Errors in replication

We’ve now seen how areas in recombination and segregation can cause problems. But before either of those things happen, DNA has to be copied. That’s about 20,000 genes, or three billion bases that need to be copied. Imagine if you were given the task of copying 120 books, word for word. That’s three billion letters you had to write out correctly and accurately. That’s what happens when DNA is copied over and over again in cell division. With such a large number of bases, it is inevitable that copying mistakes will happen from time to time. We call these errors in replication. A replication error can affect a single DNA base, several bases, or sometimes larger chromosome regions.

So how do these areas cause genetic conditions? First of all, it is important to realise that not all areas of replication are disease-causing or pathogenic. Indeed, as we discussed in week one, many errors of replication are responsible for normal human variation and drive evolution. Whether a replication error results in disease depends on its size, its position, and its effect on protein production. When we talk about gene mutations, we generally group them into base substitutions or frame-shifting mutations. Base substitutions involve the substitution of a single base and can cause synonymous, non-synonymous or stop gain mutations. Where there is a synonymous change, there is a change in the base, but it results in the same amino acid being encoded.

This is exemplified by the word “cat,” C-A-T. If it changes to “cat” with a k, the word sounds the same although it’s spelled differently. Although synonymous changes often don’t cause disease, if they occur at one of the essential splice sites which dictate how introns are removed during protein production, they can be pathogenic. A non-synonymous change, also known as a missense mutation, is where the base substitution results in a different amino acid being incorporated into the protein encoded by the gene. The effect of the amino acid substitution will depend upon whether the newly incorporated amino acid significantly alters the structure and function of the resultant protein.

This is exemplified by the example here, where C has been substituted initially for B, where the sentence makes sense, and subsequently for G, where it no longer makes sense. A stop gain mutation was previously known as a nonsense mutation, and it’s where the altered DNA sequence prematurely tells the cell to stop building the protein. This means that the protein is shorter than it should be and may not function properly. Finally, insertions and deletions change the number of bases in a gene. One or many bases may be inserted or deleted. If the number of bases inserted or deleted is not a multiple of three, the size of the codon, then the reading frame of the gene will be disrupted.

This usually results in a shortened, abnormal protein, which may or may not be destroyed by the cell.