Science Corner: 7 Things to Know About Mutations

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Mutations, or changes to DNA sequence, are often a key speculative element in science fiction. Thanks to recent advances in DNA sequencing technology over the past decade, we have a much better understanding about mutations, how and when they occur, and the effects that they can have on humans or other living things.

If you plan to write about mutations, here are seven things you should know.

1. Mutations are rare events (in humans, at least)


The human genome encompasses 3.2 billion bases, often represented by the letters A (adenine), C (cytosine), G (guanine), and T (thymine). If you compared your genome to that of another person at random, 99.99% of those bases will be identical. That still leaves over 3 million differences, but you got the vast majority of those from your parents. Rather than mutations, we call these inherited variants.

New mutations do occur between generations, but thanks to the robust DNA repair processes in our cells, they’re extremely rare: on average, about 30-40 mutations genome-wide per generation. Compared to the millions of inherited variants, that’s a small number.

2. Mutations come in different forms

Changes to DNA can take many forms, including substitutions, insertions, deletions, inversions, and large structural rearrangements. The latter can be very devastating, since they might affect many different genes. A cell might even lose or get an extra copy of an entire chromosome, which is usually bad news. Trisomy 21 (an extra copy of chromosome 21), for example, causes Down syndrome.

Most often, however, mutations occur in the form of a single base substitution, such as G->A. This holds true for inherited genetic variation as well: most of the ~3 million differences are substitutions. Moreover, 95% of those substitutions are ones we’ve seen before, and catalogued in public databases of genetic variation.

3. Many things can cause mutations

The sources (or causes) of mutations generally fall into one of four categories. First, there are natural processes during which mutations can occur, notably DNA replication, DNA repair, and meiotic recombination. Second, infection by certain pathogens, notably retroviruses, can cause alterations to the genome of a cell.

Third, and perhaps most infamously, are the growing number of chemical mutagens—such as asbestos, tobacco smoke, dioxin, benzene, and formaldehyde—that cause DNA damage through a variety of mechanisms. Finally, mutations can also occur after exposure to ionizing radiation. Ultraviolet radiation in sunlight, for example, induces mutations in skin cells, which is why sunlight exposure is a risk factor for melanoma.

4. Mutations might have no effect

The effect of a mutation depends on when and where it occurs. Mutations that affect protein-coding genes are the most serious, particularly if they alter or truncate the encoded protein. In other regions of the genome, mutations can affect gene regulation, the complex process that determines the timing and level of gene activity.

It’s important (if less exciting) for me to point out that mutations might have no discernible effect. Only a fraction of the genome (3.5%) codes for genes, and since mutations occur somewhat randomly, there’s a good chance that a new mutation won’t even hit a gene. Worst case scenario, since we have 23 pairs of chromosomes, there’s often an unaffected copy on the other chromosome that can get the job done.

5. It’s easier to be bad than good.

There are many science fiction stories in which mutations give people super-strength, magical powers, or other advantages. I love these as much as the next guy. The mundane reality is that mutations are usually not good for you. That’s because the human body is incredibly complex, and the genome has been subjected to evolutionary pressures for thousands of years. It’s a finely tuned machine, at this point. Much easier to break than to improve upon by random base changes.

There are exceptions, of course. A few thousand years ago in Africa, a mutation arose near the LCT gene, which encodes lactase. That enzyme breaks down lactose, the sugar in dairy products in milk. The mutation made it possible for adults to digest cow’s milk, right around the time humans were domesticating cattle. That was a good mutation.

6. We lied: Not all of your cells are the same

In high school biology (if not sooner), we teach students that every cell in our body has an identical copy of our DNA. This is generally true, though there are exceptions. Certain immune cells have altered receptor gene sequences that let them detect a wider array of infectious agents, so their genomes are different. The transparent cells of the lens (the part of the eye that focuses light onto the retina) lose their nuclei, so they don’t have a genome at all.

Another way cells can differ is if they pick up a mutation through one of the mechanisms I’ve already described. If that happens somewhat early in development, that mutation might be passed down to a number of daughter cells. The presence of multiple clones (subsets of cells) with genetic differences is called somatic mosaicism and it’s been daunting to study. We’ve only recently advanced to the level of DNA sequencing technology that can study low levels of mutations in human samples.

7. Somatic mutations: when a cell takes a hit


In an adult, a cell that suffers a mutation might be unaffected, or might self-destruct. That’s because our cells have built-in machinery to detect DNA damage, attempt to repair it, and hit the big red button if it can’t be fixed. A similar cascade can occur upon viral infection. Programmed cell death protects us from what could happen if a cell went rogue.

Sometimes, however, the mutation occurs in a gene that’s part of that machinery, allowing the cell to evade destruction and grow unchecked. This is how tumors arise. A well-known example is the BRCA1 gene, which plays a role in DNA repair. Some women inherit coding variants in BRCA1 that disrupt its function. That’s fine, as long as the other copy is working. When that other copy suffers a mutation, however, the DNA repair machinery that relies on BRCA1 breaks down, making the cell far more likely to become cancerous.

Women who inherit a damaging variant in BRCA1 (or a similar gene, BRCA2) are predisposed to get breast and ovarian cancer. Genetic tests for these genes are available and often performed for women who have a family history of these cancers. Mutation carriers have a higher risk of disease, but there’s a silver lining: breast cancer patients with mutations in BRCA1 or BRCA2 are more likely to respond to chemotherapy, particularly if a new class of drugs, called PARP inhibitors, are given as part of the treatment.

In Conclusion

Mutations might seem rather boring to you, now that you know a bit more about them. Hard science often works that way. Stories that reflected it precisely would probably be boring, too. Yet there are edge cases and exceptions to every rule, including these seven. I won’t mind if you break them, as long as you tell a good story.

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Dan Koboldt

About Dan Koboldt

Dan Koboldt is a genetics researcher who has co-authored more than 60 publications in Nature, Science, the New England Journal of Medicine, and other journals. Every fall, he disappears into Missouri’s dense hardwood forests to pursue whitetail deer bow and arrow. He lives with his wife and three children in St. Louis, where the deer take their revenge by eating all of the plants in his backyard. Look for his debut novel, The Rogue Retrieval (Harper Voyager), in January 2016.