Date Published: July 21, 2016
Publisher: Public Library of Science
Author(s): Kelly J. Pittman, Luke C. Glover, Liuyang Wang, Dennis C. Ko, William E. Goldman.
The first groundbreaking study in human genetic susceptibility to infection was A. C. Allison’s discovery in 1954 that individuals heterozygous for sickle cell anemia had decreased risk and severity of malaria . The geographic distribution of the sickle cell allele led to the hypothesis that there is a selective advantage for the allele in malarious environments. Allison determined rates of malaria were significantly lower in children with the sickle cell allele. Furthermore, he performed a Plasmodium challenge experiment, exposing subjects with and without the sickle cell trait to infected mosquitoes and measuring parasite burden over 40 days. The results unequivocally demonstrated that people with the sickle cell trait were less likely to be infected with malaria and developed less severe parasitemia. This entire study was done prior to DNA sequencing. Indeed, the double helix had just been discovered the prior year .
Malaria, which has afflicted humans for thousands of years, is an excellent example of how human evolution has been shaped by an ancient and persistent pathogen. Presence of the sickle cell allele affects morphology of erythrocytes, which serve as an essential site for reproduction of the parasite. Therefore, it is not surprising that other resistance alleles are associated with erythrocyte function. One such resistance allele was identified with Plasmodium vivax infection.
In other cases, genetic differences that evolved to protect against past pandemics are still present at high frequencies in populations, but now protect against a new infectious disease. The most well-characterized instance of this is the 32 base pair deletion in the gene encoding the chemokine receptor CCR5 (CCR5-Δ32). The CCR5-Δ32 allele was first identified in the 1990s when it was discovered that homozygous individuals were completely resistant to HIV infection . It was initially proposed that the allele arose approximately 700 years ago and conferred resistance to Y. pestis, coinciding with the strong selective forces of bubonic plague in Europe at this time . Others have hypothesized that the CCR5-Δ32 allele originally protected against smallpox, as poxviruses were shown to also use CCR5 for entry and it was endemic in Europe during the rise of the allele [26,27]. Still others have suggested that the CCR5-Δ32 allele is at least 5,000 years old and the frequency of the variant was caused by neutral selection or from selective pressure thousands of years ago . Thus, controversy remains as to why the CCR5-Δ32 allele has become so common in Europeans. A pathogen may have shaped the evolution of this allele, but it may be a long-forgotten and unknown organism. Still, this example highlights how susceptibility to pathogens can converge on the same genes or pathways, connecting past, present, and future infectious disease.
While resistance alleles can provide a fitness advantage, there are several reasons why a particular allele might not become fixed. One reason may be the phenomenon of heterozygous advantage as is demonstrated by the sickle cell allele having the greatest fitness in heterozygotes due to their lack of sickle cell disease and protection against malaria. Heterozygous advantage is just one of the mechanisms of balancing selection whereby diversity at a locus is maintained . Interestingly, evidence of balancing selection extends to additional malaria resistance loci: a cluster of erythrocyte membrane proteins associated with resistance to severe malaria on ancient haplotypes shared with chimpanzees suggests the host–pathogen struggle of primates with malaria may extend back millions of years [30,31]. Diversity in this case may be being maintained through a host–pathogen arms race  with host targets (glycophorins) and the parasite binding protein (EBA-175)  escalating the conflict through maintaining genetic diversity.
Resistance mutations that protect against infectious disease do not come without a cost. Although, again, malaria resistance and sickle-cell allele are a clear example demonstrating a large detrimental effect, there are several other compelling examples (Fig 1). Several HLA alleles, which encode for cell surface molecules that present antigenic peptides to T-cells, have been associated with decreased HIV-1 viral load but also lead to increased susceptibility of psoriasis . Most notably, a string of amino acids in HLA-B57 help mediate viral control in HIV-positive patients but specifically confer susceptibility to psoriasis (and not other autoimmune diseases) by an unknown mechanism [36,37].