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Genetics and Ecology of Malaria

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					Running Head: THE GENETICS AND ECOLOGY OF MALARIA              1




                         The Genetics and Ecology of Malaria
                                  Lauren M. Gineo
                            The University of Rhode Island
The Genetics and Ecology of Malaria                                                                  2


        The word malaria is Italian for bad air, as it was thought to have been caused by inhaling

swamp vapors. Although it is true that swamps, wet lands and stagnant water were all important

factors in the ecology of this disease, malaria was actually found to be caused by a specific

protozoan that was transmitted to humans by the bite of female Anopheles mosquitos which

breed in slow-moving or stagnant fresh water (World Health Organization [WHO], 1999).

        Malaria is the leading cause of death and disease worldwide (Center for Disease Control,

[CDC], 2010). It is the number one killer of children and claims one child every thirty seconds,

about three thousand children per day. Over one million people die of malaria each year, most of

which are under five years of age. More than 40 percent of the worlds population live in malarial

risk areas, 90 percent of which are located in Sub-Saharan Africa (Unicef, 2008). Malaria

functions as one of the many factors impeding childhood development due to the fact that

children who survive a serious bout of malaria are more prone to develop mental and physical

impairments. Another deterring effect of malaria is the economic strain it places upon countries

where the disease is endemic. The cost of controlling and treating this disease in Africa depletes

economic resources and slows economic growth by about 1.3 percent per year (Unicef, 2008).

        In order to fully understand Malaria and its global implications, one has to take a close

look at the life cycle of Plasmodium. In 1889 Alphonse Laveran, a French army surgeon

stationed in Algeris, discovered that a certain protist was the cause of malaria (Wills, p.153,

2006). Plasmodium is a single-celled protozoa that multiply in the red blood cells and cause

malaria (Wills, p. 300, 2006). A protozoa is a unicellular, heterotrophic protist (Freeman, p.521,

2010). There are four species of plasmodium. Plasmodium falciparum, Plasmodium vivax,

Plasmodium ovale and Plasmodium malariae. The biggest difference is seen between P.
The Genetics and Ecology of Malaria                                                                  3


falciparum, which causes the most severe form of malaria, and the other three forms (Wills,

2006, p.174-175). Plasmodium undergoes two different cycles of development, as illustrated in

Figure 1. The asexual cycle, also known as the human cycle, and the sexual cycle, also known as

the mosquito cycle.

        Malaria begins when a female Anopheles mosquito, the main vector of malaria,

penetrates the epidermal layer to feed on blood. While doing so it also injects saliva mixed with

an anticoagulant. According to the Directorate of National Vector Borne Diseases Control

Programme (2010), if the vector is infected with Plasmodium, it will also inject lengthened

sporozites (mobile, spindle-shaped asexual cells) into the bloodstream of the individual it is

feeding on. The sporozoites travel to the liver where they enter liver cells and rapidly divide

asexually, infecting the liver. This asexual division generates thousands of haploid forms, called

merozoites. Some malaria parasite species remain dormant for extended periods in the liver,

causing relapses weeks or months later. It is due to this fact this doctors recommend individuals

to seek medical council for symptoms similar to malaria for one year after returning from an area

where malaria is prevalent.

        The merozoites exit the liver cells and enter back into the bloodstream, invading red

blood cells (RBC’s). The RBC’s then release newly formed merozoites every one to three days

depending on the malaria parasite species (NIAID, 2010). This multiplication cycle can result in

thousands of infected cells in the compromised individuals bloodstream, which can lead to

illness and severe complications that can last for months if not treated properly. Some RBC’s

infected with merozoites leave the cycle of asexual replication and instead of dividing, the

merozoites form gametocytes that circulate in the bloodstream of the host.
The Genetics and Ecology of Malaria                                                                 4


        When a female Anopheles mosquito ingests blood from an infected individual that

contains gametocytes, the male and female gametes unite in the mosquito stomach to form an

ookinete. An ookinete is an actively motile zygote of the malarial organism that penetrates the

mosquito stomach to form a cyst, also known as an oocyst, under the outer gut lining. The

ookinete penetrates the stomach wall to form an oocyst, in which about a thousand sporozoites

develop (American Health Association, p. 355-356, 2008). This developmental stage take

between eight and thirty five days, depending on parasite species (e.g., P. vivax, P. falciparum,

etc.) and environmental conditions such as temperature. Sporozoites penetrate the wall of the

oocyst and are able to reach the salivary glands of the mosquito. Transmission occurs when an

infected mosquito takes a blood meal on an uninfected individual, and during the process, injects

the sporozoites through its salivary glands, thus infecting the once uninfected individual.




Figure 1. Malaria Life Cycle

Note. From figure in Diseases & Conditions A-Z Index, CDC, 2010

        According to the National Institute of Allergy and Infectious Disease (2010), Malarial

symptoms usually present ten to sixteen days after an infectious mosquito bite (this timeline
The Genetics and Ecology of Malaria                                                                  5


depends on the malaria parasite species). Symptoms usually coincide with the bursting of

infected RBC’s. This causes a cycle of malaria attacks that can reoccur at regular time periods.

Each attack is defined by three stages. The first symptom an infected individual will experience

are chills, which are usually accompanied by fatigue, headache, muscle pains, diarrhea and

vomiting. The second stage is fever, where within an hour or two of experiencing chills, the body

temperature rises and the skin becomes hot and dry. This is followed by perfuse sweating, which

occur when body temperature deceases and the body is drenched in sweat. The infected

individual is usually left felling very fatigued and weak after a cycle.

        In milder forms of malarial infection caused by certain malarial parasites, the disease can

persist for years and cause relapses of infection. In more serious forms of the infection, usually

caused by P. falciparum, malaria can be fatal. This particular variety is most common in tropical

parts of Africa. Over ninety percent of deaths due to malaria occur in sub-Saharan Africa (CDC,

2010). Most deaths caused by malaria are normally linked to various complications. These

complications include cerebral malaria, organ failure, breathing problems, low blood sugar and

severe anemia. If left untreated, malaria can wreck havoc on the human body, ultimately leading

to death.

        The first treatment for malaria came in the early 1630’s in the form of dried bark from the

cinchona tree. This bitter tasting outer skin was used by the Andean tribes of northern Peru as a

cure for shivering (Rocco, p. 52, 2003). This bark was brought back to Rome by a Jesuit priest,

who was one of many clergymen, on a mission from Pope Urban VII to find a cure for malaria.

The extract from this bark become know as quinine. Father Domenico Anda made the first

mention of quinine as a treatment for malaria (Rocco, p. 52, 2003). Today quinine, in a
The Genetics and Ecology of Malaria                                                                   6


synthesized form, is still a viable treatment for malaria, although quinine resistant has developed

in certain strains of the malaria parasite. There are various anti-malarial prophylactics and

malaria treatments available today. The problem many endemic malaria areas are facing is an

increasing drug resistance in the various Plasmodium species. This drug resistance stems from a

variety of factors including overuse, the existence of cross resistance among drugs belonging to

the same chemical family, and the ability of the parasite to develop a mutation that makes it

resistant to the specific treatment.

        Malaria is the greatest selective pressure for evolutionary selection in the recent history

of the human genome. This is due to the immense global impact it is capable of and the high

levels of mortality and morbidity it causes. From this force for evolutionary selection, various

genetic adaptations to malaria have emerged in different populations. These adaptations include

sickle cell anemia, thalassemia, duffy antigen null and G6PD deficiency just to name a few.

         In the 1940’s a geneticist and evolutionary biologist by the name of John Burdon

Sanderson Haldane, suggested that one of the principal agents of natural selection during the

course of evolution, is immunity to disease (Dronamraju, 2004). Haldane wrote, in his often

quoted paper entitled “Disease and Evolution”,

        ...the struggle against disease, and particularly infectious disease, has been a very

        important evolutionary agent, and that some of its results have been rather unlike those of

        the struggle against natural forces, hunger, and predators, or with members of the same

        species.” (p. 2)

Haldane had observed that many red blood cell disorders were prominent in tropical regions

were malaria was endemic. He also noted that in tropical regions at higher altitudes where the
The Genetics and Ecology of Malaria                                                                  7


malarial parasite cannot thrive, there was an absence of these RBC disorders in the individuals

that lived there. He was able to compare his two findings and develop his ‘malaria hypothesis’

which stated that these RBC disorders had become prevalent in these regions because natural

selection had worked to increase the prevalence of traits that protected individuals from malaria,

thus increasing the individuals fitness and allowing the trait to be passed on to offspring. This

hypothesis was verified by British medical doctor Anthony C. Allison who demonstrated that the

geographical distribution of the sickle-cell mutation was limited to Africa and correlated with

malaria endemicity as illustrated in Figure 2. Allison further noted that individuals who carried

the sickle-cell trait were resistant to malaria (Allison, 1954).




Figure 2. Global Distribution of the Sickle Cell Gene and Malaria

Note. Figure from Sabeti, P., Nature Communications, 2(1), 104.
The Genetics and Ecology of Malaria                                                                        8


        Sickle cell anemia is characterized by abnormal hemoglobin, known as hemoglobin S.

Sickle hemoglobin causes the red blood cells to be a long, skinny, sickle shape. They also tend to

be stiff and sticky, which makes it difficult for the red blood cells to flow freely through blood

vessels, sometimes causing blockages (National Heart Lung and Blood Institute [NHLBI], 2011).

Individuals who carry only a single copy of the sickle cell gene do not have sickle cell anemia

due to the fact that it is an autosomal recessive allele. These individuals have a resistance to

malaria. According to the results of Punnett squares, if a person with sickle cell disease has a

child with an individual that has normal hemoglobin and lacks the sickle cell trait, the chance

that the offspring being a carrier for the trait is 100 percent. If an individual that carries the sickle

cell trait has a child with another individual that carries the sickle cell trait, there is a 50 percent

chance of the offspring will also be a carrier for the trait, a 25 percent chance the child will have

sickle cell anemia and a 25 percent chance the child will be homozygous dominant for normal

hemoglobin. If a person who is a carrier of sickle cell disease has a child with a person who does

not have the trait, the child will have a 50 percent chance of being a carrier of the trait and a 50

percent chance of being homozygous dominant for normal hemoglobin.

        Although the exact mechanism by which resistance is bestowed to malaria by sickle cell

hemoglobin is still unknown, a number of factors are likely involved, and each one contributes in

varying degrees to the defense against malaria. If an individual is heterozygous for the sickle cell

trait, which means half of their hemoglobin is HbS (defective hemoglobin) and and the other half

is HbN (normal hemoglobin), sickling will occur when the oxygen tension in the RBC’s is

diminished. Under normal circumstances, sickling of RBC’s in an individual with the sickle trait

will not occur. Sickling has been known to occur in heterozygous, high-altitude climbers due to
The Genetics and Ecology of Malaria                                                                  9


very low oxygen tension caused by extreme exertion at high-altitude (Martin, et al., p.59, 1989).

When the malarial parasite, P.falciparum infects red blood cells that are heterozygous for the

sickle trait, sickling takes place. This is due to the fact that the malarial parasite reduces the

oxygen tension in the blood cells that they infect. Plasmodium uses the oxygen that is carried by

RBC’s for their own metabolism. The use of oxygen in parasitic metabolism causes the oxygen

tension to decrease, thus resulting in sickled RBC’s. When infected RBC’s sickle, the body reads

this as a damaged cell and they are engulfed and destroyed by phagocytes (Luzzatto, et al., p.

320, 1970). This destruction by phagocytes causes the RBC’s to prematurely rupture, which in

turn disallows the trophozoites the opportunity to mature and reproduce (Honigsbaum, p. 239,

2001). Although more research is needed to obtain a more conclusive explanation for the

association between sickle cell hemoglobin and its prevalence in endemic malaria areas, the

association is an excellent example of balanced polymorphism. Balanced polymorphism is the

genetic scenario in which a heterozygote that has two different alleles for a gene, has an

advantage over a homozygote that has either two identical dominant alleles or two recessive

alleles (O’Neill, 2011). In the cause of malaria and sickle cell anemia, heterozygotes maintained

by this balancing mechanism have a permanent advantage (as long as malaria still exists) over

homozygotes due to heterozygote malarial resistance, thus increasing the overall fitness of the

individual. This selective advantage of the heterozygote maintains that the sickle cell trait is seen

at higher levels in malarial endemic environments compared to that of areas unaffected by

malaria.

        Another genetic adaptation of malaria is thalassemia. Thalassemia is a result of an

abnormal form of hemoglobin that causes the body to make fewer healthy red blood cells and
The Genetics and Ecology of Malaria                                                                 10


less hemoglobin than normal. The disorder results in the excessive destruction of RBC’s, which

in turn leads to anemia (NHLBI, 2010). This destruction is the factor that kills malaria infected

RBC’s. The Punnett squares of individuals and their offspring follow the same statistics as the

Punnett squares of sickle cell anemia. The only difference is that in thalassemia an individual

that has an affected gene will have thalassemia and not just be a carrier. If an individual only has

one affected gene they will have minor anemia. If the individual has two affected genes they will

have moderate to severe anemia. Thalassemia provides some protection against malaria, but not

as much as the sickle cell trait. Biologists are still divided over whether thalassemias prevalence

is due to selective pressure exerted by malaria (Honigsbaum, p. 287, 2001).

        Duffy antigen null is a disorder in which individuals lack the receptor for which malaria

can enter the RBC’s. Duffy antigen is the receptor that P. vivax merozoites use to gain entrance

into RBC’s (Michon et al., p.111, 2001). The duffy null phenotype is most commonly seen in

people whose ancestors came from regions of Africa where P. vivax malaria is endemic.

Normally genetic mutations such as this would have been eventually eliminated by natural

selection, but by giving its carrier increased resistance to malaria, the mutation has been

perpetuated. Duffy antigen null’s main drawback is its specificity of resistance and its inability to

protect against other species of Plasmodium.

        G6PD deficiency is also known as glucose-6-phosphate dehydrogenase deficiency. The

G6PD gene is a general cleaning agent that aids in glucose metabolism. G6PD deficiency causes

an increased amount of membrane bound hemichromes and other species that cause reactive

oxygen species to build up in RBC’s and cause oxidative damage (Clark, Hunt, p.4, 1983). P.

falciparum grows poorly in RBC’s that lack G6PD, thus, individuals with a G6PD deficiency
The Genetics and Ecology of Malaria                                                                  11


have an innate immunity against malaria. Conversely, recent evidence suggests that as an

adaptation to the G6PD deficiency, the P. falciparum parasite has developed the capability to

produce its own G6PD (Kwiatkowski, 2005). In a study on the adaptation of P. falciparum to

oxidative stress in G6PD deficient human erythrocytes (1988), it was noted that they had

observed the ability of P. falciparum to produce its own G6PD enzyme after several cycles of

growth in G6PD deficient erythrocytes (Roth, Schulman, p.364, 1988). This is a prime example

of the back and forth struggle and selective pressures between organisms.

        In various studies it has been shown that a condition called ovalocytosis, has the ability

to protect against severe malaria in individuals that have the condition. Ovalocytosis is a rare

inherited condition that causes the red blood cells to be slightly oval in appearance instead of

their normal round shape (Coetzer, et al, p. 1656, 1996). This disorder is seen mostly in

Southeast Asian populations where malaria is endemic. A study preformed by the Institute for

Medical Research in Kuala Lumpur, Malaysia was carried out in central Peninsular Malaysia to

determine the protection efficacy of individuals with ovalocytosis and their resistance to malaria.

The malaria parasite rates and densities were compared in seventy nine ovalocytic and seventy

nine normocytic Malayan Aborigines. Rates of infection were observed over a period of six

months. Malaria infection was determined from the observation of Giemsa stained blood films

that were collected over the six month period. With a Giemsa stain, one is able to detect and

identify the specific Plasmodium species present in the blood of an infected individual (CDC,

2010). It was found that blood films from the ovalocytic individuals were found to be less

positive for malarial infection compared to that of normocytic individuals. Among the

individuals that were infected by the malaria parasite, heavy infections (defined as greater than
The Genetics and Ecology of Malaria                                                                  12


or equal to 10,000 parasites/mm3 of blood) with P. vivax, P. falciparum, and P. malariae, were

seen only in the normocytic subjects, which comprised approximately 12.5% of the malaria

positive individuals in this group (Foo, Rekhraj, Chiang, Mak, p.271, 1992).

        Still to this day, Malaria is one the most advantageous and well understood examples of

an infectious disease that has had a large affect on human evolution, due to its high degree of

selective pressure it exudes upon infected individuals. The selective pressure induced by the

malaria parasite has given rise to many resistance alleles that have allowed humans to develop a

resistance to the disease and develop immunities that allow them to survive. Investigations that

make inquires regarding the link between natural selection and disease resistance have divulged

some of the principle forces that have shaped our species. Pardis Sabeti, a professor at Harvard

University, suggested that these shaping forces haven given rise to genetic variations that protect

us from infectious diseases, help our metabolisms when faced with changing diets, adapt to help

us act against changing environments and sun exposure, and many other beneficial variations (as

cited in Songini, para. 4, 2009). Once these variations are identified and understood, the findings

may allow researchers and scientists to develop therapies for disease that utilize these insights.

There is still a great deal of information to learn in regards to how the malaria parasite functions

and how it is able to adapt and overcome change. With these findings we may, one day, be able

to create a fool proof vaccination that is capable of providing a complete resistance to the malaria

parasite, rendering it powerless against the millions of innocent lives it currently claims each

year.
The Genetics and Ecology of Malaria                                                                13


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The Genetics and Ecology of Malaria                                                                    14


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The Genetics and Ecology of Malaria                                                     15


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