Over the past couple of months, the resurgence of Covid-19 cases has been disappointing, to say the least. Just as we were gaining ground in the battle against this virus, it launched a brutal counterattack—the Delta variant. Covid-19 isn’t the first virus to employ this sort of adaptable retaliation survival strategy. In fact, quick mutation and evolution is a viral mainstay—one that enabled viruses to persist and become the most prevalent “organism” on Earth. But how does something that is essentially just some DNA wrapped in a protein shell evolve and change its strategy quickly enough to throw even 21st century medicine for a loop? It turns out that the elegant simplicity of viruses actually gives them a unique advantage in the race to evolve.
To understand how viruses evolve, we first need to explain why mutation occurs in the first place. In humans and other organisms, mutations most commonly arise during DNA replication, where all of the DNA in a cell is copied in preparation for cell division. DNA replication is a huge, multistep operation responsible for copying billions of DNA bases, and it has to happen every single time a cell divides. If you remember, we talked a little about DNA replication a year ago in our post on Sanger Sequencing, where we saw how this intricate process can be harnessed for whole-genome sequencing techniques. The most important ideas to remember are that DNA has two sets of complementary bases—A’s bond with T’s and G’s bond with C’s—and an enzyme called DNA polymerase is responsible for building a new DNA strand by matching DNA bases with the original strand. This is a difficult task—just imagine if you had to copy down the compliments of over 3 billion DNA bases. How many mistakes do you think you’d make? Impressively, the DNA polymerase in humans only makes one mistake in every 100,000 nucleotides. Unfortunately, for a human cell that means about 120,000 mistakes every time a cell divides. . . . This kind of accuracy obviously isn’t good enough to make a fully functional and intact human.
Just as you may double-check your handwritten copy, the polymerase proofreads its work as it goes. The proofreading mechanism of DNA polymerase prevents about 99% of polymerase errors (talk about the power of checking your work!). But that’s still over 1,000 errors per division, and considering how many times your cells divide, it’s still not good enough. To fix these errors, the cell employs copyeditors in the form of mismatch repair (MMR). After replication, the enzymes involved in MMR run through the genome looking for badly matched nucleotides, cutting them out and replacing them with the correct base. In addition to making corrections after replication, MMR enzymes can also correct some errors caused by mutagenic and carcinogenic chemicals and exposures, along with other repair processes like nucleotide excision repair (NER) and base excision repair (BER). Some DNA damage can cause double-strand breaks where both strands are cut at a particular location. This sort of damage is potentially lethal for the cell, so there are mechanisms in place to join the ends. But if the DNA hasn’t recently been copied, the enzymes involved don’t have a template to follow when repairing the break, resulting in guesswork and mutation.
Since replication errors are so prevalent, and we come in contact with lots of mutagens (including the sun!) daily, these repair processes are critical for maintaining stable cellular functioning and replication. But some errors persist and get passed on through cell lines. If the mutation occurs in the egg or sperm cells, it can be passed on to subsequent generations. This is one of the ways life evolves over time. Some mutations are seemingly irrelevant, occurring within the vast stretches of noncoding DNA. Other mutations are so damaging that the cell commits suicide to contain the spread. Those mutations that straddle the line between completely silent and cataclysmic have a chance of being passed on, and the build-up of several mutations over time drives evolutionary change. Mutations are a massive flaw in an extremely elegant system—a flaw that is responsible for chronic illnesses, cancers, and even aging itself. But without mutations, we would also still be microscopic organisms at the bottom of the ocean.
Since they also use DNA (or RNA), viruses are not immune to mutation. Viruses are also subject to selective pressures directing how mutations evolve. But the evolution we’re accustomed to typically occurs over million-year timescales. So how is it possible that some viruses evolve fast enough to escape our most cutting-edge defenses? The simplest answer is related to size and replication rate. The average virus has a genome that is around 200,000 times smaller than the human genome. An error in a viral genome is likely to have a much bigger impact on the structure and function of the virus. Additionally, viruses have very short lifespans, infecting a host cell and using its machinery to create a battalion of new viral particles. Many of these viruses will have some sort of error in their genetic code, and if that error is favorable to the virus’ survival and spread, the virus will be able to quickly pass it onto a new battalion of viruses. In this way, favorable mutations compound, allowing the virus to evolve past some of our most complex obstacles.
As some of the most diverse biological systems, viruses actually vary quite a lot in terms of their mutation rate. Viruses that use RNA as their primary genetic material (like SARS-CoV-2, the virus that causes Covid-19) can have mutation rates up to 10,000 times higher than viruses that use DNA. The accuracy and proofreading capability of a virus can also be a big contributing factor in mutation rate. RNA-based viruses tend to have polymerases that can’t proofread—although coronaviruses are actually the exception to this rule. Viruses with single-stranded DNA or RNA also tend to mutate faster possibly because they are more vulnerable to chemical damage or because they don’t have access to copyediting through MMR repair.
SARS-CoV-2’s larger than average genome (roughly 30,000 RNA nucleotides) and its proofreading capabilities actually make it one of the slower mutating viruses—about half as fast as the influenza virus. And yet, in the past couple of years, several noteworthy SARS-CoV-2 variants have arisen, including the Beta, Delta, and Gamma variants. In the case of the Delta variant, a single nucleotide change (an adenine switched to guanine) in the gene that encodes for the viral spike protein makes the protein more “open,” allowing the virus to more easily bind to and infiltrate cells. The result of this minuscule, random mutation is that the Delta variant is more likely to successfully infect a person it comes in contact with—which is terrible for us but is basically an evolutionary jackpot for the virus. This small change in the spike protein doesn’t seem to matter much to the antibodies that your immune system has stockpiled to fight off SARS-CoV-2, so the people who have been vaccinated for Covid-19 are still reasonably protected from contracting or being hospitalized by the virus. But unvaccinated people are at a significantly higher risk of contracting the virus and experiencing severe symptoms. Considering the rapid spread of the Delta variant, achieving herd immunity through vaccination may be the only way to curb the rising mortality rates associated with Covid-19.
Science You Can Bring Home To Mom will be back in September! For now, check out last month’s series on epigenetics and environmental inheritance. Comment on this post or email me at contact@anyonecanscience.com to let me know what you think about this week’s blog post and tell me what sorts of topics you want me to cover in the future. And subscribe below for weekly science posts sent straight to your email!
