Chemical Curiosities: Gene Mutation Hunt

There are so many ways in which the study of chemistry intersects with biology, the study of life. Generally speaking, this meeting point is known as organic chemistry. The subject’s difficulty can sometimes be notorious among medical students, but like it or not, organic chemistry is vital for understanding how carbon-based organisms function on a cellular to molecular level, for producing pharmaceuticals, for making many chemicals you use or encounter on a daily basis, and so on. Also, even if you’re not interested in becoming a doctor, drug researcher, or chemical engineer — say you’re interested in another booming bio industry like genetic research and gene therapy. To really know what’s going on with DNA (or RNA, for that matter… covid vaccine research, anyone?) you must often start with the fundamentals of what chemical compounds DNA is made out of, what chemical processes allow DNA to be self-replicating, and what chemical processes cause that replication to sometimes produce “errors,” better known as mutations.

Besides a population’s visible and invisible variations created naturally by dominant vs. recessive alleles, newly arisen genetic mutations have always been a major reason why one generation’s offspring will exhibit traits that their parents did not. In fact, a dominant or recessive allele often first emerges through mutation; and among species that reproduce asexually, i.e. essentially cloning themselves, mutations can still promise genetic variability even without competing alleles. Although the word “mutation” sometimes carries scary associations, and although lots of mutations create a predilection for certain illnesses or challenging conditions, mutations aren’t always something to worry about. In many cases a mutation is beneficial to the organism who develops or inherits it, or it creates a trait that’s neither positive nor negative. Don’t be afraid of mutations: evolution itself depends upon them!

So what are the ways that mutations arise? Well, there are a bunch, but they allllll come down to basic chemistry, of course. Here’s a thorough overview… as briefly as we can make it. 😉

Induced mutations

Let’s get the stuff with the worst reputation out of the way. These kinds of mutations arise from environmental sources. Often, these sources may outright damage an organism’s DNA, turning portions of it into abnormal chemical structures. If this damage occurs to the organism’s gametes (sperm or eggs in humans), it can make the DNA stored there become more error-prone during the copying process, which we’ll come back to in a minute.

Sources of induced mutations are too numerous to list, but here are just a few of the “big bads” you may or may not have heard of before:

• Oxidative damage – Cells in the body are strained on the molecular level by excessive redox reactions, which is where electrons in atoms are forcibly gained or lost until their electromagnetic charge equalizes. Excess reactions like this can damage DNA strands by breaking them outright. When you hear about substances like “free radicals,” these are some of the agents of oxidative damage.
• Ultraviolet light – UV exposure can increase the processes that lead to oxidative damage. It also causes reactions that alter the base connections of DNA strands, weakening them. This especially affects the nucleobases cytosine and thymine.
• Gamma radiation – Gamma radiation ionizes atoms in cells, a situation similar to redox reactions but perhaps more intense as the particles remain positively or negatively charged. Naturally this will also damage DNA.
• Ethidium bromide (and related substances) – This is intended for DNA analysis as its molecules are inserted between base pairs of a DNA strand, unwinding or twisting them. If ethidium bromide comes into contact with DNA that’s still in someone’s body, it will have the same effect, which creates the potential for damage.
• Ochratoxin A – A fungal toxin made by various molds. It can contaminate certain foods or water-damaged homes and lead to oxidative damage of cells.

Unfortunately, it’s almost impossible to avoid all these stimuli, and because of the attached cancer risks it’s hard to imagine any induced mutations from these sources being positive! But at least eating well, using sunscreen, and advocating for proper EPA and OSHA regulations can help you and other people mitigate some of these issues.

Spontaneous mutations

DNA can be healthy and still alter through natural chemical reactions without the organism being under special oxidative stress.

• Tautomerism – Hydrogen moves within a base pair, which like DNA damage causes errors during the replication process.
• Depurination – A reaction occurs with base pairs built from the nucleobases adenine or guanine, and it causes them to disappear from part of a DNA strand. This creates complications.
• Deamination – A reaction occurst that removes an amino acid from nucleobases on a section of DNA, converting those to different molecules that have no place in DNA.
• Slipped strand mispairing – DNA polymerase (see below) “loses its place” in the copying process, often after copying the same base pair several times in a row. This throws off the final result of replication, like a dropped stitch in knitting.

Errors from DNA damage and errors in repairing damage

The DNA copying process during reproduction involves proteins “unzipping” DNA, with the enzyme known as DNA polymerase catalyzing the following reaction:

deoxynucleoside triphosphate + DNA_n ⇌ pyrophosphate + DNA_n+1

The symbol ⇌ refers to achieving chemical equilibrium. As DNA polymerase works toward that equilibrium before the cell divides, it generally matches base pairs exactly as it ought, but its likelihood of making a mistake increases if it’s working from “confusing” data. This confusion may arise from the various sources of damage mentioned above… but it may likewise arise from cells’ natural process of repairing DNA that’s sensed to be damaged. In that situation, the attempt at DNA repair accidentally inserts a base pair that’s not the same as what was there before; or there can be similar issues. This mistaken repair then becomes a mutation.

Also, even when it’s not necessarily an inheritable mutation, it’s worth knowing that damage occurring to DNA in any part of the body may impact the replenishing of the cells there, which is why the sources of induced mutations are carcinogenic. If it sounds weird to imagine an organism’s genes changing partway through their life, just remember that all our cells are cyclically dying and being replaced by new ones through DNA replication as well. Even when we’ve stopped gestating in the womb, our bodies always need to reference DNA encoded into every cell. This is what allows gene editing technology like CRISPR to work: CRISPR can sometimes perform the equivalent of a “controlled” mutation, as well as add or remove particular genes, although the chemical mechanisms behind its functionality are not the same as what we’re talking about in this post.

Now… if your head’s not spinning too hard, it’s time to look for some “mutations” on Eyewire. That is, we’ll have a cell online that’s had mergers added to it by a mischievous admin. There are 12 mergers in the Hunt cell; you have 5.5 days and 24 guesses to locate them all, between midnight EST on 2/18 and noon EST on 2/23.

How to identify and report mergers

1. 1. Select Hunt cell from Change Cell menu. Stay in the overview.
   2. Type /debug into chat. This will reveal a special box with information about the cell (located above the “Start Playing” box).
   3. Use ALT+click to select the origin point of the merger you have identified. It is a good idea to zoom in close on the merger before you select it to get the most accurate coordinates.
   4. Find the coordinates of the merger’s origin in the cell information box. These are next to the word “center.”
   5. In the chat pm thehunt bot your coordinates. For example: /pm thehunt 5123 4321 5678.
   6. thehunt bot will let you know if you got it right or wrong and tell you how many guesses you have left.
   7. To check how many mergers you have found and to check what guesses you have submitted, type “/pm thehunt !list”; the bot will give you a list of all the coordinates you have guessed, and whether or not there was a merger at each set of coordinates. A + means there was a merger there, a — means there was not a merger there.
   8. If you accidentally submit the same coordinate a second time, it does not count as two guesses.

Do not reveal your coordinates to other players. Do not do anything against the spirit of the Hunt. Anyone caught cheating will be automatically disqualified from the event and will not receive any points.

Proximity to merger start point is determined by number of voxels (1 voxel = approx. 1/250th of a cube’s width). Mergers are only counted as found if guessed within a distance of 250 voxels. Pieces of dust floating in space don’t count as mergers, so please don’t report them! We also do not count fused mergers that could not be removed during the Hunt prep process.

Swag: The top scoring player wins the choice of a notebook or a mug, plus a sticker/magnet set! Second and third place will each also win a sticker/magnet set.

Bonus info is available in your in-game notifications. Good luck, and happy hunting!

Image by Zephyris (CC BY-SA 3.0)