Supervillain or Superhero? The effects of autosomal recessive disorders on human evolution  

Often when we watch movies, we root for the superhero and despise the supervillain. After all, why would we want Dr. Evil and Mr. Bigglesworth to successfully dominate the world by turning the moon into a death star? His success offers no benefit to anyone other than himself and his cohort of miscreants.  If he were to succeed, civilization and freedom would be compromised, effectively squashing humans as individuals. But, by supporting the devilishly carnal Austin Powers, we identify with his saving the world, and maintaining human civilization without any form of the unexpected or undesired disorder. With a little creative interpretation, we can find these same characters of Superhero and Supervillain in evolutionary biology.

“Yeah baby, yeah!”

There is the basic belief in evolutionary biology, that a gene will only survive over the course of generations if it can provide some form of advantage to a species (the superhero). If a gene provides a disadvantage (the supervillain), such as a lethal disorder or disease, then it should eventually disappear from the gene pool, since carriers of the gene will not have as many reproductive opportunities as those who do not carry the flawed gene (17). However, certain genes, in fact, act as both a superhero and a supervillain. As genes combine to form a trait, the variation of alleles can sometimes confer both positive and negative assets within the trait. In genes resulting in autosomal recessive disorders, the amount of negative alleles present within an individual can provide an advantage and a disadvantage, making these genes both superhero and supervillain!

Typically, we each have 46 chromosomes on which all of our genes are located (6). Arranged into 23 different pairs, one of each of the chromosomes that creates the pair is passed from either your mother or father. Out of the 23, 22 of these chromosomal pairs are known as autosomal chromosomes. Autosomal chromosomes decide every trait you have aside from gender. Differences in traits will emerge depending on the variation of alleles that make up your genes. These can be anything from hair and eye color to the rate at which you may obtain a genetic disorder or disease. When the variation within a gene results in a negative trait, it is often referred to as a pathogenic variant or mutation. And, when a negative variation is passed from both parents this is known as a recessive mutation (6).

All of us receives one allele from both parents. It is our first ever birthday present.

An autosomal recessive disorder develops when a recessive mutation occurs on an autosomal chromosome. However, you will not necessarily develop an autosomal recessive disorder simply because your parents have a form of the same mutation. If both of your parents are homozygous with the same mutation and have the same autosomal recessive disorder, you have a 25% chance of having inherited the mutated gene and developing the disorder. If, however, both of your parents are heterozygous, you have a 50% chance of having inherited only one of the mutated genes, making you a carrier, and a 25% chance of having inherited none of the mutated genes (7).

Life can truly be unfair.

Autosomal recessive disorders are typically extremely harmful and deadly to the afflicted. Those burdened with any of the three most common disorders, for example, sickle cell anemia, cystic fibrosis and Tay-Sachs find themselves with complicated health issues and shorted lifespans.  However, those who are carriers, but did not develop the disorder, can demonstrate increased resistance to diseases such as Malaria, Cholera, and Tuberculosis. Thus, in the lottery of inheritance, if you have developed an autosomal recessive disorder, you have unfortunately inherited the negative effect of the gene. But, if you bare either one or none of the mutated genes, you have inherited its positive counterpart.

When hemoglobin S is present the blood cell will sickle under certain environmental stressors.

Sickle-cell anemia is a rare condition in which there are not sufficient healthy red blood cells to carry an adequate amount of oxygen through the body (1). Sickle cell anemia is caused by a mutation in the gene that affects hemoglobin. When hemoglobin is affected, the usual round and flexible shape becomes rigid and sticky, resembling sickles (1). The mutated hemoglobin, known as hemoglobin S., can cause a wide variety of negative complications in the afflicted, such as anemia, pain caused by blocked blood flow, swelling of the hands and feet, delayed growth, increased infection rate, and vision problems. However, when an individual is strictly a carrier for sickle-cell anemia (known as sickle cell trait), there is instead an increased resistance to malaria diseaseMalaria is a mosquito-borne infectious disease, that is caused by parasitic protozoans. Transferred to humans only through the female Anopheles mosquito, these protozoans have a complex life cycle that occurs within their secondary hosts (2)

Nope, Nope, Nope!

Once a human host becomes infected, the protozoans move through blood vessels to liver cells and reproduce asexually, eventually releasing back into red blood cells to continue their life-cycle (2). If, however, a host is strictly a carrier for the sickle-cell trait and not afflicted with the condition, the defective hemoglobin S present within their body will rupture, preventing the malaria parasite from continuing its cycle. Unfortunately, these protective benefits do not apply to individuals afflicted with sickle-cell anemia(2).  Rather, afflicted individuals become more vulnerable to malaria, since all of their red blood cells will sickle, causing a lack of oxygen throughout their body.

Cystic fibrosis is a mutation in the CFTR gene which prevents chloride channels from properly regulating the flow of chloride ions and water across cell membranes (18). As a result, mucus, sweat and digestive juices that line organs of the body (liver, pancreas, etc.) become thick and sticky rather than thin and slippery.  The secretions, then, no longer act as lubricants, rather they plug tubes, ducts, and passageways within the body, causing pain, acute bronchitis, infection, male infertility, pulmonary hypertension and many other painful complications.

Tay-Sachs disease occurs when the enzyme, hexosaminidase-A (Hex-A), is defective (14). Without adequate Hex-A, a fatty substance known as GM2 ganglioside lipid begins to accumulate in cells, eventually building up to toxic levels in the nerve cells of the brain. Once GM2 ganglioside lipid reaches toxic levels, progressive damage will occur throughout the body. Individuals with Tay-Sachs disease will lose overall body function, leading to blindness, deafness, cognitive impairment, paralysis and eventually death (13).

Tay-Sachs occurs on the 15th chromosome.

Both Cystic fibrosis and Tay-Sachs autosomal recessive disorders are devastating and deadly. However, being a carrier of each has been shown to provide protection against Cholera and Tuberculosis respectively. Cholera is an infectious disease causing severe dehydration by watery diarrhea, which can eventually lead to death if left untreated (3). It is often caused by consuming food or water contaminated by the Vibrio cholera bacterium. Also an infectious disease, Tuberculosis is caused by a bacterium known as Mcobacterium tuberculosis. Mainly affecting the lungs, it is highly contagious, spreading from host to host through tiny droplets released into the air when the infected either coughs or sneezes (3). Carriers of cystic fibrosis have a protective advantage against Cholera since portions of the CFTR genes are inhibited, preventing fluid loss associated with Cholera. Carriers of Tay-Sachs, likewise, have a protective advantage against Tuberculosis, due to their increase in Hex-A which is known to increase defense against Mycobacterium. Sickle-cell anemia, cystic fibrosis, and Tay-Sachs occur across all population groups. However, each is more prevalent in populations which have long histories of Malaria, Cholera, and Tuberculosis (27).

Throughout the 18th century, tuberculosis was considered highly fashionable among Victorian women.

Observing these three particular disorders and their heterozygous carriers, certain populations show higher rates. However, it is important to note that a higher occurrence of a specific disorder is not directly related to a particular race, nor does it indicate that a certain population is at a disadvantage to others. Rather, it is directly related to the geographic region, and subsequently, the environmental pressures, an individual’s or group’s ancestry adapted to. If a population group resides in an environment where potentially dangerous diseases are prevalent, the fitness of that population will select for traits that confer a genetic advantage. As a result, over generations, that population will be more resistant and at an advantage for living in that particular environment. For example, when looking at both sickle-cell anemia and sickle cell trait, higher percentages are found among peoples in Sub-Saharan Africa (up to 30% in Nigeria alone), the Chalkidiki district of Greece (18-32%), and on the Eastern Province of the Arabian Peninsula (20-30%)(26&34). Within these three geographical locations, and consequently among their populations, higher rates of malaria are seen, promoting a need for the continued production of the sickle cell gene.

10.1038_nrmicro795-f1a_full

Spread of Malaria Worldwide

15799_sickle_cell_anaemia_map

Spread of hemoglobin S Worldwide

However, these are not the only locations in which we see sickle cell. High rates of sickle cell can also be seen among African American populations in the United States. This has been attributed to the dispersal of population groups specifically associated with higher rates of sickle cell. Review of historical documents has enabled researchers to track these lineages. Movement of large populations from the coasts of the Sub-Saharan African region can be seen in records documenting the United States Atlantic slave trade. Movement of sickle cell has also been documented originating in Greece and advancing to Sicily. And, large-scale immigrations in the 1950’s of Turkish nationals originating from the Arabian Peninsula, carried the gene into Germany (34).

So, while genes that result in autosomal recessive disorders negatively affect the individual who carries them, the more the common heterozygous carriers of the disorders are protected from other diseases. This heterozygous advantage allows the carrier individuals to reside in environments with strong selective pressures without hindering their fitness, enabling them to effectively pass on their genes to future generations to continue their lineage, history, and culture. Though the majority of individuals will never experience the negative effects of having an autosomal recessive disorder, we must all strive to help resolve the calamity of these supervillain genes. 

To donate or learn more about the fight against autosomal recessive disorders:

 

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