What is the evolutionary advantage of sickle cell trait in malaria prone areas?

Sickle cell disease [SCD] is a major cause of death in young children in Africa. The condition is caused by a mutation in the gene encoding the β-globin subunit of the hemoglobin molecule in red blood cells. It is a recessive hereditary disease, meaning that sufferers have inherited the mutated form of the gene from both parents. The mutation causes red blood cells to take on an abnormal sickle like shape, and sufferers of the disease may experience severe infections, attacks of acute pain and stroke. They also have an increased risk of death. Despite the existence of vaccines and therapeutics to manage the condition, 176,000 people died of the disease in 2013.

Carriers have inherited the mutated form of the gene from only one parent and are said to carry the sickle cell trait [SCT], but do not suffer from the disease. SCT confers resistance to malaria and it is generally accepted that this accounts for the high levels of SCT in some parts of the world where malaria is endemic – in fact SCT prevalence is in excess of 15% in much of Central Africa. However, the degree of association between malaria and SCT prevalence is not well characterized.

Gabon

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Therefore, Eric Elguero and colleagues conducted an epidemiological study to investigate the relationship between present day malaria and SCT prevalence in Gabon. They took blood samples from 3,959 people of whom 21.7 % had the SCT genotype and 52% showed evidence of Plasmodium infection. Elguero and colleagues go on to show that an increase in malaria prevalence of 10% is associated with an increase of 4.3% in SCT carriers. There is, they conclude in their study, a strong association between malaria and SCT prevalence. This means that malaria continues to be a selecting factor for SCT.

Furthermore, age [though not gender] is also associated with SCT prevalence – an increase of 10 years increasing SCT prevalence by 5.5 %. Two possible hypotheses are offered by Elguero’s team to explain this association: firstly, the selective pressure of malaria has decreased with time due to improved health care, or alternatively the genotype that gives rise to the SCT confers protection against severe malaria in adult life as well as in childhood.

Finally, Elguero and colleagues claim the impact of their findings goes beyond that of public health and illustrates that humans are still evolving in response to their environment. This is contrary to many scientific and non-scientific reports that state humans have stopped evolving and now rely only on culture and technology for survival.

There are plenty of references showing malaria and other diseases have shaped the human genome in the past – Sarah Tishkoff and Scott Williams review this relationship specifically in Africa – and there is a growing body of evidence showing ‘recent’ human evolution can be due to environmental impact, but Elguero’s study argues that it is still happening in the case of malaria and SCT. His study alone may not convince the skeptics, especially if Elguero’s theory that better medical care could reduce the selective pressure of malaria on SCT is correct, so further investigations will be required to change people’s minds. And to expand on this, it will be interesting to see if other infectious diseases or agents are currently pushing [or may in the future push] human evolution, especially with the rise in antimicrobial resistance making it more difficult to control infectious diseases.

The latest issue of the journal Cell carries an article that is likely to help solve one of the long-standing mysteries of biomedicine. In a study that challenges currently held views, researchers at the Instituto Gulbenkian de Ciência [IGC], in Portugal, unravel the molecular mechanism whereby sickle cell hemoglobin confers a survival advantage against malaria, the disease caused by Plasmodium infection. These findings, by the research team lead by Miguel P. Soares, open the way to new therapeutic interventions against malaria, a disease that continues to inflict tremendous medical, social and economic burdens to a large proportion of the human population.

Sickle cell anemia is a blood disease in which red blood cells reveal an abnormal crescent [or sickle] shape when observed under a conventional microscope. It is an inherited disorder -- the first ever to be attributed to a specific genetic modification [mutation], in 1949 by Linus Pauling [two-times Nobel laureate, for Chemistry in 1954, and Peace, in 1962]. The cause of sickle cell anemia was attributed unequivocally to a single base substitution in the DNA sequence of the gene encoding the beta chain of hemoglobin, the protein that carries oxygen in red blood cells.

Only those individual that inherit two copies of the sickle mutation [one from their mother and the other from their father] develop sickle cell anemia. If untreated, these individuals have a shorter than normal life expectancy and as such it would be expected that this mutation would be rare in human populations. This is however, far from being the case. Observations made during the mid-20th century and building on Pauling's findings, revealed that the sickle mutation is, in fact, highly, selected in populations from areas of the world were malaria is very frequent, with sometimes 10-40% of the population carrying this mutation.

Individuals carrying just one copy of the sickle mutation [inherited from either the father or mother] were known not to develop sickle cell anemia, leading rather normal lives. However, it was found that these same individuals, said to carry the sickle cell trait, were in fact highly protected against malaria, thus explaining the high prevalence of this mutation in geographical areas where malaria is endemic.

These findings lead to the widespread believe in the medical community that understanding the mechanism whereby sickle cell trait protects against malaria would provide critical insight into developing treatment or a possible cure for this devastating disease, responsible for over a million premature deaths in sub-Saharan Africa. Despite several decades of research, the mechanism underlying this protective effect remained elusive. Until now.

Several studies suggested that, in one way or another, sickle hemoglobin might get in the way of the Plasmodium parasite infecting red blood cells, reducing the number of parasites that actually infect the host and thus conferring some protection against the disease. The IGC team's results challenge this explanation.

In painstakingly detailed work, Ana Ferreira, a post-doctoral researcher in Miguel Soares' laboratory, demonstrated that mice obtained from Prof. Yves Beuzard's laboratory, that had been genetically engineered to produce one copy of sickle hemoglobin similar to sickle cell trait, do not succumb to cerebral malaria, thus reproducing what happens in humans.

When Prof. Ingo Bechman observed the brains of these mice he confirmed that the lesions associated with the development of cerebral malaria where absent, despite the presence of the parasite.

Ana Ferreira went on to show that the protection afforded by sickle hemoglobin in these mice, acts without interfering directly with the parasite's ability to infect the host red blood cells. As Miguel Soares describes it, "sickle hemoglobin makes the host tolerant to the parasite."

Through a series of genetic experiments, Ana Ferreira was able to show that the main player in this protective effect is heme oxygenase-1 [HO-1], an enzyme whose expression is strongly induced by sickle hemoglobin. This enzyme, that produces the gas carbon monoxide, had been previously shown by the laboratory of Miguel Soares to confer protection against cerebral malaria. In the process of dissecting further this mechanism of protection Ana Ferreira demonstrated that when produced in response to sickle hemoglobin the same gas, carbon monoxide, protected the infected host from succumbing to cerebral malaria without interfering with the life cycle of the parasite inside its red blood cells.

Miguel Soares and his team believe that the mechanism they have identified for sickle cell trait may be a general mechanism acting in other red blood cell genetic diseases that are also know to protect against malaria in human populations: "Due to its protective effect against malaria, the sickle mutation may have been naturally selected in sub-Saharan Africa, where malaria is endemic and one of the major causes of death. Similarly, other clinically silent mutations may have been selected throughout evolution, for their ability to provide survival advantage against Plasmodium infection."

This research was carried out the at the IGC in collaboration with the Team of Prof. Yves Beuzard [Université Paris VII et XI, France], an expert in sickle cell anemia, and Prof. Ingo Bechman an expert in neuropathological diseases [Institute of Anatomy, University of Leipzig, Germany]. Other IGC researchers involved in this study are Ivo Marguti, Viktória Jeney, Ângelo Chora, Nuno Palha and Sofia Rebelo. This project was funded by Fundação para a Ciência e a Tecnologia [Portugal], GEMI Fund Linde Healthcare and the European Commission's Framework Programme 7.

What is the evolutionary advantage of sickle cell in some populations?

But there is a biological advantage associated with sickle cell anemia: patients are better protected against malaria. The scientists performed computer simulations under different evolutionary selection scenarios, and discovered that balancing selection is a driving force in the human genome.

Does sickle cell trait help against malaria?

Sickle cell trait [AS] confers partial protection against lethal Plasmodium falciparum malaria. Multiple mechanisms for this have been proposed, with a recent focus on aberrant cytoadherence of parasite-infected red blood cells [RBCs].

What is adaptive advantage of sickle cell trait?

The sickle cell trait provides a survival advantage against malaria fatality over people with normal hemoglobin in regions where malaria is endemic. The trait is known to cause significantly fewer deaths due to malaria, especially when Plasmodium falciparum is the causative organism.

What are the evolutionary relationships between sickle cell anemia and malaria?

What's interesting to note is that humans began developing the abnormal HBB gene as an evolutionary response to malaria. This is because the parasite that causes malaria is halted by sickled cells, making people who carry sickle cell trait more resistant to the disease.

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