The Red Queen’s race
Alice did all she could to keep up with that damn rabbit. Her curiosity kept leading her into deeper trouble, but through sheer will, some wit, and a dose of dumb luck, she always managed to get away. Even in this crazy Wonderland, there was one constant: when she ran, she got somewhere, regardless if it was the intended place. So fittingly, that constant would be challenged when Alice re-entered the realm and met the Red Queen. In the Queen’s country “it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!” In other words, Alice must exert all of her energy just so she didn’t get left behind. For someone used to running into and out of trouble, this realization didn’t sit well for Alice.
The frustrating Red Queen’s race in Lewis Carroll’s “Through the Looking-Glass” has been used to illustrate many paradoxes, including how nothing can ever reach the speed of light and the continuous process of evolution. The latter explains how organisms must constantly evolve, not to gain an advantage, but to simply survive in a world that is constantly changing around them. This “Red Queen hypothesis” is especially useful when illustrating the coevolution of organisms. In this scenario, Alice is the host, and the Queen’s treadmill-like environment represents fast-evolving pathogens within Alice’s body. So instead of Alice outrunning the pathogens, it is really an evolutionary arms race between her and the Queen’s microbes.
A real-life example of the Red Queen’s race is the evolutionary battle between humans and one of its oldest foes, the malaria-causing parasite Plasmodium. Ancestors to modern Plasmodium parasites have likely been around for more than a 100 million years and adapted to a very complex life cycle involving sexual reproduction in mosquitoes and generating large populations within vertebrate animals (Figure 1). Plasmodium species became so successful with this process that they radiated to infect many different reptiles, birds, and mammals – including humans. It is estimated that a particularly successful human parasite, Plasmodium falciparum, evolved ~100,000 years ago; however, it didn’t become a major human pathogen until ~10,000 years ago, coinciding with the advent of agriculture and large civilizations. The sudden expansion in human population meant that the human malaria parasites now had more opportunities to adapt to their hosts. Plasmodium evolved a range of biomolecular strategies to evade the host’s immune response, and in the process, became more virulent. With the human general immune responses becoming less effective, the human population needed to quickly change – just like Alice needing to run faster to keep pace.
A particularly important stage of the Plasmodium life cycle is during infection of human red blood cells. Not only does infection of red blood cells lead to the clinical manifestations of malaria, but here the parasites develop into male and female gametocytes that are required to complete their life cycle when ingested by a blood feeding mosquito. Hence, there is a strong selective pressure within human populations to block red blood cell infection. A common mechanism to block infection is to produce abnormal hemoglobins – like hemoglobin S stemming from a mutation that changes to confirmation of round red blood cells to a sickle shape. Individuals carrying two copies of the hemoglobin S mutation develop severe anemia and often die. Having one copy leads to a less severe anemia, but importantly, provides resistance to Plasmodium. There are many other red blood cell defects collectively constitute some of our most compelling examples of human evolution in response to a pathogen. This selection did not put human populations permanently ahead of malaria, as evident by the millions of infections per year, but rather it simply helped to maintain their survival.
In a recent study led by Ardem Patapoutian’s lab at The Scripps Research Institute, we found another human mutation that provides protection against malaria (Figure 2). About ⅓ of people of African descent, including African Americans, carry the mutation. In all other people, < 1% are carriers. Scientists have been scanning the human genome for years looking for signatures of malaria-driven selection, so how did they miss something this common? Likely because the popular screening tools do not actually use full human genome sequences, but rather biomarkers similar to 23andMe. The simplest answer is that these assays probe for common DNA base changes in the human genome, like a “C” to a “T”. The mutation that we found is a three base deletion in a highly repetitive region of DNA, making it difficult to find. So how did we, researchers whose primary interests are not human genetics or malaria, discover something so well disguised?
The answer lies in the protein that contains the mutation, a ion channel called Piezo1 that is important for sensing stimuli (e.g., touch, pain, sound, and stress), regulating blood pressure, and maintaining red blood cell water balance. The Patapoutian lab are experts in ion channels and they made several important leaps for this story. First, shortly after they discovered this ion channel in 2010, they were approached by a clinician who found that a mysterious and rare red blood cell disorder of caucasians (called xerocytosis) was linked to Piezo1 defects. This disorder leads to dehydration, which alters the shape of the red blood cells. Still at this point, the group was not interested in malaria, but rather how mutations to Piezo1 may alter cell signalling and disease. The Patapoutian lab spent nearly 3 years (from 2011-2014) engineering mice that express a human equivalent of Piezo1 to study its function. In 2015, their Piezo1 mice were ready for the main stage. When they altered the channel to contain the xerocytosis mutation, the mice had deformed red blood cells, just like in humans with the rare disease.
It’s a little hazy who first came up with the idea, but someone came across an old paper that dehydrated red blood cells in a petri dish were less susceptible to Plasmodium. Thus, their second important leap was connecting that mutant Piezo1 ion channels causing deformed red blood cells might block Plasmodium infection. And through their tour de force mouse engineering work, they also had an animal model to test their hypothesis! Their studies in mice with a rodent malaria parasite confirmed that Piezo1 mutations did protect the host from severe disease. These results posed an interesting conundrum: if some Piezo1 mutations are protective against malaria, why is the disease only described as a rare condition in caucasians? Specifically, why wasn’t this common in people of Africa who have been battling malaria for >10,000 years?
The most studied human genomes reflect the scientists – white males from the US or Europe. So it was entirely conceivable that Piezo1 mutations may be common in African populations, just no one has looked. Because we had a gene of interest, we didn’t have to rely upon the biomarker data that most have used previously to find signatures of malaria selection, we could look directly at the human genome. Out of 22 candidate Piezo1 mutations, one (called E756del) altered the function of the protein similar to the xerocytosis mutation and was found in ⅓ of the African population. To follow up this amazing discovery, we obtained blood from 25 apparently healthy African American donors and found that 9 (36%) had the E756del mutation and deformed red blood cells (Figure 2a; they were negative for all other related genetic diseases). Importantly, human Plasmodium poorly infected their blood.
One of the more interesting aspects of this winding story is that the African American blood donors were reported to be healthy, not something that one would state if they had a severe anemia like with the sickle cell trait. So, does this Piezo1 mutation cause apparent disease? Is this another reason why xerocytosis is thought to be so rare, because people with the disorder do not feel sick? And more on point, how many other human mutations were selected during their epic battle with malaria? Studies like these tend to open a lot of doors and many future studies are necessary to explore them all. What is clear is that Alice needed to do a lot of running to keep pace with this well conditioned foe.
Shang Ma, the study’s lead author, contributed to this story.
Ma S, Cahalan S, LaMonte G, Grubaugh ND, Zeng W, Murthy SE, Paytas E, Gamini R, Lukacs V, Whitwam T, Loud M, Lohia R, Berry L, Khan SM, Janse CJ, Bandell M, Schmedt C, Wengelnik K, Su AI, Honore E, Winzeler EA, Andersen KG, Patapoutian A
Common PIEZO1 allele in African populations causes RBC dehydration and attenuates Plasmodium infection
Cell 173(2), 1-13 (2018)
Interested in our work? See our job posting!