How do point mutations arise from mistakes in DNA replication?

Question

Hi! I'm trying to make sense of this illustration (from the textbook Biological Science by Scott Freeman).

The general question is: How do point mutations arise from mistakes in DNA replication?

If you don't mind, however, I'd like to explain how I interpret the illustration so you can see the confusion. As the original molecule of DNA is replicated (in gray), a mistake occurs in the synthesis of the bottom strand in the new molecule (the noncomplimentary bases G and T have been paired together). Now, it seems like a second replication is required for the mutation to arise: the defective molecule is replicated resulting in two new molecules, one free of mistakes (because it takes as its template the top strand) and one "wrong" where the mutation is present.

But my doubt is, wouldn't the middle molecule already constitute a mutation? If a mRNA were to transcribe that sequence, the codon is already different from the original molecule. Must a DNA molecule be replicated two times for a mutation to arise (where the first time a mistake is made and a second where such mistake is, let's say, "consolidated")?

Thank you very much in advance.

Answer 1

Source of your misunderstanding

Your misunderstanding is very comprehensible as the figure is misleading.

The figure only shows a single event of replication. What you see as a second replication resulting into two double stranded molecules is NOT an event of replication. It actually represents the two possible outcomes from a 'mismatch repair mechanism'. The term DNA replication written on the figure should be replaced by Possible outcomes of DNA repair. The molecule that contains the G-T mismatch is therefore just a temporary state that will very quickly be changed to either the T-A state (bottom right of your figure) or to the G-C state (upper right of your figure). More information below.

DNA repair

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome.

The type of DNA repair that is of interest on the figure is called "DNA mismatch repair"

DNA mismatch repair

DNA mismatch repair is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.

There are specific enzymes to repair a mismatch such as the G-T mismatch represented on your figure. These enzymes can either repair G-T into G-C or into A-T. If the repair is A-T (lower outcome in the figure) then a mutation would have occurred. If the repair is G-C (upper outcome in the figure) then we are back to the original sequence and no mutation would have occurred.

Note that the probability of the two possible outcomes is different from 0.5 as these enzymes have ways to try to figure out which was the original strand and which was the newly replicated strand. You can learn much more about the mechanism of DNA mismatch repair on the wikipedia > DNA mismatch repair.