Gene Mutation and DNA Repair

Gene Mutation and DNA Repair

• Mutations are changes in the DNA nucleotide sequence. They are variations in DNA that can arise from mistakes during DNA replication, where the wrong base is inserted or a base is skipped as the strand is formed. The word "mutation" comes from the Latin word "mutare," meaning "change."
• Mutations can have various effects. Some mutations can be quite harmful, which is why organisms have developed ways to repair damages DNA.
• Mutations can occur at the chromosomal level or the gene level.
  • Chromosomal changes affect more than one gene.
  • Gene mutations usually affect only one gene. They include changes from one nucleotide to another or deletions or insertions of nucleotides.
• Point mutations are changes in one or a few nucleotides in the DNA sequence, usually occurring during replication. If a gene in one cell is altered, the alteration can be passed on to every cell that develops from the original one.
  • A point mutation that involves a base substitution is a simple change of one or more bases.
    • A transition is a change of a pyrimidine (C or T) to another pyrimidine or a purine (A or G) to another purine.
    • A transversion is a change between a pyrimidine to a purine or vice versa. Transitions are more common than transversions.
  • Deletions or additions may also involve the addition or deletion of short sequences of DNA.
• Mutations in coding sequences can include:
  • Silent mutations do not change the amino acid sequence. It is due to the degeneracy of the genetic code.
  • Missense mutations do change the amino acid sequence. Some missense mutations may not affect protein function and are neutral mutations like in sickle cell anemia.
  • Nonsense mutations change a codon to a stop codon, producing a truncated polypeptide.
• Frameshift mutations add or delete nucleotides in multiples of one or two, but not three (the size of one codon). This shifts the reading frame downstream from the mutation. Except for silent mutations, new mutations are more likely to produce polypeptides with reduced function than enhanced function.
• Mutations in noncoding sequences affect gene expression:
  • Promoter mutations can increase or decrease transcription levels.
  • 5' and 3' UTR alterations can influence mRNA stability and translation efficiency.
  • Regulatory element/operator site mutations disrupt gene expression regulation.
• Mutations have consequences on both genotype and phenotype.
  • A neutral mutation doesn't change protein function.
  • A deleterious mutation reduces survival and reproduction chances. A lethal mutation results in death.
  • A beneficial mutation enhances survival and reproduction.
• Mutations can be either beneficial or deleterious depending on environmental conditions.
  • Heterozygotes can have an increased survival in malaria-affected regions, for example, sickle cell trait.
  • Conditional mutations only show their effects under specific conditions.
• Chromosomal mutations involve changes in the number or structure of chromosomes.
  • Duplication, deletion, inversion, and translocation are four types of chromosomal mutations. Deletion occurs when a portion of a chromosome is lost. Duplication means an extra chromosome segment is added. An inversion involves a change in the chromosome segment order. Translocation is when there is a rearrangement between different chromosomes.
• Changes in chromosome structure can affect gene expression due to position effect. Movement to a new location near regulatory regions or movement to a heterochromatic region can alter expression.
• Mutations can appear in germ-line or somatic cells. Germ-line mutations are found in sperm or eggs and are passed to subsequent generations. Somatic mutations are found in all the rest of the cells and are not inherited.
• Mutations can be spontaneous or induced.
  • Spontaneous mutations arise from abnormalities in cellular processes, such as errors during DNA replication.
  • Induced mutations are caused by environmental agents known as mutagens.
    • Mutagens can be chemical or physical. Examples of chemical mutagens include base modifiers, intercalating agents, and base analogs. Examples of physical mutagens are ionizing radiation such as X-rays and gamma rays, and nonionizing radiation such as UV light.
• DNA repair systems correct genetic damage.
  • Direct repair methods fix nucleotide alterations directly.
  • Base excision repair and nucleotide excision repair correct abnormal bases.
  • Homologous recombination repair repairs double-strand breaks by using a homologous DNA template.
  • Nonhomologous end joining repairs ends of double-strand breaks directly without a template.