Mutations

In multi-cell organisms, mutations can be somatic or germ-line.

  • Somatic: non sex cells, passed to daughter cells in the area. individual would still be able to reproduce without passing on the mutation

  • Germ-line: sex cell, passed to a new organism


Reduce the frequency of errors

  • proofreading: any eukaryotic or prokaryotic DNA polymerase has the ability to check the last base that is added

  • Mismatch repair system

    • scans recently synthesized DNA looking for mismatches and hemimethylated DNA

      • once you have methylated the daughter strand, there is no way of telling who is the parent and daughter

    • MutH: scans DNA and looks for hemimeythlated sequences

    • MutS: scans DNA looking for problems

    • MutL: where MutH and MutS meet and communicate to fix problems

    • MutH cuts nonmethylated strand. it then recruits an exonuclease where it removes bases just beyond mismatch

    • DNA polymerase III fills the gap. Ligase seals the nick


If mutation slips through uncorrected

  • Point mutations: you can point to a spot in the genome where a very localized thing happened

    • base substitution

      • same sense, misense, nonsense

    • frameshift

  • Chromosomal level: affects thousands of base pairs

    • Insertion, deletion, translocation, duplication, inversion


Base Substitution Mutations

  • Transition

    • base pair did not change families

    • Pyrimidines: C & T

    • Purines: A & G

  • Transversions

    • Changes Families


Same Sense mutations:

  • nucleotide changed to a different codon that specifies the same amino acid

  • no effect on protein or product function


Nonsense mutations:

  • codon specifying an amino acid is changed to a stop codon causing premature termination

  • protein is truncated and virtually always inactive


Missense mutations:

  • codon specifying an amino acid is changed to a codon fro a different amino acid, the effect on the protein varies

    • EXAMPLES: His/Arg vs His/Asp might be okay because a positive charge was removed and replaced with a positive charge. Glu/Asp vs Glu/Val in soluble protein was not be okay because Val is hydrophobic so there would be issues.


Sickle-Cell anemia:

  • defective b-globin subunit in hemoglobin protein

  • a single base pair substitution changes charge of the protein

  • distorted cells get stuck in vessels, causing intense pain and anemia in low oxygen conditions

  • Has an exposed hydrophobic region and makes chains


PKU

  • newborns screened to prevent severe mental impairment; can be prevented by special diet

  • caused by a single amino acid change in a 451 amino acid enzyme

  • High levels of phenylalanine and low levels of tyrosine


Frameshift mutations:

  • shifts the reading frame

  • addition or removal of a small number of bases not divisible by three

  • usually results in premature appearance of stop codon


Cystic fibrosis

  • 70% of CF cases are due to an in frame deletion of a Phe codon at AA

  • mutation doesn’t fold properly and never gets to the cell membrane


Chromosomal level mutations:

  • insertion/deletion: section of DNA got deleted from chromosome. it can also get inserted

  • duplication

  • inversion: where piece of DNA got cut out flipped and glued back into place

  • Translocation: reciprocal


Disorders:

  • lymphomas and leukemias are caused by translocations

  • many oncogenes are activated and become cancers through duplication

  • fragile x syndrome and huntingtons disease are also caused by duplications of short, repeated sequences

  • if inversions dont involve the loss of DNA, they are often silent, but have been known to cause infertility

  • haemophilia A is often caused by insertions

  • duchenne’s muscular dystrophy is caused by deletion