Hidden deep in the rural villages of sub-Saharan Africa, a neglected tropical disease called African sleeping sickness kills tens of thousands of people every year. Sleeping sickness is caused by a single-celled parasite named Trypanosoma brucei, which can infect humans and other mammals (such as cattle and deer) and is transmitted from one host to another through the bite of the tsetse fly. Overlooked for decades, researchers are now trying to better understand both the unique biology of this important human parasite and how T. brucei might have directed the course of human evolution. It seems as though this microscopic organism has left a mark of its presence on the human genome, which scientists are only now beginning to uncover.
Trypano-what?: Trypanosome Basics
Trypanosomes live inside the human bloodstream, where they feast on the nutrients that normally keep us healthy. By doing so they cause fever, headaches and joint pain [1]. Eventually, some of the rapidly-multiplying trypanosomes wiggle their way across the blood-brain barrier, which separates the circulating blood from the central nervous system. Once the parasites enter the central nervous system, they can trigger changes in behavior, cause confusion and disrupt the sleep cycle (hence the name “sleeping sickness”). Without treatment, an infected person will likely fall into a coma and succumb to the disease, sometimes within weeks of showing the first symptoms.
Figure 1. T. brucei (colored in blue) shown with the red blood cells with which they coexist in the human bloodstream (red). Image credit: http://www.parasitemuseum.com/trypanosome/
African trypanosomes can be divided into two subspecies – one from East Africa (T. brucei rhodesiense) and one from West Africa (T. brucei gambiense). For reasons we don’t fully understand, T. brucei rhodesiense causes acute disease lasting from a few weeks to months and almost always results in death, while infection with T. brucei gambiense results in chronic disease that can last for many years and sometimes resolves without complications. Unfortunately, treatment for sleeping sickness caused by either subspecies is only moderately effective and involves “medicines” that sometimes do more harm than good to the infected person. Throughout much of the twentieth century, the only treatment for sleeping sickness after the parasites had infected the central nervous system was a drug called Melarsoprol, which contains arsenic in its chemical structure and kills approximately one in ten patients who take it [2]. To learn more about African sleeping sickness and the people affected by the disease, see the documentary film posted at [3].
The evolutionary give and take of human-parasite relationships
So, what can this terrible disease caused by a tiny, single-celled parasite teach us about human evolution? Quite a bit! A study recently published in the journal Science describes possible links between differences in the Apoliprotein L1 (ApoL1) gene and kidney disease in African Americans [4]. The differences the authors found are two genetic variants within the gene that codes for ApoL1. The protein made by the ApoL1 gene binds to lipids and forms a component of high density lipoprotein (HDL, more commonly known as “good” cholesterol). The authors discovered that the variants they found in the ApoL1 gene that are associated with kidney disease in African Americans also seem to make the variant ApoL1 protein able to lyse (break open and kill) T. brucei rhodesiense parasites. This is an example of how mutations that have arisen in the human genome can enhance the body’s ability to fight off pathogens. Another example of this is the case of sickle cell anemia, whereby people with genetic variants that cause sickle cell anemia are less susceptible to malaria [5]. Such survival-enhancing mutations as those found in ApoL1 and sickle-cell anemia arise through the process of natural selection.
To understand the basis of evolution and natural selection, imagine that Nature is constantly introducing mutations in our genomes, randomly over time. These random mutations are usually neutral (neither good nor bad), but in rare instances, a mutation gives an individual a comparative advantage over their peers. Mutations can be advantageous if they lead to a greater chance of survival in a particular environment and reproductive success, and both of these ensure that beneficial mutations will be preserved and passed on to the next generation. Conversely, deleterious mutations are removed from the “gene pool,” as individuals bearing them are unable to survive as well as their peers.
The authors of the ApoL1 study started with a curious observation: African Americans seem more likely to develop kidney failure than their European American counterparts. Wondering whether there is a genetic basis for this phenomenon, the authors looked for genetic variations between African Americans who either did or did not have kidney disease. It turns out that the variants they uncovered in the ApoL1 gene conferred an approximately 10-fold increase in the risk of kidney disease; in other words, if you possessed these two variants you would be 10 times more likely to develop kidney disease. These variants only exist in African Americans and do not account for all cases of kidney disease, but having a mutated ApoL1 gene may be a reason for the increased disease incidence among people of African descent.
From an evolutionary perspective, a mutation that makes a person more likely to develop kidney disease should be “weeded” out of the population over time, as natural selection acts upon the weakest individuals of a population to remove their gene variants from the gene pool. However, the authors speculate that the same genetic differences they found in the ApoL1 gene may have also given ancestral Africans an advantage against a more pressing threat — infection with T. brucei. The authors tested the ability of mutant versions of the ApoL1 protein to kill T. brucei rhodesiense (the parasite that causes the acute, quick-killing version of the disease) and found that human serum containing variant ApoL1, but not the normal version, was able to kill the trypanosomes.
Thus, a mutation that was likely selected for its protective effect against infection with the T. brucei parasite also seems to contribute to kidney disease in African Americans later in life. Further work is certainly needed to identify whether the ApoL1 variants identified in this study actually exist in African communities often plagued by T. brucei infection. Screening patients for these variants can also help guide treatment for kidney disease and might prolong the time before kidney disease turns into kidney failure. Lastly, the hunt is on for other variations in the human genome that make us more or less susceptible to various infectious diseases, such as tuberculosis and influenza. It is amazing to think about all the other ways that human pathogens may have shaped our genomes, without our knowing it.
Daria Van Tyne is a graduate student in the Department of Immunology and Infectious Diseases at the Harvard School of Public Health.
References
[1] WHO Factsheet on African trypanosomiasis (World Health Organization) http://www.who.int/mediacentre/factsheets/fs259/en/
[2] MSF Campaign for Access to Essential Medicines: Sleeping sickness (Medicins Sans Frontieres) http://www.msfaccess.org/main/other-diseases/sleeping-sickness/
[3] Survival – The Deadliest Disease (Survival TV and BBC World News) http://www.survival.tv/documentaries/sleeping_sickness.php
[4] Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science Aug 13 2010. 329(5993): pp. 841-5
[5] Evolution: Library: A Mutation Story (PBS) http://www.pbs.org/wgbh/evolution/library/01/2/l_012_02.html