Genetic Variation in disease

• Types of DNA change

  • Single base substitutions
  • Sometimes known as  SNPs (single nucleotide polymorphisms)
  • Replacement of a single nucleotide by another
  • Deletions of one or more nucelotides
  • Insertions of one or more nucleotides
  • Need to consider the consequence on the resultant protein
• Allele = alternative forms of gene/locus/variant
• Homozygous = two copies of same allele at same locus (genotype AA or BB)
• Heterozygous = different alleles at same locus (genotype AB or BA)
• Non-Synonymous Mutations

  • Changes amino acid sequence of protein
  • Can changes structure of the protein
  • Can change function of the protein
  • Can cause disease and normal variation
• Synonymous / Silent variation

  • No change to the amino acid sequence
  • No change in function
  • Doesn't not cause disease
• Silent - mutation does not alter the polypeptide product of the gene

  • Often a single base-pair substitution at the third position of a codon
  • Degeneracy of the genetic code, will often result in another triplet that codes for the same amino acid
  • No alteration in the properties of the resulting protein.
  • Could be outside of the coding region – in an intronic region
• Formation of a stop codons will result in premature termination of translation of a peptide chain

  Premature stop codon may lead to expression of a truncated protein HOWEVER usually  the mRNA is degraded by nonsense-mediated decay so NO protein is made.
• Nonsense mediated decay is a form of RNA surveillance that is believed to have evolved to protect the body from the possible consequences of truncated proteins interfering with normal function.
• Missense -  coding for a different amino acid 

  the synthesis of an altered protein, 

  If the new amino acid is chemically dissimilar, for example has a different charge, the structure of the protein will be altered
• Missense - 

  • coding for a different amino acid 
  • the synthesis of an altered protein
• If the new amino acid is chemically dissimilar, for example has a different charge, the structure of the protein will be altered

  • Non-conservative substitution
  • Gross reduction, or even a complete loss, of biological activity. 
  • Qualitative changes in the function of a protein may also occur

  I.e. the protein retains its normal biological activity but maybe less stable for example 
• Some single base-pair substitutions result in the replacement of a different amino acid that is chemically similar, 

  • No or very little difference in functional effect.
  • Conservative substitutions.
• Frameshift mutations

  • Insertion or deletion of nucleotides
  • If not a multiple of three, it will always disrupt the reading frame 
  • The amino-acid sequence of the protein subsequent to the mutation bears no resemblance to the normal sequence 
  • Adverse effect on the function of the protein. 
  • Usually result in a premature stop codon downstream to the mutation. 
• Polymorphism - variation in the DNA sequence that occurs in a population with a frequency of 1% or higher, non-disease causing
• Mutation - rare change in the nucleotide sequence (compared to polymorphism, which is a common variation), disease causing
• Variant can be used to describe an alteration that may be benign, pathogenic or of unknown significance. The term variant is increasingly used in place of mutation