Mutation

For part II of this series, we’ll tackle the big one – perhaps one of the most misunderstood natural phenomena in all of fiction. In writing, movies, television shows, video games and countless other media, genetic mutation is often viewed as something frightening or uncontrollable, frequently brought about through the abuse or misuse of science, or else through unfortunate accidents. For instance, genetic mutation turns the physicist Bruce Banner into the Hulk – a violent, simple-minded brute whose favorite hobby is smashing things.

In reality, mutation is neither a good thing nor a bad thing. It is simply a natural process, like the weather or plate tectonics. Mutation is the raw fuel for natural selection and evolution. It is the spontaneous change in DNA sequence over generations due to either environmental factors (e.g. exposure to ionizing radiation or mutagenic chemicals) or DNA replication errors. This last part is important – mutations would occur in a population over time even if it were magically shielded from any environmental factors that cause mutation. Most small-scale mutations are single nucleotide polymorphisms (SNPs), where a single nucleotide is changed, for instance changing the sequence ATTGCTCCA to ATTGATCCA. This can also include deletions: ATTGCTCCA to ATTGTCCA, and insertions: ATTGCTCCA to ATTGCATCCA. However, larger-scale mutations such as the deletion of entire genes are also possible.

How Does Fiction Get it Wrong?

In general, fictional accounts of genetic mutation fail to grasp one major concept: the difference between somatic mutations and germline mutations. Germline cells are the small number of cells in your body that are involved in passing your genes on to your progeny. They include eggs, sperm, the cells of the ovaries involved in egg formation (oogenesis), and the cells of the testicles involved in sperm formation (spermatogenesis). Because these cells pass genetic information on to offspring, mutations arising in them will potentially be passed on to every cell of an offspring’s body as it forms through a complex series of cell divisions following the fusion of an egg and sperm. In general, female mammals are born with all of their eggs already made (there is some debate on this though). Therefore mutations to the cells involved in oogenesis after birth will not be passed on to a woman’s offspring. This is not the case in males, where the cells involved in spermatogenesis are busy creating sperm throughout most of their life.

In contrast to germline cells, somatic cells make up nearly the entire mass of your body. While some are involved in the act of reproduction (e.g. the uterus in women, or the urethra in males), the defining characteristic of somatic cells is that they do not pass any genetic information on to an organism’s progeny. This brings us to the primary error regarding mutation in fiction – mutations to somatic cells cannot effect an organism’s body as a whole. For instance, a mutation occurring in a skin cell on your forearm due to ultraviolet light exposure is unlikely to give you any superpowers. In contrast, an organism can acquire a mutation in a germline cell, which is then passed on to all cells in their offspring. These two distinct outcomes of mutation continue to get confused in science fiction. Below we’ll shed a little more light on the difference between the two.

The Effects of Somatic Mutation

Usually, mutations in somatic cells have no effect. Your genome contains a large amount of genetic material that doesn’t directly affect your phenotype. This includes repetitive elements – somewhat autonomous DNA sequences that either “copy and paste” or “cut and paste” themselves across the genome. It also includes genes that have been epigenetically silenced, and pseudogenes, which are genes that have lost their function (due to prior mutations). Mutations within any of these regions, and many others, will typically not have any measurable effect on a cell’s phenotype.

But what if a mutation occurs inside a gene?

Then things can get a little more interesting. There’s still a very good chance that a mutation inside of a gene will have little or no effect. Genes are first transcribed, when an RNA copy of the DNA sequence is created. Then the RNA transcript is translated into a protein (which is a chain of amino acids linked together). However, after transcription and before translation, portions of the RNA are removed. Since these regions, called introns, don’t make it to the final protein product of the gene, mutations within them are often “silent.”

But what if a mutation occurs in a coding region in a gene?

The regions of genes that are transcribed in RNA and then translated into proteins are called exons. Even if a mutation occurs in one of these regions, it may not have any effect. For one thing, the genetic code is degenerate. This doesn’t mean that that it’s out making trouble (usually). Rather, the genetic code consists of three-letter “words,” called codons. Each codon is translated into an amino acid – the building blocks of proteins mentioned above. So, for instance, the three codons CTTGTTGGC will be translated into the amino acid chain Leucine-Valine-Glycine. However, nearly all the amino acids are encoded by multiple codons. For instance, glycine is encoded by the codons GGC, GGT, GGA, and GGG, so any substitution of the last base of a codon starting with “GG” will not have any effect on the protein that is translated from the gene. This is what is referred to as a “synonymous” mutation.

But what if a coding region mutation isn’t synonymous?

Now things start to get more interesting. A mutation that results in a change to an amino acid is referred to as a “missense” mutation. These mutations can have little or no effect, or major effects depending on how the amino acid swap changes the overall shape or function of the protein. In addition, there are two types of mutations that can have more dramatic effects. One is a premature stop formation. There are three codons that signal for transciption to stop – TAG, TAA, and TGA. If a mutation converts, for instance, a cysteine codon (TGC) into the stop codon TGA, then it will result in a shortened protein, which can have highly significant effects. This is referred to as a “nonsense” mutation. Finally, the other more serious type of mutation is a frame shift. This occurs when an insertion or deletion of one or more bases completely changes the “words” (codons) of the genetic code in a coding sequence. To illustrate, here’s an English sentence that happens to consist of three-letter words, like the genetic code: “The fat cat and big dog ate.” If we insert an adenine (A) at the beginning of the sentence, but keep the word separations at the same place, we end up with: “Ath efa tca tan dbi gdo gat e.” Basically, a frameshift mutation scrambles codons, resulting in the production of a completely different protein.

Mutations with Major Effects

As we have seen, mutations often have no beneficial or detrimental effect. In fact, the neutral theory of molecular evolution, proposed by Motoo Kimura in 1968, posits that the majority of evolution on the molecular scale is due to the genetic drift (the random change in allele frequencies over time) of mutations with neutral effects. However, there are cases where mutations can have major phenotypic effects. Germline mutations with major effects may be enriched in or purged from a population through natural selection. Highly deleterious mutations may be lethal to organisms, while highly beneficial mutations may grant an organism greater fitness, increasing the likelihood that the mutation will be passed on to future generations.

In somatic cells, we only really see the outcome of deleterious mutations. The cells making up your body must all “play by the rules.” Specifically, they have to behave as part of a multicellular organism. Mutations that allow a cell to function beyond its very narrowly-regulated niche within the body can have very dangerous consequences. Cells have many contingencies to deal with such situations. Apoptosis is programmed cell death, whereby a cell is triggered, either internally or externally, to self-destruct. Many cells within your body undergo this process every day. There are many ways in which apoptosis is initiated; one way is in response to mutations that alter how a cell grows and multiplies. In this way, cells that pick up mutations that could allow them to stop playing nice with the other cells around them often automatically self-destruct. Unfortunately these mechanisms don’t always work. Sometimes the very pathways meant to induce apoptosis become corrupted. Unfortunately these changes don’t give us new superpowers – instead they may lead to the formation of cancerous cells.

Who Gets it Right

Given all the intricacies of how mutation works in reality, different works of fiction fall close to or wide of the mark. In the Marvel Universe, mutants are those born with mutations (presumably acquired as germline mutations by their parents or other ancestors), whereas mutates are characters who acquire their powers from some external force, energy, catastrophe, etc. So, comics that focus mostly on mutants, such as the X-Men, largely get the concept of genetic mutation correct. It’s still not clear how mutations seem to give everyone big muscles or big breasts. Nor is it clear how they occasionally give people god-like powers. In contrast, comics about mutates, such as The Hulk, Spiderman, or the Fantastic Four, have a less realistic depiction of the effects of mutations (relatively speaking), as we are supposed to believe that the exposure of a fully-developed human to some mutagen could alter their entire body. As we have seen, the most dramatic effect on somatic cells due to exposure to mutagens is cancer. This isn’t quite as exciting a subject as heroes fighting monsters, though there is a genre of comics and graphic novels dealing with illness and medicine. Interestingly, there are some cases in the Marvel Universe where mutates later give birth to mutants. One example are the mutates Sue Storm and Reed Richards of the Fantastic Four, who give birth to the mutant Franklin Richards. It turns out Franklin is essentially a god – he can alter reality itself and create universes. It’s not clear how the Marvel Multiverse still exists at all when children wield this much power.

Who Gets it Wrong

There are too many to list here – take your pick really. We already mentioned the mutates in the Marvel Universe. We could add to that an almost unlimited number of fictional characters, including many of the characters and monsters from the Resident Evil video game series, the supermutants from the Fallout video games, Joker from the Batman comic books, the Teenage Mutant Ninja Turtles – the list goes on and on.

Room for Artistic License

There is one potential mutagen that could more feasibly create mutations in a wide range of somatic cells – viruses, specifically retroviruses. These are viruses with RNA genomes which are reverse-transcribed into DNA copies, which are then inserted into the host cell genome. In this way, retroviruses naturally genetically modify their host cells. For this reason, retroviruses are the vectors of choice for gene therapy. Therefore it’s not too hard to imagine a scenario in which gene therapy is used not just to cure disease, but to grant some enhancement or even powers to humans. This ignores the many hurdles that have made successful gene therapy difficult to achieve, but it is at least within the realm of possibility. Interestingly, the human genome contains many inactive endogenous retroviruses. These were retroviruses which at one time infected germline cells in our ancestors, and have since been passed down through the generations. While retroviruses are a (somewhat) plausible method of creating body-wide mutations in an adult, we first need much more research into using them to cure disease, before we start using them to give people rockin’ bods and superpowers.