Mutation and DNA Repair

Mutation and DNA Repair

•     When information gets altered

Introduction to Mutations

• Definition: Mutations are alterations or changes in the biological information encoded within the DNA sequence.

• Impact: These changes can vary significantly in their cause and effect on an organism's biology.

  • Mutations are not by definition BAD; in fact, they can be beneficial, neutral, or harmful depending on their nature and the environmental context in which the organism exists and their competition. (More neutral and harmful effects than beneficial, but the chance is not ZERO)

• Types of Mutations Based on Nucleotide Changes:

  • Substitution: A change where one or more bases are replaced by different bases. (point mutations, changing a singular nucleotide) (changing ingredient/amount of the ingredient)

  • Deletion: The removal of one or more nucleotides from the DNA sequence.

  • Insertion: The addition of extra nucleotides into the DNA sequence.

Mutation and Transmission to Offspring

• Mutation Location: The impact of a mutation depends heavily on the type of cell in which it occurs.

• Somatic Cell Mutations:

  • Occur in somatic (body) cells.

  • If a mutation occurs in a somatic cell, approximately half of the daughter cells resulting from its division will inherit the mutation.

    • These mutations are not inherited by offspring.

    • Somatic cell mutations accumulate in an individual's lifetime, contributing to aging and disease (e.g., cancer).

• Germ Cell Mutations:

  • Occur in germ cells, which are specialized cells located in the gonads (ovaries and testes) responsible for producing gametes (sperm and egg cells).

  • If a mutation arises in a germ cell, the gametes produced by that cell may contain the mutation.

  • These mutations can be passed on to offspring, as they are present in the reproductive cells that form the next generation.

Causes of Mutation

• Natural Errors During DNA Replication: Mutations can naturally occur during the process of DNA replication when mismatches between bases are not recognized and corrected. (2/3 are from mistakes in replication 1/3 is from mutagenic agents)

  • Initial Error Rate: Approximately 1 in 100,000 bases are incorrectly added during replication.

  • Proofreading by DNA Polymerase: DNA Polymerase III has a 3'-5' exonuclease activity, which acts as a proofreading mechanism. It corrects approximately 99\% of these initial errors.

  • Post-Replication Repair: An additional 99.9\% of the remaining replication errors are corrected by various post-replication repair mechanisms.

  • Final Error Rate: The combined efficiency of these correction systems results in a remarkably low final mutation rate of approximately 1 in 10 billion bases.

• Exposure to Mutagenic Agents: Mutations can also be induced by external factors, known as mutagenic agents. These agents can cause damage to DNA, leading to sequence alterations.

Point Mutations: Effects on Protein Structure and Function

• Definition: Point mutations are specific chemical changes that affect only a single base pair within a gene.

• Consequence: Even a change in a single nucleotide in the DNA template strand can significantly alter the resulting messenger RNA (mRNA) and, consequently, lead to the production of an abnormal or nonfunctional protein.

• Types of Point Mutations (Substitutions):

  • Silent Mutations:

    • Result from a base-pair substitution that replaces one nucleotide and its partner with another pair of nucleotides.

    • These mutations have no discernible effect on the amino acid sequence of the protein.

    • This is possible due to the redundancy (degeneracy) of the genetic code, where multiple codons can specify the same amino acid.

    • Example: If a codon changes from UCA to UCG, both still code for Serine (Ser).

  • Missense Mutations:

    • Also caused by a base-pair substitution.

    • The new codon still codes for an amino acid, but it is not necessarily the correct (original) amino acid.

    • This leads to a change in the amino acid sequence of the protein.

    • The impact can range from negligible (if the new amino acid has similar properties) to severe (if it significantly alters protein structure or function).

    • Example: A change from TCA (DNA) to TTA (DNA) leads to UCA (mRNA) changing to UUA (mRNA), which changes Serine to Leucine.

  • Nonsense Mutations:

    • Result from a base-pair substitution that transforms an amino acid codon into a stop codon.

    • This prematurely terminates translation, leading to a much shorter, truncated protein.

    • Nonsense mutations nearly always result in a nonfunctional protein.

    • Example: A change from AGT (DNA) to ATT (DNA) leads to UCA (mRNA) changing to UAA (mRNA), which is a stop codon.

Point Mutation and Human Disease: Sickle Cell Anemia Example

• Mechanism: Sickle cell anemia is a classic example of a human disease caused by a single point mutation.

• Genetic Change:

  • DNA: A base-pair substitution changes CTC (encoding Glutamic acid) to CAC (encoding Valine).

  • RNA: Consequently, the mRNA codon GAG changes to GUG.

  • Protein: This single amino acid substitution changes the sixth amino acid of the beta-globin chain from Glutamic acid (Glu) to Valine (Val).

• Phenotypic Effect:

  • No Aggregation (Normal): Normal hemoglobin molecules (containing Glutamic acid) do not aggregate.

  • Abnormal Aggregation (Sickle Cell): The presence of Valine at this position, due to its hydrophobic nature and different charge, causes hemoglobin molecules to aggregate into long fibers when oxygen levels are low.

  • Cellular Impact: This aggregation distorts the normal discoid shape of red blood cells into a characteristic sickle (crescent) shape.

  • Clinical Consequences: Sickle cells are rigid and can block small blood vessels, leading to pain, organ damage, and anemia.

Insertions and Deletions

• Definition: These mutations involve the addition (insertion) or loss (deletion) of one or more nucleotide pairs within a gene.

• Severity of Effect: Insertions and deletions often have a more disastrous effect on the resulting protein compared to substitutions.

• Frameshift Mutations:

  • Insertion or deletion of nucleotides can alter the reading frame of the genetic code.

  • The genetic code is read in codons (groups of three bases).

  • If nucleotides are added or removed in numbers that are not multiples of three, the entire downstream sequence of codons will be misread.

  • This shift in the reading frame leads to a completely different protein sequence from the point of the mutation onwards, often resulting in a nonfunctional protein and premature termination (if a stop codon is encountered).