If you’ve ever taken a biology class, you’ve probably heard about the sickle cell hemoglobin variant. In case you need a refresher, here are the basics. Hemoglobin is a blood protein that carries oxygen, encoded by a gene as all proteins are. Every human has two copies of the gene, one from each parent. Hemoglobin comes in two main versions, A and S. Most people have two copies of A. People with two copies of S have misshapen blood cells causing debilitating and deadly sickle cell anemia. People with both A and S do not have the disease, and are also largely resistant to malaria, a parasitic infection that kills half a million people every year. So, sickle cell disease persists in the human species because of the way S can protect against malaria if coupled with A. When natural selection maintains more than one version of a gene within the same species, it’s called balancing selection. Sickle cell hemoglobin is probably the best-known example of balancing selection.
I’m getting pretty tired of it.
This example gets invoked all the time. I’ve had at least five college classes that covered it. I’m guilty of this myself, but it’s a self-reinforcing cliché. You use it because you know your audience will be familiar with it. Especially in the context of infectious disease and natural selection, I can hardly avoid it. But it’s frustrating, because the sickle cell case is largely an anomaly. In several ways, it’s not representative of how balancing selection usually operates.
Balancing selection is a fascinating and often misunderstood phenomenon. In the early days of molecular biology, scientists got so excited every time they saw a protein with more than one version, they assumed balancing selection was rampant. Then came the years of the neutral theory, when genetic variants were judged to have equivalent effects on health and wellness, and balancing selection was thought to be negligible. In the past few years, balancing selection has been undergoing a renaissance, as sophisticated computational tools are increasingly able to detect it in large genome-scale datasets. Balancing selection is probably important for the prosperity of species. But it’s a weird sort of evolutionary compromise. For any balancing selection scenario, it would be possible for evolution to fix the variation in the genome so that every member of the species could enjoy the full spectrum. This could happen several ways. Take the sickle cell example (dang it, I’m doing it again!). It’s normal for genes to get copied and pasted numerous times in the genome. If the hemoglobin gene were copied and pasted in the right way, everyone could have the S version and the A version permanently cemented in their genome. Evolution just hasn’t done that, at least not yet, because evolution isn’t perfect. As another example, consider black and white mice coexisting because black mice can hide better on black rocks and white mice can hide better on white rocks. A mouse can’t be simultaneously black and white. But, a mouse could have the genes for making either black or white fur, and then develop whichever coat best matched its habitat. And so on. Balancing selection is always a kludge. It’s the first solution that evolution happened to find, even if a better one is available.
So what’s wrong with the sickle cell example? Let me contrast it with one of the genes I studied in grad school. This gene is found in leopard frogs and encodes an antimicrobial peptide, a substance that kills bacteria and other germs. Unlike with hemoglobin, I don’t really know the whole story of how this gene affects traits in frogs. That’s not uncommon in science, and is one of the reasons the sickle cell example is so popular: it’s been very thoroughly characterized. So let me explain what I think is happening at the frog gene, based on the evidence we do have. There are three main versions of this frog gene. I suspect they all have different combinations of microbes that they are efficient at killing. Frogs with two different gene versions could have an advantage over frogs with two of the same kind. After all, they can tolerate a wider range of plagues. But most of the time, I suspect the majority of frogs are healthy, and natural selection is pretty much ignoring this gene. However, when there is an outbreak of a particular disease, the frogs with the peptide that can best fight that disease have an advantage. As the survivors reproduce, the version of the gene encoding that peptide becomes more common in the population. When a different epidemic hits, another peptide gets the spotlight. Usually, no one peptide is advantageous for long enough to completely eliminate the others. In the long run, some versions of the gene do occasionally go extinct, but then variation is restored through mutation or from interbreeding with closely related species.
So, relative to sickle cell, balancing selection on antimicrobial peptide genes is likely weaker and more dynamic. The peptides probably don’t affect two completely unrelated traits, like functional blood cells and resistance to malaria. Rather, one peptide might kills a particular kind of bacteria, while another kills a slightly different kind. Frogs occasionally die of infection, but there isn’t massive collateral damage every generation. In general, balancing selection provides a cushy bonus to an otherwise genetically uniform species. It’s extra security, insulating against future threats. Balancing selection helps keep species adapted to their environment by gently pushing on the gene pool from multiple directions. It’s rather like the inept thermostat in my aging campus building that runs both the heat and the air conditioning all year long and simply adjusts the amount of each as needed. Inefficient, but comfortable for everyone at least. In contrast, a human population with disparate hemoglobins is like the guy with one foot in scalding water and one foot in ice water. Doing fine on average, but no so much for certain members. It’s such an ugly hack, evolution is likely to find an alternative solution quickly, which is why such extreme cases are rare. But numerous other balancing acts aren’t so stark. Tons of other immunity genes undergo trench warfare with parasites. Reproductive proteins on sperm or pollen are bandied about by the tides of sexual conflict. There’s genetic diversity we don’t even know the cause of like our mysterious blood types. And the most persistent one of them all is the maintenance of separate male and female sexes.
Genetic variation is both essential for evolution and aesthetically beautiful. We should laud balancing selection as a beneficial force. That’s easy with antimicrobial peptides. No combination is peptides is universally detrimental, and any one combination could be the best depending on the shifting microbial landscape. But sickle cell is hard to celebrate. Few would choose to be an SS with anemia. It especially doesn’t feel right for me, a white American, to praise a gene variant that primarily causes disease in black people, most severely in developing countries. Sickle cell should be lumped in with the other genetic diseases, most of which have no benefit to either survival or well-being. Compare that to most genetic variation favored in some way by natural selection. Think of gender, immunity to varying suites of viruses, perhaps even complex traits like handedness. For these, there are no absolute winners and losers. All our lives are enriched because of the differences.
Adaptive diversity, the first two words of my PhD dissertation, is all around us. But it’s often subtle. Logically, there can’t be that many balanced traits as serious as sickle cell. If every one of our tens of thousands of genes had a similar death toll, there would be none of us left. Still, sickle cell is so vivid and so overtouted that many folks are left with the impression that it’s a typical case. However, most genes are not under any kind of balancing selection. If they are, they typically experience a milder form of it. Genomes are huge, though, and that still leaves lots of room for interesting variation. These are major questions that drive my own research: what are the variants under balancing selection, what are their effects, and why are they favored in evolution? Sickle cell is barely even the start of the story. There’s so much more to explore.