7 Mutations and Genetic Variation

Origins and inheritance of mutations

A mutation is a lasting change in the DNA sequence. Mutations create a source of genetic variation, but their effects range from undetectable to substantial. DNA damage, also called a lesion, is not necessarily a mutation: it becomes one if copying or repair permanently changes the sequence.

Mutations can arise spontaneously or after exposure to a mutagen, an agent that damages DNA or interferes with accurate copying. Sources include:

• Replication errors: DNA polymerase can insert the wrong nucleotide or add or skip nucleotides. Proofreading and repair correct many errors, but some persist.

• Chemical changes within cells: Oxidation or spontaneous reactions such as deamination can alter DNA bases.

• Environmental damage: Ultraviolet radiation can produce pyrimidine dimers that distort DNA. Ionizing radiation, including X-rays, can damage bases and break DNA strands. Some chemicals modify bases or disrupt accurate copying.

Whether a mutation can be inherited depends partly on the cell in which it occurs. A Germ cell mutation, or one in a cell that gives rise to a germ cell, may pass to offspring. A Somatic cell mutation affects that cell and its descendants but is generally not inherited by offspring.

Takeaway: DNA damage and copying errors are possible sources of mutations, but a lasting sequence change results only when an alteration persists.

Mutation types and their effects

Mutations range from changes to a single nucleotide to alterations affecting larger chromosome regions.

• Substitution: One nucleotide replaces another. In a protein-coding sequence, the result may be:

  • Silent: The altered codon still specifies the same amino acid.

  • Missense: The codon specifies a different amino acid.

  • Nonsense: The codon becomes a stop signal, often shortening the protein.

• Insertion or deletion: Nucleotides are added or removed. If the number changed is not a multiple of three in a coding sequence, it causes a Frameshift: downstream codons are grouped differently, often changing many amino acids and potentially creating an early stop. Changes in multiples of three add or remove amino acids without shifting the reading frame.

• Larger-scale changes: Deletions, duplications, and rearrangements can affect part of a gene, a whole gene, or a broader chromosome region.

A mutation’s effect depends on where it occurs and what it changes. A coding-sequence change may alter a protein’s shape or activity. A change in a regulatory sequence may instead affect when or how much RNA is produced. Mutations can reduce or eliminate function, create a new or increased activity, or have no detectable effect. The same DNA change can have different consequences in different biological contexts.

Takeaway: The size and location of a mutation help determine its consequences, but neither alone guarantees a particular effect.

How cells repair DNA

Cells use several layers of DNA repair to reduce the chance that damage or copying errors become permanent mutations. During replication, DNA polymerase proofreading corrects many errors. Mismatch repair then recognizes certain mismatched bases or small insertion–deletion loops left behind, removes part of the newly copied strand, and replaces it using the original strand as a template.

Other pathways address different kinds of DNA damage:

• Base-excision repair removes a damaged or chemically altered base, then fills and seals the gap.

• Nucleotide-excision repair removes a short stretch containing a bulky, helix-distorting lesion, such as ultraviolet-related damage; the DNA is then resynthesized and sealed.

• Double-strand break repair can use a matching DNA sequence as a template through Homologous recombination, or join broken ends directly through non-homologous end joining. Direct joining can sometimes introduce small sequence changes.

Repair can restore the original sequence, but it is not perfect. Damage that escapes repair or is repaired inaccurately can become a permanent mutation when the altered sequence is copied. Mutations in repair genes can also weaken repair and allow other mutations to accumulate.

Takeaway: Proofreading and repair limit mutation, but errors that escape these systems—or result from inaccurate repair—can become permanent.