Why does DNA mutate?

Question

I just read that pregnancy in space would be super dangerous because - among other reasons - of a higher risk of mutations due to radiation. This made me wonder: why does the DNA in organisms mutate? What are the main natural reasons? Is this due to the construction of DNA and would happen even in "perfect" conditions or is it due to something that is in the environment, like radiation?

So far I got two answers on reddit and also asked this question to a doctor and what I heard is along the lines of "this is how it is". I heard about "cells being worn out". But what makes the process non-deterministic, probabilistic? I guess I don't know enough about biochemistry to formulate the question, but I guess it's related to "given certain conditions, what determines at which point (and what kind of) a mutation occurs?"

Answer 1

If I am not mistaken, the vast majority of mutations happen during DNA replication.

DNA must replicate itself so that cells can replicate itself. The DNA polymerase is one very important protein that replicates DNA. The human genome (to consider this example) is 3.5 billions nucleotides long. Just to realize how long is 3.5 billions letters, let's make a book analogy.

Book analogy

• In the Harry Potter series, there are about one million words (ref).
• In the LOTR series, there are about one 400 thousands words (ref).
• In the Chronicles of Narnia series, there are about 230 thousands words (ref)
• In the King James Bible, there are about 788 thousands words (ref)

This sums to about 2.4 millions words. As, in english, there are 5.1 letters on average per word (ref), this lead to a total of about 12.3 millions letters. Imagine you have to rewrite all of these books almost 300 times (12.3 millions * 300 ≈ 3.5 billions)! How many typos would you make?

There are several cell divisions between a zygote and the ovule/spermatozoid produced by this individual but as most mutations happen during meiosis, I will just ignore mitotic mutations. The DNA polymerase makes about one typo every 100 millions nucleotides (Kong et al. 2012; Rahbari et al. 2016)! So really, the DNA polymerase is doing a pretty good job!

What is causing mutations?

Shit happens

I am hoping that form the above analogy, you may have a sense that mutations are just small mistakes. They happen because the replicating machinery is not perfect. Sometimes a molecule comes sideway, does not bind very well and another molecular passing by sticks to the DNA, etc.. Errors happen just like you would be making a lot of typos, rewriting books.

Mutagens

There are of course factors that can affect this mutation rate. Physical, chemical and biological agents increasing the mutation rate are called mutagens and they include radiation decay, ultraviolet radiation, ROS, benzene as well as some viruses and some parasitic bacteria.

Variation along the genome

Note also that the mutation vary along the genome too. Regions with high repeats (e.g. AATAATAATAATAATAATAATAAT) such as microsatellites for example tend to have a much higher mutation rate.

Variation among species and Drake's rule

Mutation rate also vary among species. There is a general tendency that the per nucleotide mutation rate negatively covary with the genome size, a phenomenon called Drake's rule (see for example Bradwell et al. 2013 or one of the early Drake's paper).

Answer 2

Short answer, Chemistry runs off probability, and life and DNA replication are in the end chemical reactions.

DNA is a chemical, and the bonds between different nucleotides sequences are all extremely similar, if there was not an opposing strand, mutations would be extremely common becasue any sequence is essentially equally energetically favorable,(AKA equally likely probabilistically/chemically). Having two joined strands means you cant just swap nucleotides becasue they can't bond across strands equally well, there is a heavy chemical bias for only bonding with the opposing partner. A=T C=GT. Any other bond is less energetically favorable ( AKA less likely, which is not the same thing as impossible). The dual strand nature of DNA makes errors less likely but we are still talking chemistry and no chemical process is absolutely perfect, even if you burn carbon and oxygen in perfect ratios to get CO2 you will still get CO, carbon monoxide, just do to the physical (and thus probabilistic) nature of chemical reactions. Even the strength of the bond between the two stands can work against it as f a mutation does slip in the DNA will still hold together, and if it gets replicated before an error correcting mechanism catches it it will stick around. The kicker is although a DNA is very unlikely to mutate, there is a lot of it so even the extremely unlikely still occurs, DNA also has to be split apart to be replicated, during which mutations are far less energetically unfavorable.

Cells actually have dozens of error checking mechanisms and chemical stabilizers to limit how many of these can get through or occur however again this is a physical chemical process, thus it will not be perfect. Even without these mechanisms DNA replications is still fairly reliable, but many organisms have gigantic genomes meaning even reliable as a swiss watch is still not good enough. It is simply impossible to create a perfect copying mechanism that has high turnover that operates in the real world there are just to many interactions. the fact many replications are happening at once does not help since sometimes these many disjointed strands can end up bonding together causing the error correcting mechanisms to cut out entire sections, or mix them up trying to fix it.

Answer 3

Mutations occur due to sudden and unpredictable changes in the structure of DNA. Radiations, particularly those of energies of ultraviolet and higher are capable of breaking the bonds that make up DNA. This fragments the DNA. While DNA has mechanisms to counter this, and reform as a complete strand, it’s not perfect and the original DNA might not be made. Oftentimes, a small error such as base pair swaps or a missing pair could occur. These changes are reflected as mutations.

Answer 4

As ultraviolet radiation forms thymine diamers due to free radical addition reactions, this is one of the environmentatally caused damage to DNA. There are various mutagens which do the same. Since DNA is a chemical molecule the fate of any chemical molecule is the tendency to undergo changes, even during normal conditions chemical reactions occur. Take for example the transformation caused by deamination of cytosine residues which changes it into uracil or deamination of adenine to form hypoxanthine. Another important reaction is hydrolysis of glycosyl bonds between sugar and nucleotides creating a DNA lesion more commonly called depurination. 10000 purines are estimated to be lost in 24 hrs in mammalian cells increasing concentration of acids by any random mechanism might also accelerate the depurination process. So DNA like any chemical material is subjected to changes though there are processes to check this process still it happens. Moreover during replication there are practical chances of error in spite of various check points. Depending upon the chemistry of the reaction DNA is undergoing at which point a mutation would occur might be studied, numerous biochemical process takes place simultaneously further complicates the precise location where a mutation might take place.