As my last post was highlighting the depressing fact that microbes are kicking our derrières in a chemical arms race, this week I’m hopefully going to alleviate any lingering doomsday gloom by examining some cases of how we have evolved resistances against infectious diseases. On that note, let’s not dwell on the fact that many of the resistances increase as a result of massive epidemics that wipe out a high percentage of a population. Instead, think of how cool it is that 95% of the population is resistant to leprosy!
The Starting Point: Population Variation
Variation within a species is the basis for evolution, as natural selection acts upon these differences. Consequently, the overall pattern of genetic diversity in a species is the result of evolutionary processes of natural selection. Demographic history such as population size and substructure, as well as migrations, mutations, genetic drift (random change in gene frequencies in a population), selective pressures, and recombination rates (creation of new combinations or forms of genes) all impact our genetic diversity . This genetic diversity is important to understand how prominent resistances come about.
Through the wide range of clinical presentations of diseases, the racial differences in severity and susceptibility to diseases, and various twin studies, researchers realized there was a correlation between our genetics and susceptibility to diseases. Human genes provide some susceptibility or, conversely, resistance to specific infectious diseases in individuals as well at the population level [4,5].
Disease as a Selective Force
For a resistance genotype to spread through a population or to drastically change in frequency, some selective pressure is likely to play a role. Most commonly this is due to genetic drift or selection events in a severely bottlenecked or small population [2,11].
For example, consider a population of 100 members that is about to get struck by a disease. Before the outbreak only a small portion of the population, say 10 (10%), had a mutation that provided resistance to the pathogen while 90 (90%) did not. However, when the disease sweeps through the population it kills 50 of the susceptible population and no resistant members. Now the population has 50 members, 10 of which (20%) are resistant and 40 (80%) of which are susceptible. The frequency of the resistance doubled through that event, and the disease was the selective force for that increase. This example is simplified and exaggerated, but you get the idea. Hopefully. If your brain imploded when I first started to include math, the figure above might help.
Research has shown that an infectious disease can indeed act as a selective force and the variation in resistance and susceptibility conferred by such selection events depends on a number of characteristics. A study in 2012 analyzed 40 diseases to estimate variation of susceptibility and determined which disease characteristics are influential. The severity of the disease, measured by mortality or reduction of reproductive success, along with the epidemiological scope (geographic range, lifetime risk of infection, and historical record of the disease) both play a role in determining the existence of evolved resistance. Immune effectiveness in terms of the disease’s incubation period, duration of infection, ability to reinfect, and vaccine development plays a role along with the type of pathogen and its mode of transmission .
In order to explore how this occurs more realistically, let’s look at some actual examples where resistances to infectious diseases have spread in certain populations!
Perhaps the most well known resistance is that which is provided by sickle-cell anemia to malaria. Malaria is one of the leading causes of death in the global human population, with 500 million people infected and two million people dying of it per year . Sickle-cell anemia is a genetic condition that results in misshapen red blood cells, and the crescent-shape helps prevent the malaria pathology. While this can be fatal if it is homozygous (both copies of the gene) and is detrimental in heterozygous (one copy of the gene) form, the malarial risk-reduction incurred by carrying this heterozygous mutation is advantageous enough to compensate for the cost, to such a degree that 1 in 12 of Americans of African descent carry a gene for it [2,4]. However, sickle-cell anemia is not the only mutation conferring resistance to malaria.
The G6PD gene encodes an enzyme that is involved with glucose metabolism. Researchers found that a mutation in this gene exists in high frequency in locations of past or present malarial outbreaks, suggesting a possible resistance correlation. The mutation comes with a cost, as it causes a form of anemia, which suggests some selective pressure must have contributed to the high frequency. Researchers dated the mutation origin to between 3,840 and 11,760 years ago, a time period associated with severe malaria outbreaks. The mutation has been found to provide a 46-58% risk reduction of malaria, which provided resistance to the population thousands of years ago and has consequently increased in frequency [10,11].
If you were worried about consuming beef after reading the previous entries on prion diseases, I’m happy to inform you that there is a pretty decent chance that you are resistant to prion diseases! In the 1980’s researchers started questioning why some mammals appeared susceptible to prion diseases (sheep with scrapie and cows with BSE), while others were resistant. This suggested some genetic component could be involved. In the next decade, researcher John Collinge analyzed the prion gene PRNP in Britons to discern if there was a relationship between susceptibility to prion diseases and a polymorphism (different form) of the PRNP prion gene. He discovered that almost all human patients of acquired and sporadic CJD had a specific form of PRNP: a section of the gene codes for the amino acid valine, and prion disease patients were homozygous for valine at this position. When he sampled the healthy population of Britain he found that this form of the gene was rarer than chance or random genetic drift would dictate. Further, in Papua New Guinea in the tribe where the prion disease kuru had run rampant, the population that survived the cannibalistic rituals without acquiring the disease was almost entirely heterozygous for valine. In fact, that population has the highest frequency of heterozygosity in the world (likely due to the selective force of prion diseases: only those who were heterozygous survived!) .
As it turns out, being heterozygous for valine in your prion gene provides a resistance to prion disease. Heterozygosity, and consequently the resistance, is overrepresented worldwide. In Britain, 50% of the population is heterozygous or resistant to prion diseases while 40% are homozygous for methionine, which confers some risk of prion disease. That means only 10% are homozygous for valine and at the highest risk of being able to be infected by prions .
As the ratio of resistance is prevalent in all races, there is likely some common ancestor population that underwent a selective event that increased the frequency. It was either a worldwide event or it occurred early enough in history that all human ancestors were located in one place. The exact event is unknown and the mutation was dated to 500,000 years ago at the earliest, which doesn’t exactly narrow things down. One theory for its origin is that it arose about 70,000 years ago when the human population was bottlenecked at a few thousand members in Africa. There’s quite a bit of evidence of various hominids practicing cannibalism, so it is possible that the population of Homo sapiens in Africa also ate their dead. If that was the case, a prion disease could have easily spread and decimated the population during that period, resulting in this high frequency of resistance . While it’s a little bizarre to contemplate our ancestors chowing down on each other, the result has turned out to be quite beneficial for us–so go and eat that steak! (Disclaimer: there’s still a chance of susceptibility. Please don’t sue me.)
HIV-1 and AIDS
HIV/AIDS has caused over 30 million deaths worldwide and continues to be considered a pandemic. Its origin as a human disease is quite recent, crossing over from monkeys in the 20th century. As such, it might come as a surprise that there is actually a resistance to it in certain populations.
The resistance involves a gene called CCR5, which encodes a receptor on your immune T-cell surfaces. When it is activated, it triggers an immune defense response. Unfortunately, this receptor is also what the HIV-1 virus binds to when it infects a human . Scientists discovered a mutation (denoted by CCR5Δ32) which exists in significant frequencies in certain populations of Europe. The mutation has no effect on the function of your immune system, however it has been found to reduce the ability of the HIV-1 virus to bind to cells and cause the disease [9,11]. In fact, people that are homozygous for this mutation are almost completely protected against HIV-1, even with repeated exposures [6,9]! Heterozygosity, meanwhile, provides a delay in the onset of the virus for 2-3 years due to hindering the viral infection . The resistance is mainly isolated to Europeans, and is completely absent in African, most Asian, and Native American populations. In Europe, the frequency occurs in a north-to-south gradient, with the northern regions having the highest prevalence of resistance: up to 16% [7,11].
Studies have suggested that the CCR5 mutations originate from a single mutation event that occurred within the past few thousand years. Due to its high frequency, recent origin, and the size of the population during those periods (a few thousand to 400 million in the Neolithic period), a selection event is more likely than genetic drift. While the origin is generally accepted as Northeastern Europe, possibly the Finno-Ugrian tribe, the dates are highly contested. Studies set the range from 3,500, 275 to 1,875, or 700 years ago [7,9,11].
The agent of the selective event is also controversial. It has been speculated that the resistance could have been caused by a plague outbreak in Europe, especially the bubonic plague. This is an especially appealing explanation as the bubonic plague not only killed 22-33% of Europeans during the Black Death outbreak 700 years ago, but its pathogen Yersinia pestis actually uses the exact same receptor as HIV-1: CCR5 [4,9]! While this may have increased the frequency of resistance, other researchers argue that it is not the origin as the mutation was prevalent in prehistoric Europeans, long before this bubonic outbreak. The mutation has been found in samples of human remains dating back to the Bronze Age (2,900 year old skeletons). This suggests an earlier selection event, possibly due to smallpox, shigella, tuberculosis, syphilis, or influenza[6,9].
Unlike HIV, leprosy is a disease with a long history of human infection, reaching back into the papyrus records of Egypt over 5,000 years ago. It still affects approximately 300,000 people a year worldwide, with outbreaks mainly occurring in developing countries such as Africa, Asia, India, and South America. Twin studies and a tendency of leprosy infections to aggregate in families suggests that a genetic component contributes to susceptibility or resistance [1,3,4].
Research has uncovered several genes that influence the susceptibility to leprosy in a range of populations. These have been organized into two groups: gene polymorphisms that confer resistance to the initial infection and genes that impact what type of leprosy develops. Genes such as PARK2, LTA, 13q22.1, and 20p12.3 all fall into the former group, while the latter contains the genes HLA-DRB1*15 and 10p13 (there is a distinct lack of creativity in naming genes, unfortunately).
Remarkably, 90-95% of the world population is completely resistant to leprosy due to these genes. That means only 5-10% of the population will actually gain an infection upon exposure to the leprosy pathogen .
This resistance frequency is one of the highest in the world against infectious diseases. There are likely a number of selection events that have contributed to this, including the many outbreaks of leprosy that ravaged populations across the globe. While in modern times the disease is rarely fatal by itself, resulting infections increased the death rate of leper populations in the era before antibiotics.
In order to determine if leprosy outbreaks could have acted as selection events, one study investigated resistance genes in areas that had high populations of lepers during the Crusades, such as the island of Mljet. The results showed that these locations did indeed have higher resistance genes than control populations . The plagues that ravaged Europe could have been another force of selection, especially as the European population has the highest leprosy resistance. Lepers were particularly vulnerable to the plague, and the Black Death decimated the leper population in the 1300’s, bottlenecking the population and possibly raising the resistance frequency.
Alter, A. et al. “Leprosy as a genetic disease.” Mamm Genome. 2011. 22:19-31.
 Baker, C. and Antonovics, J. “Evolutionary determinants of genetic variation in susceptibility to infectious diseases in humans.” PLoS ONE. 2012. 7(1): e29089.
 Bakija-Konsuo, A. et al. “Leprosy epidemics during history increased protective allele frequency of PARK2/PACRG genes in the population of the Mljet Island, Coratia.” European J. of Medical Genetics. 2011. 54:548-552.
 Blackwell, J. “Genetics and genomics in infectious disease susceptibility.” TRENDS in Molecular Medicine. 2001. 7(11): 521-526.
 Casanova, J-L. and Laurent, A. “Human genetics of infectious diseases: a unified theory.” The EMBO Journal. 2007. 26: 915-922.
 Hummel, S. et al. “Detection of the CCR5-delta32 HIV resistance gene in Bronze Age skeletons.” Genes and Immunity. 2005. 6:371-374.
Libert, F. et al. “The deltaCCR5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe.” Human Mol. Genetics. 1998. 7(3):399-406.
 Max, D. T. The Family That Couldn’t Sleep: A Medical Mystery. New York: Random House, 2006. Print.
Stephens, J. et al. “Dating the origin of the CCR5-delta32 AIDS-resistant allele by the coalescence of haplotypes.” Am. J. Human Genetics. 1998. 62:1507-1515.
Tishkoff, S. et al. “Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance.” Science. 2001. 293(455).
 Tishkoff, S. and Verrelli, B. “Patterns of human genetic diversity: implications for human evolutionary history and disease.” Ann. Rev. Genomics Hum. Genet. 2003. 4:293-340.