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Chapter 18 – Gene Mutations and DNA Repair Mutation • Inheritable change in genetic material – Cells from cell division; offspring from reproduction • Somatic mutations – Mitosis yields genetically identical cells • can lead to mosaicism – Tumor – uncontrolled growth • Germ-line mutations – Arise in cells destined to become gametes – Passed to offspring; present in every cell of organism • Gene mutations – Affect a single gene • Chromosomal mutations – Large-scale changes – May be observable with a microscope Types of mutations • Base substitution/point mutation – One base is replaced by another – Transition • One purine replaced by another purine; one pyrimidine replace by another pyrimidine – Transversion • Purine replaced by a pyrimidine, or vice versa Types of mutation • Insertion or deletion – One or more nucleotides – Frameshift mutation • In mRNA genes, affect all amino acids downstream, unless in groups of three in normal codon place • Expanding trinucleotide repeats – Certain genes contain tandem repeats – Number of repeats can increase in offspring due to strand slippage or uneven crossing over Phenotypic effects • Missense mutation – Causes incorrect amino acid to be placed in polypeptide – Neutral mutation – protein function is not affected due to amino acids having similar properties • Nonsense mutation – Introduces a premature STOP codon – Results in a truncated polypeptide • Silent mutation – Due to codon redundancy, mutation still codes for the same amino acid Phenotypic effects cont • Loss of function – Functional polypeptide is not made – Recessive • Normal gene still makes correct polypeptide • Gain of function – Abnormal polypeptide is produced – dominant Causes of mutations • Spontaneous – Natural changes/errors – Replication errors or chemical changes • Induced – Caused by environmental agents • Chemical, radiation Spontaneous replication errors • • • • Tautomers Wobble Strand slippage Unequal crossing over Tautomers • Various forms of nitrogenous bases – Position change of a proton (hydrogen ion) • Can exhibit unconventional base pairing – Rare form of C can bond with A; rare form of G can bond with T • Originally thought to be major source of mutation – no supporting evidence Wobble • Flexibility in DNA helix • Incorporated error – TA base pair becomes CA • One new molecule will have correct TA, other will have CG – Since all bases are correctly paired, no repair mechanism can fix Strand slippage • Causes small insertions or deletions • One nucleotide loops out – On new strand – results in an insertion – On old strand – results in a deletion Strand slippage in trinucleotide repeats • Slippage of new strand can result in expanded number of repeats in offspring cells • Cause of anticipation Unequal crossing over • Incorrect alignment of homologous chromosomes • Crossing over results in an insertion in one molecule and a deletion in the other molecule • Can also cause expanded trinucleotide repeats Spontaneous chemical changes • Depurination – Nucleotide loses its purine base; apurinic – Can’t act as a template – A is usually the base placed in the new strand Deamination • Removal of an amino group • Deaminated cytosine becomes uracil – Since U is not present in DNA, usually correctly by repair mechanisms • Deaminated methylcytosine becomes thymine – Causes CG to AT – not detected by repair mechanisms Chemically Induced Mutagens • Mutagen – environmental agent with ability to alter DNA sequence • Base analogs • Alkylating agents • Deamination • Oxidative reactions • Intercalating agents Chemically induced mutagens • Base analogs – Have structure similar to normal nucleotides – When ionized, exhibit unconventional base pairing – Transition or transversion mutation shown? Chemically induced mutations • Alkylating agents – Donates alkyl groups to bases – Incorrectly base pair • Deamination – Can occur spontaneously or be induced – Adenine becomes hypoxanthine (pairs with C) – Guanine becomes xanthine (pairs with T) Chemically induced mutagens • Oxidative reactions – Reactive forms of oxygen – Causes transversions • G pairs with A • Intercalating agents – Insert themselves into DNA – distorts molecule – Often causes frameshift mutations Radiation • Ionizing radiation – High energy breaks phosphodiester bonds – Results in double-stranded breaks • UV light – Pyrimidine dimers – usually thymine dimers – Causes TpT to covalently bond • Replication of DNA is blocked and cell dies, or transcription is blocked DNA repair • • • • Mismatch repair Direct repair Base excision repair Nucleotide excision repair Mismatch repair • Corrects replication errors/improper base pairing not fixed by DNA polymerase III • Recognizes structural distortions • New strand section is cut out and replaced – Old strand is methylated – strand distinction Direct Repair • Converts altered nucleotide back to original form • Methylguanine binds with A – Enzymes remove methyl group to return to normal guanine • Photolyase – Found in E. coli and some eukaryotes (not humans) – Break covalent bonds of dimers Base Excision Repair • Repairs abnormal/ modified bases • Nitrogenous base is first removed – Apurinic or apyrimidic site • Followed by removal of rest of nucleotide • DNA polymerase replaces nucleotide; DNA ligase seals nick by forming phosphodiester bond Nucleotide excision repair (NER) • Removes lesions that distort DNA helix • Several enzymes/ genes involved – Recognize distortion • DNA strand is separated; singlestrand binding proteins stabilize • Large section is removed • DNA polymerase fills in; DNA ligase seals nicks