Mutations

• Mutation = alteration in the nucleic acid sequence of the genome
• Detecting mutations:

  • maize - mutation in the C allele leads to a single white seed, allowing mutation rate to be calculated
  • frequency of spontaneous neurofibromatosis (dominant mutation) and haemophilia (sex-linked loci)
  • sequencing genes over subsequent generations
• Indirect methods of detecting mutations - problems with incomplete penetrance, variance in loci mutation rate, and effect on the environment (e.g. thalidomide and phocomelia)
• Somatic mutations - because cells constantly replace themselves, associated with cancers (proto-oncogenes) (the higher the age, more likely risk of cancer because the body accumulates mutations over time)

  Can also be increased by the environment, e.g. smoking
• Retinoblastoma - can affect in one eye due to a spontaneous mutation in somatic cells, but also can affect both eyes as they inherit a mutation-carrying allele from a parent then get a second spontaneous mutation
• DNA repair enzymes - correct mutation errors, resulting in a low mutation rate in the human genome

  Genetic failure in these enzymes is associated with cancer (Bloom syndrome)

  Werner syndrome - associated with detrimental ageing due to faulty enzyme
• Transposable elements - loci which increase the mutation rate at other loci, introducing the idea that the genome changed and was intrinsically (naturally) unstable
• Mutagens = agents that increase the mutation rate
• Electromagnetic radiation - X-rays are mutagens, a tiny amount has a large effect

  WW2 atomic bomb - initial survivors suffered from radiation sickness and fears of health of future generations
• Ultraviolet as a mutagen - leads to formation of thymine dimers which inhibit DNA replication

  Can be repaired by excision enzymes, but mutations in this mechanism leads to xeroderma pigmentosum (very high sensitivity to sunlight)
• Chemical mutagens (e.g. mustard gas) can cause radiomimetic burns and can be checked for using the Ames test

  Aflatoxin - mould on cheese and wheat and has a mutagenic effect

  Carcinogens, e.g. in coffee because of caffeic acid
• Age as a mutagen - due to a build up in germ line mutations

  Paternal age associated with achondroplasia, autism and schizophrenia
• Sequencing in Iceland - shows age as a mutagen and over 3 generations to calculate mutation rate
• Telomeres - at the ends of chromosomes and lost every time it divides

  HeLa cells have an overactive telomerase enzyme which delays the ageing of cells