Point Mutation: DNA Changes

• Mutation is a permanent change in the nucleotide sequence of DNA.
• A mutagen is a physical or chemical agent that causes mutation.
• Mutagenesis is the process of producing a mutation, which can be spontaneous or induced.
• Cells can repair some DNA mistakes, but unrepaired changes in the DNA sequence will be permanent after DNA replication.
• Mutations from damage to DNA nucleotides or unrepaired replication errors can be transcribed into mRNA, potentially resulting in translation of a protein with an abnormal amino acid sequence.

Point Mutation

• Point mutations involve the substitution of one base for another.
• There are two types: transition and transversion.
• Transition mutations occur when a pyrimidine is changed to another pyrimidine, or a purine is changed to another purine.
• Transversion mutations occur when a purine is changed to either of the two pyrimidines, or a pyrimidine is changed to either of the two purines.

Effect of Point Mutations

• Point mutations can lead to silent, missense, or nonsense mutations.
• Silent mutations do not affect the amino acid sequence of the protein, as the changed base still codes for the same amino acid.
• Silent mutations have no detectable effect due to the degeneracy of the genetic code and usually occur at the third nucleotide of the codon because of wobbling.
• Missense mutations involve the codon coding for a different amino acid, leading to the incorporation of a different amino acid in the protein molecule, resulting in an abnormal protein like in sickle cell anemia.
• Missense mutations can be acceptable, partially acceptable, or unacceptable
  • Acceptable missense mutations replace an amino acid with another with a similar functional group, resulting in a protein molecule that is indistinguishable from the normal one.
  • Partially acceptable missense mutations result in a protein molecule that has partial but abnormal function.
  • Unacceptable missense mutations result in a protein molecule that is not capable of functioning in its assigned role.
• Nonsense mutations involve the codon becoming a termination codon, resulting in premature termination of translation of the polypeptide.

Frame Shift Mutation

• Frame shift mutations result from the deletion or insertion of one or two nucleotides in the coding region of a message sequence, altering the reading frame.
• Frame shift effect may cause a garbled translation of mRNA, a premature termination of the polypeptide, or the addition or deletion of a single amino acid.
• The machinery translating mRNA does not recognize that a base was missing or added.
• Premature termination occurs due to a stop codon, leading to the synthesis of a truncated product.
• Altering the reading frame of mRNA distal to the deletion or insertion results in an altered translation with the production of abnormal protein.

Insertion or Deletion of Three Nucleotides

• If three nucleotides are added, a new amino acid is added to the peptide.
• If three nucleotides are deleted, an amino acid is lost.
• Loss or gain of three nucleotides causes diseases like cystic fibrosis.

Other Mutations

• There are other mutations which alter the amount or structure of the protein produced by translation.
• Trinucleotide repeat expansion involves the amplification of a sequence of three bases repeated in tandem.
• Trinucleotide repeat amplification within the coding region of a gene can result in the protein containing many extra copies of one amino acid.

Trinucleotide Repeat Expansion

• Amplification of the CAG codon leads to the insertion of many extra glutamine residues in the huntingtin protein, causing Huntington disease.
• The extra glutamines result in unstable proteins, causing the accumulation of protein aggregates.
• Splice site mutations can alter the way in which introns are removed from pre-mRNA molecules, producing aberrant proteins.
• About 15% of all genetic diseases result from mutations that affect RNA splicing.
• Incorrect splicing of β-globin mRNA can be responsible for some cases of β-thalassemia.

Diseases from Mutation

• Sickle cell anemia, a hemolytic disease, results from a substitution of thymine with adenine in DNA and HbS contains two normal alpha chains and two mutant beta chains, in which glutamate at position six has been replaced by valine.
• Cystic fibrosis is caused by a deletion of three nucleotides from the coding region of a gene of a protein responsible for chloride channels.
• Cystic fibrosis affects mainly the pulmonary and digestive systems and results in the loss of phenylalanine from the CFTR.