Module 16; Mutations and Errors in Protein Synthesis

DNA Variant: Any change in the DNA sequence.
Mutation: A DNA variant that causes a change from the normal state, potentially leading to disease.
Polymorphism: An acceptable DNA variant occurring in >1\% of the population (e.g., Single Nucleotide Polymorphism or SNPs).
Germline Mutations: These are transmitted through generations via reproductive cells.
Somatic Mutations: Occur in non-reproductive cells and are not inherited.
Large Scale Mutations: Involve chromosomal segments, partial rearrangements, or non-disjunction of entire chromosomes.
Small Scale Mutations: Involve one or a few base pairs, commonly referred to as point mutations.

Silent Mutations: Nucleotide substitution results in no change to the amino acid sequence.
Missense Mutations: Nucleotide substitution changes one amino acid in the polypeptide chain (e.g., Sickle-cell anaemia where Glutamic acid is replaced by Valine at position 6 of the $\beta$ subunit).
Nonsense Mutations: Nucleotide substitution results in a premature stop codon ( $UAA$ , $UAG$ , or $UGA$ ), halting translation early.

Caused by the insertion or deletion of nucleotides not in multiples of 3.
Alters the reading frame of the gene, leading to a completely different amino acid sequence downstream of the mutation site.

Mutagens: Agents that increase the mutation rate beyond spontaneous levels.
Physical Agents: UV radiation and ionizing radiation (e.g., Chernobyl accident linked to increased thyroid cancer).
Chemical Agents: Chemicals that interact directly with DNA.

Cancer: A disease characterized by altered gene expression.
Proto-oncogenes: Normal genes involved in cell cycle and division regulation.
Oncogenes: Mutated proto-oncogenes that cause excessive cell growth (e.g., Ras oncogene).
Tumour Suppressor Genes: Genes whose protein products normally inhibit cell division (e.g., $p53$ and $RB1$ ); mutations here lead to uncontrolled replication.
Epigenetic Mechanisms: Cancer often involves gene silencing via methylation of Cytosine residues on $CpG$ islands and a lack of Histone acetylation.
Transcriptional Control: Mutations can activate transcription factors (e.g., via increased phosphorylation) or alter promoter/enhancer binding affinity, leading to aberrant gene expression.

Caused by mutations in genes for haemoglobin resulting in a disruption of the $1:1$ ratio of $\alpha$ to $\beta$ chains.
$\alpha$ -thalassemias: Deletion of one or more $\alpha$ -globin genes on Chromosome 16; can involve stop codons or be lethal in utero.
$\beta$ -thalassemias: Deletion of the $\beta$ -globin gene on Chromosome 11, or mutations in the promoter/splice sites.

Question: Proto-oncogenes can change into oncogenes that cause cancer. Which of the following best explains the presence of these potential time bombs in eukaryotic cells?
Response: D) Proto-oncogenes normally help regulate cell division.
Question: Rank the following one-base point mutations (from most likely to least likely) with respect to their likelihood of affecting the structure of the corresponding protein: