How can a single change in a DNA base lead to malfunction in the body?

Answer 1

DNA codes for the production of proteins, ribozymes and other RNA products. These all have vital functions in every cell that are necessary to sustain life. DNA has to be 'decoded' from it's nucleotide base sequence to produce the proteins, and it does this using codes of three bases at a time representing one amino acid. Because there are four possible bases in DNA, a set of three could code for 43 (which is 64) different things.

There are 20 amino acids used in the human body (some modification may take place to create variations, but there are 20 used in translation). Each of these amino acids has unique and very specific properties that contribute to the final function of the protein, whether it becomes an important catalytic residue, or whether it has a less direct role by contributing to the shape (fold) the protein takes.

A change of one DNA base may in some circumstances have no effect at all, if it codes for the same amino acid as it did before. However, if that region of DNA codes for a ribozyme, siRNA, tRNA or other RNA produce, the product will have slightly different properties from before and may not function correctly. A more likely outcome is that the single base change results in that codon of DNA coding for a different amino acid in a protein. If this is the case, that residue of the protein will have a different chemical and structural property from before, and this may cause the protein to denature (lose its shape) or lose its catalytic activity.

The loss of shape would result from changes in chemical interactions between the amino acids, or be due to an amino acid being too large, or too small, for the space it was meant to occupy. A variety of intramolecular (hydrogen bonds, hydrophobic interactions, disulhpide bridges, electrostatic interactions) forces between amino acids are important for sustaining the shape of the molecule, and the shape of a protein is directly related to its function (small changes may result in complete loss of activity - indeed, some proteins rely on tiny shape changes to drive reactions). At the catalytic site of an enzyme, catalysis often relies on an interaction between the substrate and the amino acid side chains, such as polarisation of a bond in a substrate due to attractive forces from a charged amino acid. Changing that amino acid to one with a different charge could have a devastating effect on the catalysis of the protein.

Metabolism in organisms is a complex equilibrium of many different enzymes. Reducing or changing the effect of one would have devastating effects on several areas of metabolism, and not necessarily the one directly involved with the enzyme. Just one mutated enzyme is enough to prevent embryos from developing in the womb, and reduce life expectency of successful births to less than 10 years.

Examples include a single base mutation in the DNA that codes for beta hemoglobin. The single change results in a single amino acid changing in hemoglobin, which is the sole cause of sickle cell anaemia (a life threatening disease). The mutated hemoglobin aggregates when deoxygenated, which makes red blood cells clot more easily. The pancreas recognises that the red blood cells are an unusual shape due to the hemoglobin aggregation and destroys them. The rate of this destruction is higher than the rate at which bone marrow can create red blood cells, leading to aneamia and eventually death.

In other cases the mutation may alter some sort of signal sequence in the nucleotide, such as the KDEL sequence, which is usually responsible for retaining enzymes in the rough endoplasmic reticulum. If this sequence were altered, those enzymes may be secreted instead of retained. As a result, other proteins would not be modified succesfully in the RER, leading to a huge array of dysfunctional enzymes just because of a single base change in DNA. Mutation of other processing enzymes would have similar effects, since they are invovled in the production of many other proteins.

A final consideration is that the single base mutation changes a promotor sequence for a gene in DNA, or any other part of DNA responsible for the expression or regulation of a gene. These parts of DNA are not translated into DNA, but they are involved in deciding when the rest of the gene is translated. A single mutation here could result in a gene not being expressed when it is needed, or being overexpressed when it isn't. Either of these may produce only minor problems in the body, such as an inability to tolerate certain foods (eg phenylalanine), or cause major metabolic breakdown.