is missing from the mutant protein Example: • GTGGTCCGAAACACC –– GTGGTCTGCCGAAACACC • Val-Val-Pro-Asn-Thr Val-Val-Cys-Pro-Asn-Thr Possible Results of a Mutation…3 5. Frame Shift: • When a deletion or insertion results in a different base pair being the beginning of the next codon, changing the whole sequence of amino acids Example: • GTGGTCCGAAACACCT –– GTGGTCGAAACACCT • Val-Val-Pro-Asn-Thr Val-Val-Glu-Thr-Pro Types of Point Mutations – Effects on Protein • Missense mutations are point mutations that result in a single amino acid change within the protein • Nonsense mutations are point mutations that create a premature "translation stop signal" (or "stop" codon), causing the protein to be shortened • Silent mutations are point mutations that do not cause amino acid changes within the protein Distinguishing Frameshift from Inframe Mutations Frameshift mutation – – – – Genetic information is altered DNA sequence no longer divisible by three Genetic information is read out of phase (incorrect order) Triplet nature of gene expression (codon) disrupts reading the frame – Incorrect information = mutant (inactive, or abnormal) protein – Result; altered phenotype and/or premature death Inframe mutation – Insertion or deletion which is evenly divisible by three Effects of Substitution (Missense mutation) - SCA • Effects at DNA level Effects at the protein level Effects on structure of RBCs Summary - SCA Revisit from here, after completing MUTATION 2 Effects on the organism’s fitness Negative effects: • At high altitude and intense exercise, a carrier of the sickle cell allele experiences pain and fatigue Positive effects: • Carriers are resistant to malaria, because the parasites that cause this disease are killed inside sickle-shaped red blood cells Beneficial mutations Bacteria – Antibiotic resistance through mutation – Transfer between bacterial species – Superbugs such as MRSA have arisen this way MRSA stands for methicillin-resistant Staphylococcus aureus – The term is used to describe a number of strains of the bacteria, Staphylococcus aureus – That are resistant to a number of antibiotics, including methicillin RNA viruses - such as HIV – Mutates it’s protein coat so that the host human is unable to make antibodies quick enough against it Neutral mutations • Neither harmful or beneficial to the organism • May be important in an evolutionary sense • Silent mutations • Virtually impossible to detect • No observable effect Summary…1 • A mutation can be • A replicable change in nucleotide sequence Or • DNA damage which is a non-replicable alteration in DNA structure • Mutations come in a variety of (often overlapping) categories including – – – – – – – Point mutations Silent mutations Missense mutations Nonsense mutations Insertions Deletions Frameshift mutations Summary…2 • A mutation may also involve changes in the number of chromosomes – Ploidy; aneuploidy, diploidy • Have deleterious effects • Down’s syndrome; Kleinfeler’s syndrome; Turner’s syndrome Summary…3 • Mutations – Are generally deleterious – Have negative effects on affected individuals • Mutant types – Are not able to compete favourably with normal individuals – Appear less frequently in a population – Kept at low frequency by natural selection