Banner by Julia Meikle

Mutation Accumulation

by Noah Gafen

Mutation is a scary word. Despite the vital role of mutations in producing genetic variation, they are often associated with the negative implication of disease. A mutation can be anything as large as a chromosome deletion or as small as a single nucleotide swap. A single change in nucleotide sequence alters its corresponding mRNA, which may or may not alter the shape and function of the final protein product. We are often scared by the mutations that do change the protein, such as the substitution of a valine for a glutamate that causes sickle cell anemia. The effects of these mutations can be immediate and lethal, so a “mutation” is this context is understandably frightening.

But not all mutations are so catastrophic, at least not immediately. So-called “silent mutations” present as fairly innocuous. These mutations are single base changes, but they don’t dramatically alter protein functionality because the new amino acid is similar enough to the original that function isn’t compromised. Special silent mutations called “synonymous mutations” don’t change the protein at all because the encoded amino acid is unchanged due to redundancy in the genetic code. For example, a common silent mutation is when a glutamate amino acid is swapped for an aspartate. Both amino acids have similar reactivity and only differ in their sizes, and so functionality of the final protein isn’t compromised. As such, hearing “silent” precede “mutation” is a relief. But should this really be the case?

Less immediately destructive mutations could still have wide-ranging implications in disease. These mutations are capable of altering biological processes within the cell by tinkering with non-coding DNA regions. For these sections of DNA, no corresponding protein product is ever formed, yet they still play a crucial role in the survival of the cell. These regions can be involved in regulation of gene expression or define splicing sites. It is also crucial to consider that a single non-synonymous silent mutation does change the protein, just not enough to have a measurable effect. These mutations can accumulate over the lifetime of an organism, giving silent mutations a louder voice. As such, silent mutations could be implicated in any disease that has a genetic basis.

Sure, any given single nucleotide swap can be silent, but what if there are two of them? Or three? Or ten? What if they occur on the same gene? The same regulatory element? While a single silent mutation might not have the same effect as removing a member of a house of cards, the cumulative impacts of many can result in disaster. It has recently been discovered that silent mutations play a much larger role in cancer than previously thought. While the mutations themselves do not cause cancer directly, they can contribute to a collective series of mutations that make tumors increasingly difficult to destroy. For example, in a 2014 study in Cell, Zheng et al. analyzed nearly 4000 cancer cell exomes and found that the mRNA coding for the tumor suppressor p53 had synonymous mutations that inactivated its splice site. Imperfect splicing, means p53 cannot do its job of regulating the cell cycle and uncontrolled cell division (cancer) ensues. This brings a new meaning to “silent,” especially considering that between 20 and 40 percent of somatic mutations are silent in cancer. Previously, these mutations were thought to occur by happenstance and carry negligible tumorigenic capacity; however, a broader understanding of gene regulation and expression has revealed the truly ugly outcomes they can promote.

From a clinical perspective, the prospect of silent mutations contributing to cancerous activity is a nightmare for oncologists. No longer can gene therapy approaches be targeted to the correction of a handful of disease-causing mutations. Rather, in cancer patients, the whole structure of oncogenic proteins may be compromised. If treating cancer was once akin to replacing a piston in a car engine, now it seems the whole engine may cease to adequately make the car run -- and no new fancy piston can alleviate that burden. To combat this, the growing emphasis on precision medicine must be encouraged. You may be able to describe two patients as both having lung cancer, but the reality is that the disease-causing mutations of the two may be completely different and thus demand radically distinct treatments. While the onset of each may have had a similar trigger, knowing the minutia of the internal environments under which the tumor cells thrive could be the difference between life and death.

While this revelation is frightening, there are some positives that come from it. As we unveil more and more factors that contribute to the lethality of cancer, we will inevitably unearth novel ways to fight such a horrible disease. This discovery also serves as a good lesson to all members of the scientific community: we must always question what we accept to be true. The intricacies of biochemical processes in the context of a living organism are innumerable, so making general assumptions that appear to always hold can lead us down a dangerous path.