Single Gene Mutations

Mutations can occur in many forms:

  • Missense: Change in a single amino acid

  • Nonsense: Change in a stop codon

  • Deletion: Loss of a single base pair, with frameshift

  • Insertion: Gain of a single base pair, with frameshift

  • Duplication: An extra gene with more protein production

  • Splice site: Abnormalities at the intron-exon boundary

  • Triple repeats: Increased tandem repeats

Mutation "hot spots" occur in places where there is a methylated CG dinucleotide sequence that can easily lose the methyl group on the cytosine base, converting it to thymine. Mutation rates are higher in genes where this sequence is present.

Genetic mutations can involve autosomes or the X chromosome.

In general, a mutation involving a gene coding for an enzyme appears as a recessive trait because, in the heterozygote, one gene copy is present and enough enzyme is made to provide for sufficient metabolic function. Recessive traits tend to result from "loss of function" of a protein. Thus, mutations involving genes coding for enzymes involving autosomes typically lead to autosomal recessive conditions. New mutations involving these genes are rare, but the rarity of these traits also makes tracking a family history difficult.

If the mutation involves the X chromosome, and the trait is recessive, then the outcome depends upon whether you are male or female. If you are female, then you have two X chromosomes. One of them becomes inactivated (appears as a Barr body), but this is random, so in general, with a defective gene, you will have at least 25% enzyme activity. If you are a male, you are out of luck, and the trait appears. This is known as an X-linked recessive trait. In a pedigree, such a trait appears to involve only males (rare females unlucky enough to inherit two bad X chromosomes could be affected).

In general, a mutation involving a gene coding for a structural protein appears as a dominant trait, because one copy of the abnormal gene leads to formation of an abnormal protein that interferes with formation of tissues. Structural genes tend to be large, so spontaneous new mutations are likely to occur, so a family history need not be present. Such genes can display locus heterogeneity, where different mutations in the same large gene can lead to similar phenotypic expression.

The pattern of transmission can be confounded by reduced penetrance and by variable expression. Reduced penetrance means that the gene is present and can be transmitted to offspring but does not produce the phenotype in the parent, leading to a "skipped" generation in a pedigree. More complex yet is variable expression, where the disease is present (complete penetrance) but the severity of gene expression varies from mild to severe. Modifier genes or allelic heterogeneity (different mutations of the gene) may explasin variable expression.

For autosomal recessive conditions, the standard recurrence risk for parents having further children is 25%. For autosomal dominant conditions, the recurrence risk is 50%. Bear in mind that about 3% of all births have some sort of birth defect, from a variety of causes, not all of which can be diagnosed completely. Thus, the recurrence risk for any pregnancy is 3%.