Week 11

• What is a structural chromosomal abnormality?


  Large piece of chromosome deleted, duplicated, translocated or inverted.

  Most likely occurs during meiosis
• What is a numerical chromosomal abnormality?


  Number of chromosomes may be altered

  Most likely occurs during meiosis
• How are numerical chromosomal abnormalities caused?

  Unequal distribution of chromosomes during meiosis

  (non-disjunction at first or second meiotic divisions)
• How can DNA be damaged?

  • Smoking
  • UV light
  • Ionising radiation

  DNA repair mechanisms can repair this
• What can mutations in somatic cells cause?


  Cancer

  Cancer cells more susceptible to mutation (genetic instability) so mutations can accumulate in genome
• What can mutations in germ cells affect?


  Offspring
• What are mutation hotspots?


  Segments of DNA that are especially prone to genetic alteration.
• What is depurination?


  Purine (A or G) comes off

  Can lead to loss of a nucleotide pair
• What is deamination?


  Amine residue (amino group) comes off from cytosine to form uracil

  Can result in substitution
• How does UV light damage DNA?

  Promotes covalent linkage between 2 adjacent pyrimidine (C or T) bases forming e.g, a thymine dimer

  Causes kink in DNA molecule
• What happens if cytosine is methylated?


  Amino group may come off easily to form thymine

  (epigenetic modification)
• How can mistakes occur during DNA replication?


  Mistaken pairing

  Mistake often corrected as DNA polymerase has a proof-reading function
• How can dimers be corrected?


  • DNA helicase unwinds DNA double-strand
  • Endonuclease cuts DNA at site of dimer
  • Exonuclease removes dimer & nearby nucleotides
  • DNA polymerase fills the gap
  • DNA ligase joins the 2 tandem fragments

  
• What is Xeroderma pigmentosum?


  • autosomal recessive
  • mutations in helicase or endonuclease gene
  • Thymine dimers not repaired
  • Protection from sunlight helps
• What are BRCA1 & BRCA2?


  • Genes that encode proteins to repair damaged DNA & destroy cells if DNA not repaired
  • If mutated, damaged DNA not repaired- increased risk of breast & ovary cancer
  • Autosomal dominant inheritance with high penetrance
  • NHS genetic test available
• What does RAD51 recombinase do?


  DNA repair

  Repairs double strand break

  Coded by BRCA1 & 2
• What 2 factors together increase the risk of DNA damage?

  • genetic
  • environmental
• Knudson's 2-hit model:


  In order for cell to be cancerous, both of the cell's tumour suppressor genes must be mutated (recessive)
• What is a silent mutation?


  A mutation that does not result in a change to the amino acid sequence of a protein.
• What is a nonsense mutation?


  Change of amino acid codon to a stop codon
• What is a missense mutation?


  Change of encoding amino acid
• How is the genetic code being degenerate an advantage?


  • Multiple codons can encode a single amino acid
  • More frequently used amino acids have more codons- can protect from mutations
• What type of mutation is deletion?


  Frameshift in translation

  amino acid sequence always wrong

  large deletion= block of DNA removed
• What are splice site mutations?


  Mutations that affect the splicing of pre-mRNA during gene expression.

  • can skip exons
  • can keep introns
• What is locus:


  Position of a gene on a chromosome
• Homozygote:


  Organism in which the 2 alleles of a gene are same
• Heterozygote:


  Organism in which the 2 alleles of a gene are different
• Allele:


  1 of the 2 homologous genes on the same locus
• What is a dominant mutation?


  Mutation on the single allele causes the phenotype

  Presence of a single copy of the wild-type gene doesn't help
• What is a recessive mutation?


  Phenotype presented only if both alleles have the mutation

  Mutant phenotype masked if a single wild-type gene is present
• Autosomal dominant inheritance:


  • E.g, Marfan's syndrome
  • Single affected allele causes phenotype
  • No generation skip
  • Often, affected offspring are from affected heterozygote & unaffected parent
• Autosomal recessive inheritance:


  • Recessive homozygote affected
  • Often, affected offspring is from 2 carrier parents
• X-linked dominant inheritance:


  • E.g, Rett syndrome
  • Responsible gene on X chromosome
  • Presence of 1 affected allele causes disease
• X-linked recessive inheritance:


  • E.g, red-green colour blindness (more common in men)
  • Responsible gene on X chromosome
  • Girls- only homozygotes affected
  • Boys- mutation always causes affected phenotype
• What type of disease is cystic fibrosis?


  Recessive
• What type of disease is familial hypercholesterolemia (FH)?


  Dominant
• What type of disease is Marfan's syndrome?


  • Dominant
• What is epigenetic modification?


  • Ways to modify genetic info & gene expression without changing the genetic info (DNA sequence)
  • Makes specific genes, alleles or chromosomes more or less accessible to gene expression machinery
• What is genomic imprinting?


  Gene/allele is silenced (transcriptionally inactive)

  1 allele active & the other imprinted

  Epigenetic modification e.g, DNA methylation & histone de-acetylation

  Methylated state inherited through cell division & from parent to child
• How can genes be silenced?

  • DNA methylation
  • Histone hypo-acetylation (+ charged histones more tightly packed)
  • Inhibit access of protein binding (e.g, T.factors) to DNA