Our Savior and Our Executioner: Evolutionary Standoffs Between Infectious Disease and Genetic Disorders

It is only to be expected that when a new disease is raging across the world, scientists desperately search for the qualities and risk factors that make individuals more likely to be susceptible to severe infections. For many infectious diseases, lifestyle choices and pre-existing conditions can have a significant impact on an individual’s reaction. For COVID-19, these risk factors include chronic conditions like asthma and diabetes, as well as behaviors like smoking.

But another kind of susceptibility will likely take longer to study - it will require large cohorts of individuals and comparisons across populations. And we may not have the full answer before intense vaccination efforts bring COVID-19 under control.

Genetic susceptibility to COVID-19 infection refers to how an individual’s genes influence their likelihood of contracting infection or the likelihood of a severe reaction. Genes have long been implicated in individual responses to infections - research has identified strong associations between genomes and various diseases, including HIV, Hepatitis B and C, dengue, and more. In a previous post, I wrote about how my own genetic susceptibility to HIV is altered because of a single mutation in a gene, CCR5.

But how do genes influence our reaction to infections? If you think about the complexity of our genes and our immune systems, you’d be right to assume that the influences can be broad and various, and much information still needs to be discovered. But for now, we understand that just as genetics influence the behavior of our cells in ways that lead to different color hair and different heights, so too can our genes lead to differently behaving immune systems. For example, genetics coding for the human leukocyte antigens (HLA), which regulate our immune system, vary significantly within individuals. These HLA profiles can result in differing susceptibility to some infectious diseases. Researchers have also suggested that as much as two-thirds of our adaptive immune response traits (the response we generate after exposure to a disease, compared to before) are influenced by genetics.

You can imagine it would be a great benefit to have genetics that make you less susceptible to a disease - and it certainly would be. Individuals lucky enough to be born with those genes in a world without modern antibiotics and treatment would find themselves generally more successful at surviving, enabling them to better reproduce. This would bias future populations to carrying the genes of those less susceptible individuals, and the gene would be positively selected for in that population. In this way, those beneficial genes influencing our immune system would start to spread.

Similarly, you would expect a genetic mutation that is harmful to an individual to be negatively selected for in a population. If there were a mutation that negatively affected our immune systems--or, even a step further, actually caused disease in an individual--then carriers of that mutation would be less fit, and therefore less likely to survive and reproduce, eventually removing the gene from the population’s genetic pool. The diseases resulting from those mutations would not be infectious diseases themselves, but rather genetic disorders.

While these observations appear straightforward, what is fascinating is that there are certain “genetic diseases” that persist in populations longer than one might expect, given their negative impact on health. And this is where genetic disorders, genetic susceptibility to infectious diseases, and infectious diseases collide.

Infectious diseases can be extremely clever at infecting humans, which means our immune systems have to maintain extremely unique defenses. If someone were born randomly with a genetic mutation that conferred this unique defense, and it conferred a strong enough benefit against an infectious disease that was prevalent in that individual’s environment, they would likely survive longer to pass along the gene.

But sometimes that unique defense has a tradeoff. What if the same mutation that made a person less susceptible to an infectious disease also made  them more susceptible to a genetic disorder? The individual is locked in a standoff in their own genetic code. Is the benefit to being less susceptible to the infectious disease stronger than the negative impact of the genetic mutation? If so, the mutation may persist in the population.

One way scientists have identified these genetic tradeoff mutations is by identifying genetic disorders that have persisted in populations when you wouldn’t have otherwise expected them to. It’s unexpected for a recessive disease to remain prevalent in a population without being selected out, unless it confers some kind of benefit. In fact, there are a number recessive genetic disorders that, in heterozygous cases, confer a benefit against infectious disease, but in homozygous cases, lead to a genetic disease that is extremely detrimental. The evolutionary payoff of the benefit to the heterozygous individuals wins out over the harm done to homozygous individuals.

Here are three examples of inherited genetic diseases that one would not have expected to persist in human populations (without modern medical care) for as long as they have, that have also been associated with conferring a benefit by reducing susceptibility to an infectious disease.

Sickle Cell Anemia

Perhaps the most well known example of a genetic disorder with an evolutionary benefit is sickle cell anemia. Sickle Cell is an inherited genetic condition caused by a single base pair mutation, which leads to the malformation of red blood cells. Specifically, the cells take on a sickle shape, which makes them less capable of carrying oxygen.

In patients with one copy of the Sickle Cell mutation (heterozygotes), the genetic disease is typically either minor or not symptomatic. In patients with two copies of the gene, however, the delivery of oxygen around the body is slowed or blocked. This can lead to anemia, episodes of intense pain, delayed growth, and more. Modern medical treatment can provide some symptom relief, but there is currently no cure.

Someone observed that the highest rates of Sickle Cell Anemia seemed to arise in areas where Malaria was particularly prevalent, mainly in parts of Sub-Saharan Africa. Malaria is an infectious disease passed by mosquitoes carrying the Plasmodium parasite. The parasites colonize red blood cells and use them to reproduce, creating byproducts that act as toxins in the human body. These toxins result in the symptoms of Malaria, which can lead to death.

In sickled red blood cells, however, the Plasmodium parasites are less able to survive. Scientists have found that in individuals who carry the Sickle Cell mutation, red blood cells express heme oxygenase-1, (HO-1), a component of hemoglobin that isn’t typically found in healthy red blood cells.  This “free heme” leads to the production of Carbon Monoxide, which interrupts the infectious abilities of the parasites and provides protection. Additionally, heterozygous carriers of Sickle Cell Anemia appear to have more efficient clearing mechanisms for damaged or diseased blood cells, making the body better prepared to recognize and destroy infected cells.

In this way, individuals who were heterozygous for Sickle Cell Anemia were able to avoid the detriments of the genetic disease while receiving the benefits against an infectious disease. The benefit conferred in resistance to Malaria on average outweighed the evolutionary risk of an individual reproducing with another heterozygote and having a child with the disease who did not survive to reproductive age. And so, the Sickle Cell mutation persisted in populations.

Cystic Fibrosis

The most common genetic mutation that causes Cystic Fibrosis is a three base pair deletion in the CFTR gene. Like Sickle Cell Anemia, only individuals who carry two copies of the deletion will exhibit symptoms of Cystic Fibrosis. Unfortunately, those symptoms can often be fatal in late childhood or early adulthood. The mutation in the CFTR gene blocks the transport of chloride in cells, which leads to a build up of sticky and thick mucus in various organs. It particularly affects the lungs, the airways of which become clogged and can trap pathogenic bacteria.

The persistence of Cystic Fibrosis in human populations has come to be associated with Cholera, a bacterial disease spread by infected water. The bacterium Vibrio cholerae travels to the small intestine and produces a terrible toxin, which causes violent diarrhea and the rapid loss of electrolytes. Individuals can die from cholera infection rapidly if rehydration methods are not available to them, as they certainly weren’t for the majority of human history.

In mouse models, carriers of two copies of the CFTR mutation did not secrete fluid in response to the cholera toxin, while heterozygote carriers released only 50% of the amount of fluid. A 50% reduction in dehydration could mean a dramatic improvement on an individual’s likelihood to survive the devastating infections of cholera infection. Before modern medicine, the pressure applied by a rapidly fatal bacterial toxin could be enough to encourage the persistence of a recessive disease as harmful as Cystic Fibrosis.

Tay-Sachs Disease

Tay-Sachs disease has perhaps the most tenuous correlation with an infectious disease of the three examples. It is also the most fatal of the three diseases - children born with two copies of the Tay-Sachs gene have a buildup of fatty acids in the brain which affects nerve cells. The progression of the disease leads to a loss of motor function; few children survive beyond four years old.

Like Cystic Fibrosis and Sickle Cell Anemia, carriers of the Tay-Sachs mutation (heterozygotes) don’t show symptoms of the disease. But the effect of the one mutated copy causes a partial upregulation of hexosaminidase, which has been associated with increased control over mycobacterium. Tuberculosis is a mycobacterial infection that can be fatal, typically after a long period of infection.

The association between Tay-Sachs disease and Tuberculosis was similarly identified through the particular communities in which it is prevalent. Ashkenazi Jewish populations have an especially high carrier rate, and it has been hypothesized that the crowded ghettos into which Jewish populations were forced in the 19th and 20th centuries may have increased the rate of Tuberculosis spread and, subsequently, the selection pressure on Tay-Sachs mutations.

In conclusion

In each of these scenarios, two evolutionary scenarios exhibited opposite pressures, and the pressure of the infectious disease was strong enough to enable the prolonged survival of genetic mutations that, in an occasional homozygous case, would more frequently than not result in an individual’s failure to reproduce. It is important to note that none of these infectious diseases could have exhibited such a strong selection pressure except that they existed before modern medicine and lasted for hundreds of years in specific populations. Because these generations of individuals were exposed to these diseases on a recurring basis, these mutations were able to take hold.  

It’s also important to note that all of these diseases are recessive, and so only carriers of two mutated copies expressed the genetic disease. This would only happen if two individuals who were both carriers had a child - an event that was evidently rare enough for the mutation to persist.

What could this mean for COVID-19? We live in a very different world than the isolated populations where these mutations first arose - a world with modern medicine. And so far, the majority of COVID-19 deaths have been people past childbearing age, which means the disease is unlikely to impact gene lines in the way that an infection that is particularly lethal in children, like cholera, frequently would.

But these genetic diseases and the infections with which they are associated provide a powerful lens through which to understand our immune systems in the context of our environments. It is an important reminder that our bodies and our inheritance are the product of our surroundings, and by understanding those critical environmental influences, we are better prepared to understand our own health and wellness.

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Sonja K. Eliason

November 16, 2020