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Lecture 3 - Mutation and Genetic variation

Lecture 3 - Mutation and Genetic variation - Mutation and...

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Mutation and Genetic Variation Genetic Variance (V G ) Generation Change in V G = mutation rate x average effect x time +/+ x/x +/+ +/+ +/+ +/x +/+
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Mutation Definition : Change in the composition of the genome from parent to daughter strand (Total DNA damage – repaired damage) = mutation Occur in both somatic and germline cells (only considering heritable mutations - which occur in the germline cells)
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Mutations occur because… Spontaneous errors in DNA replication (“mismatches”) Mutagenic damage to standing (non-replicating) DNA “selfish” elements replicate themselves, often to the detriment of the host genome
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Causes of Mismatches Polymerase base misincorporation (~1x10 -7 in E. coli ) Recall that DNA polymerases have 3’ 5’ and/or 5’ 3’ exonuclease (“proofreading”) function Tautomerization Spontaneous deamination (e.g, deaminated cytosine is uracil, leads to C/G U/A T/A
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Examples of tautomerization
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Spontaneous deamination C pairs w/ G; U pairs w/ A (recall RNA), so deamination leads to C/G A/T transition
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Mechanisms of mutagenic damage Base analogs (purines/pyrimidines that mimic legitimate bases but pair differently) Direct damage to DNA (e.g., deamination, alkylation, intercalating agents, UV) Indirect damage to DNA (e.g., agents that generate oxygen free radicals, e.g., metabolism) Oxygen free radicals predominantly cause G/C A/T via 5- hydroxyuracil from cytosine deamination and G/C T/A via 8- oxoguanine
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Intercalation of DNA (e.g., by ethidium here)
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Mechanisms of DNA repair Direct repair : damage repaired directly (e.g., nicks, photolyase repair of cyclobutyl dimers) Excision repair : damaged DNA excised and repaired using undamaged strand as template; base excision, nucleotide excision Mismatch repair : recognizes misincorporated bases, removes the mispaired base (on the daughter strand) and repairs using the parent strand as a template Recombination repair (double-strand break repair): employs the recombinational machinery Transcription-coupled repair (ER, specific to transcribed strand during transcription)
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Categories of mutations Nucleotide sequence mutations Chromosomal rearrangements Transposable elements
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Terminology Base Substitution (1) a mutation consisting of substituting one nucleotide for another (2) The outcome of an evolutionary process culminating in the fixation of the new nucleotide at a given homologous site Homologous (1) 2 entities in different taxa descended from the same entity in the common ancestor - in this case from the SAME particular nucleotide in the common ancestor (“evolutionary homology”; draw ) (2) Similar sequence (“sequence homology”)
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The Genetic Code
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