EvolMed

Robbing Peter to Pay Paul: The Evolutionary Trade-Offs of Hemochromatosis

Given Darwinian principles of natural selection, it might seem unusual that genes coding for hemochromatosis persist in humans. Hemochromatosis is a disease that causes excess iron to accumulate in cells, tissues, and bloodstream. Untreated, hemochromatosis leads to premature death. It is unlikely that a gene with such detrimental effects would exist without some benefit for humans; therefore, there must be a trade-off to having the condition. For years, this trade-off remained an enigma. Recent research, however, suggests that this trade-off likely lies in the decreased susceptibility to certain types of infection for individuals afflicted by hemochromatosis. Accordingly, hemochromatosis is heavily selected for in populations afflicted by such pathogens.

EvolMed

Hemochromatosis is a heritable, autosomal recessive disease. Its etiology is rooted in genetics. Hemochromatosis can be traced to a single nucleotide mutation, called a point substitution. This mutation is on chromosome six, known as the C282Y mutation. Over 80% of all individuals with hemochromatosis have this mutation [1]. This simple mutation significantly affects the regulation of hepcidin synthesis. Hepcidin is a protein which, among other functions, regulates the entry of iron into circulation. It is also responsible for preventing the release of iron from both duodenal cells and from macrophages. The implication is that excess iron cascades into the plasma, ultimately leading to severely deleterious side effects, including cardiac, neurological, and orthopedic diseases and cancer [2]. However, proximate causes have an ultimate explanation. After all, what could have caused this deleterious mutation to persist? Natural selection provides the explanation to this mystery.

The initial clue of an evolutionary basis for hemochromatosis stems from surprising allele frequencies in certain populations. A study by Merryweather-Clarke and colleagues (1997) found that the C282Y mutation was common in European populations while almost nonexistent in Asian or African populations [3]. This strongly suggests a situation specific to Europe affected the prevalence of the allele.

The ability of the C282Y mutation to remain in populations is deeply rooted in the principle of evolutionary trade-offs. Evolutionary trade-offs involve characteristics that enhance one aspect of performance while decreasing another. For example, in a population afflicted by infection, natural selection favors traits that can prevent death from infection, ensuring survival at least until reproduction, even if the trait itself ultimately leads to harmful consequences. It is more important to ensure survival before reproduction than survival after reproduction – so that an organism survives long enough to reproduce. The detrimental effects of hemochromatosis typically begin affecting the body during middle age, after the age of reproduction [2]. This suggests that hemochromatosis might have been beneficial, enabling survival until reproduction by providing immunity to infection.

Through natural selection, the human immune system has developed an array of defense mechanisms to prevent pathogens from entering the body. Perhaps most vital to pathogenic bacterial survival, and survival of most organisms, is access to iron. In defense against pathogens, the human immune system normally restricts iron access to areas of the body that are prone to invasion by pathogens, such as the eyes, nose, mouth, and genitalia. However, if pathogenic bacteria evade human defense mechanisms and enter the body, iron is much more plentiful, especially in the blood. To fight this, the body utilizes various proteins that serve to prevent pathogenic bacteria from obtaining iron molecules.

Just as humans have adaptations to prevent pathogenic bacteria from obtaining bodily iron, bacteria have adaptations to hijack iron from its host. There are several mechanisms by which pathogenic bacteria obtain iron from their hosts. One most relevant to hemochromatosis is this: bacteria allow themselves to be engulfed by macrophages, and obtain iron from within the macrophages. Macrophages store iron.

Macrophages also function in phagocytosis—the process of engulfing potentially dangerous items such as foreign substances, cancerous cells, and microbes. In the human immune system, macrophages are vital to the process of the non-specific innate immunity. Once a macrophage happens upon a microbe, they recruit other immune cells to partake in the active immune response. The macrophage surrounds the microbe and attempts to kill it, bringing it to the lymphatic system for disposal.

The macrophage’s storage of iron is a major weakness. The presence of iron within a macrophage is somewhat counterproductive to the function it serves. After all, if pathogenic bacteria thrive on iron, it is illogical to have surplus iron in the very cells that engulf bacteria. In fact, virulent pathogens such as M. tuberculosis, S. typhi (typhoid fever), and Y. pestis (bubonic plague) survive in the macrophage [4]. This is particularly problematic considering macrophages travel to the lymph system after engulfing the bacteria. The lymph system contains lymph nodes that are the sites of production and storage for cells involved in the immune system.

Once arriving in a lymph node, the bacteria divide rapidly, overwhelming the immune system (think about the swollen lymph nodes commonly seen in bubonic plague, tuberculosis and typhoid fever). The body attempts to counter attack by inducing a high fever intended to kill the bacteria. Unfortunately, this is often too little, too late. Once in the lymph nodes, the rapidly reproducing bacteria can travel easily throughout the body, making it considerably more difficult for the immune system to fight it. Untreated, the victims of these three pathogens have high mortality rates. Modern advances in medicine have been effective in aiding infected individuals, but unfortunately these advances did not exist until the twentieth century.

The question still remains of how natural selection for hemochromatosis helped battle these destructive pathogens. Of course, it seems utterly absurd that hemochromatosis, a condition characterized by excess iron stores in the body, would somehow confer resistance to bacterial infection when such bacteria rely on iron for survival. Although, excess iron accumulates in the body as a result of hemochromatosis, the distribution of the iron is not uniform. In fact, there is one type of cell in the body that has less iron than usual in hemochromatic individual: the macrophage (5).

As for the principle of evolutionary trade-off, natural selection favors traits that ensure reproduction, despite deleterious consequences later. This “robbing Peter to pay Paul” interaction seems to be in play in hemochromatosis. Hemochromatosis leads to premature death. However, if the innate ability of hemochromatosis to expel iron from macrophages is in presence of strong selective pressures, namely, high mortality rates from pathogens that rely on macrophage iron stores, hemochromatosis could rapidly increase in prevalence. It appears that exactly this occurred, through the presence of some combination of the three pathogens M. tuberculosis, S. typhi, and Y. pestis.

Scientific research corroborates the idea that hemochromatosis was selected for as a means of preventing death resulting from infection. Recent studies have analyzed M. tuberculosis, S. typhimurium and S. enterica (the latter two are closely related to S. typhi) in hemochromatic individuals relative to nonhemochromatic individuals. The results have been profound. Nairz and colleagues (2007) found that the survival of S. typhimurium and S. enterica in knockout hemochromatic mice was decreased compared to controls. This appeared to be a result of increased efflux of iron from the macrophages following infection (decreasing the quantity of iron within the macrophages). Further, iron supplementation of the macrophages in the same mice led to massive bacterial proliferation [6]. Olakanmi, Schlesinger, and Britigan (2007) studied M. tuberculosis and its growth in the macrophages of hemochromatic individuals versus nonhemochromatic individuals. They found iron uptake by the bacteria to be reduced by 90 percent in the hemochromatic macrophages relative to the nonhemochromatic macrophages. As a result, M. tuberculosis growth was decreased by nearly 50 percent in these individuals [7].

In essence, mutations causing hemochromatosis seem to decrease the quantity of iron within macrophages. This is a beneficial adaptation if deadly bacteria require macrophage iron for survival. If hemochromatosis promotes such a strong resistance to such a virulent bacteria, it is extremely likely that it was selected for in Europe, which historically has experienced mass death as a result of pathogens (e.g. Black Death), poor sanitation, and nonexistent infection control procedures.

In an environment of deadly pathogens, selective pressures likely increased the prevalence of hemochromatosis. Its inherent ability to fight disease enabled short-term survival while deleterious side effects of hemochromotosis occurred after the age of reproduction [1]. Although it is unclear which pathogen spurred the high C282Y allelic frequencies among Europeans, it is extremely likely that the iron-depleted macrophages of hemochromatic individuals served an immunological advantage at some point in history.

Why would natural selection allow a trait to exist which, untreated, kills the individual by midlife? The answer is simple: to survive until midlife, and thus, to reproduce.

References

[1] Moalem, Sharon, Maire E Percy, Theo Kruck, and Richard R Gelbart. “Epidemic Pathogenic Selection: An Explanation for Hereditary Hemochromatosis?” Medical Hypotheses, 59, no. 3 (2002): 325-29.

[2] “Hemochromatosis.” National Institute of Diabetes and Digestive and Kidney Diseases. 2014. Accessed November 22, 2014. http://digestive.niddk.nih.gov/ddiseases/pubs/ hemochromatosis/.

[3] Merryweather-Clarke, A., J. Pointon, K. Shearman, K. Robson. “Global Prevalence of Punitive Haemochromatosis Mutations.” Journal of Medical Genetics, 34, no. 4 (1997): 275-278.

[4] Weinberg, Eugene D. “Survival Advantage of the Hemochromatosis C282Y Mutation.” Perspectives in Biology and Medicine, 51, no. 1 (2008): 98-102.

[5] Beutler, E. “Iron Absorption in Carriers of the C282Y Hemochromatosis Mutation.” The American Journal of Clinical Nutrition, 80, no. 4 (2004): 799-800.

[6] Nairz, Manfred, Igor Theurl, Susanne Ludwiczek, Milan Theurl, Sabine M. Mair, Gernot Fritsche, and Günter Weiss. “The Co-ordinated Regulation of Iron Homeostasis in Murine Macrophages Limits the Availability of Iron for Intracellular.” Cellular Microbiology, 9, no. 9 (2007): 2126-140.

[7] Olakanmi, O., L. S. Schlesinger, and B. E. Britigan. “Hereditary Hemochromatosis Results in Decreased Iron Acquisition and Growth by Mycobacterium Tuberculosis within Human Macrophages.” Journal of Leukocyte Biology, 81, no. 1 (2006): 195-204.

Christiaan van Nispen is a sophomore double majoring in Psychology and Biology at George Washington University. Follow The Triple Helix Online on Twitter and join us on Facebook.

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