Human beings carry a lot of genes – the exact number is still unknown, but the current estimate is 20,500 genes in a single human being. Occasionally, a gene will mutate, causing a genetic disease or other anatomical problem. As these genes are not, in general, advantageous to the individual, the problem gene is not usually passed on.
Sometimes, however, there is a high prevalence of a recessive genetic disease within a population – a greater prevalence than would be estimated by sheer chance. Many of these genetic problems are caused by recessive genes: it takes two copies of the gene to actually develop the disease in question. In this case, having one copy of the gene would merely make an individual a “carrier” of the genetic disease – in general, the individual would have no symptoms of carrying the faulty gene.
Studies have shown that there is often an advantage to being a carrier for some of the high-prevalence diseases in certain populations. This advantage keeps the gene circulating at a higher-than-average rate within a population, as the carriers have an advantage over those who have no trace of the genetic mutation.
This benefit has been dubbed the Heterozygote Advantage: people who carry one copy of the mutated gene are more robust than those with a “normal” genotype or with two disease-causing mutations.
Cystic Fibrosis: An Example of the Heterozygote Advantage
Cystic Fibrosis is a recessive genetic disease caused by a mutation in the CFTR gene. This gene is responsible for the transport of chloride ions into and out of cells. If an individual carries two mutations of the gene, Cystic Fibrosis will develop: the disease alters the production of sweat, digestive juices, and mucus. Eventually, pancreatic obstruction leads to difficulty with food digestion, and thickened pulmonary secretions lead to life-threatening lung infections.
Cystic Fibrosis is a fairly common genetic trait among Europeans. The highest prevalence is in Ireland, whereas many as 1 in 19 people carry the disorder. With a high concentration of carriers in a specific geographical area, scientists wondered if there could be a benefit to carrying the Cystic Fibrosis gene.
As it turns out, carriers of the CFTR genetic mutation do have an advantage over those who do not carry the gene. Individuals infected with certain diseases, like cholera or typhus, often succumb to an electrolyte imbalance and dehydration caused by severe, acute diarrhea. At the University of Chapel Hill in North Carolina, mice with the Cystic Fibrosis genetic mutation were infected with cholera. None of the mice succumbed to dehydration, as their intestines did not have the chloride channels to secrete fluid. Of course, these mice did have the actual disease of Cystic Fibrosis, which is not an advantage to survival in the long run.
For a heterozygote, however, a balance is achieved. The carrier of the CFTR mutation will not have Cystic Fibrosis, but will have only half as many chloride channels as a non-carrier. This limits the amount of fluid lost to diarrhea in the event a carrier gets infected with a disease like Typhoid or Cholera.
The question remains, why would the advantage be limited to the European population? Typhoid Fever and Cholera exist throughout the globe, but the increase in Cystic Fibrosis carriers is only seen in the norther climate of Europe. Another theory accounts for this finding: carriers of the CFTR mutation will lose more salt in their sweat. This is a relative disadvantage in hot climates - dehydration would occur more quickly for a carrier in a hot environment. For those in hot climates, carrying the CFTR mutation would not be a benefit. In cold climates, however, carriers are unlikely to dehydrate due to sweating - carrying the CFTR mutation offers protection from diarrhea-causing illness without the worry of heat-induced dehydration.
Connexin 26: Deafness and Cell Repair
The most common cause of non-syndromic genetic deafness is a recessive gene called GJB2, which codes for a protein known as Connexin 26. Up to 50% of genetic, non-syndromic deafness is caused by this gene. As many as 1 in 30 Americans carry the 35delG mutation for this gene: this large ratio of carriers in the general population has caused researchers to search for a heterozygous advantage for the gene.
Researchers have found that carriers of the Connexin 26 genetic mutation will not experience deafness, but will have a thickened epidermis (skin layer), and increased cell repair capacity. A thicker skin layer creates a greater barrier to infection, preventing bacterial invasion.
Sickle Cell and Malaria
Sickle Cell Disease is caused by having two genes for "Hemoglobin S," which distorts the shape of red blood cells into a crescent, or sickle, shape. Heterozygotes for this condition carry a typical "Hemoglobin A" gene and a "Hemoglobin S" gene: they have Sickle Cell trait, but not the disease.
Carriers of the Hemoglobin S gene are resistant to Malaria, which is quite deadly in warm, tropical locations like Africa and the Mediterranean. In areas with high rates of Malaria infection, people without sickle cell trait are likely to fall ill, and possibly succumb, to Malaria. Those with Sickle Cell trait are immune, and more robust than either those without the trait, or those who have Sickle Cell Disease.
Beta-Thalassemia Major: A Child Fights Anemia
Thalassemia and Heart Attacks
Β-Thalassemia causes a form of microcythemic anemia, a severe, life threatening disease in individuals with the thalassemia major (Cooley's anemia) form of the disease. A less severe form exists (thalassemia minor), which leads to slow growth and a milder form of anemia. Thalassemia is seen in roughly the same areas as Sickle Cell disease, and confers a similar resistance to Malaria for carriers.
Carriers of thalassemia trait, however, also have resistance to coronary heart disease. Carriers have a lower arterial blood pressure, but do not have the anemia associated with the disease.
Preventing Disease: Testing
While the heterozygous advantage is apparent for many autosomal recessive genetic diseases, the effects of having the actual disease can be devastating. Prenatal genetic testing is available to people in certain high -risk populations. Testing for Sickle Cell and Cystic Fibrosis are now commonplace, allowing many carriers to determine if there is a risk of passing along the gene. If only one parent carries the recessive trait, there is no danger of the children developing the genetic disease. If both parents are found to be carriers, genetic counseling may be advised for the family, so that fully informed decisions can be made, prior to any pregnancy occurring.
The company 23andMe has developed genetic testing kits, available over-the-counter, which will determine carrier status for a number of genetic diseases. The kit is available online, and delivers ancestry information in addition to health and genetic disease carrier status.
Questions & Answers
Question: How is being a carrier of Cystic Fibrosis advantageous?
Answer: Carriers of the mutations which cause Cystic Fibrosis do not have the disease, but they are more resistant to dehydration caused by electrolyte imbalances. This conveyed an advantage to Europeans during Typhoid and Cholera epidemics.
Question: Why is Ireland the area most likely to have a higher incidence of cystic fibrosis?
Answer: Ireland has the highest per capita rate of cystic fibrosis in the world. The incidence is three times higher than the average rate in the USA or the rest of Europe. 1 in 19 people are carriers of the CF gene in Ireland. Having one copy of the gene confers protection against the effects of cholera, which is one reason the gene is highly prevalent in Europe (cholera caused many fatalities prior to the invention of antibiotics). Germany has the highest total number of patients, but a larger population. The concentration of the gene appears to increase across the northwestern part of Europe. A population called the Bell Beaker Folk carried the F508 deletion and migrated throughout Europe. The Bell Beaker group distributed heavily throughout Britain and into Ireland, changing the demographics there forever. It is likely this founder effect that has concentrated the genetic material in this one area of Europe, though it is only a theory and not proven.
Question: Does hemophilia have heterozygote superiority?
Answer: There are many causes to hemophilia, caused by a deficiency of various clotting factors. Hemophilia A is the most commonly known and is an X-linked trait causing factor VIII deficiency. The clotting factors include Factors II, V, VII, and X (extrinsic factors) and Factors VIII, IX, XI, and XII (intrinsic factors). There is a known heterozygote survival advantage to carrying a mutation on the Factor V gene. This mutation is known as Factor V Leiden and can lead to activated Protein C resistance (causing a propensity to generate blood clots) in homozygotes. Heterozygotes have demonstrated an increased resistance to sepsis in studies done on mice. (Kerschen E, Hernandez I, Zogg M, Maas M, Weiler H. Survival advantage of heterozygous factor V Leiden carriers in murine sepsis. J Thromb Haemost 2015; 13: 1073–80)
Shivani on December 21, 2017:
I have a question
What is the reason for prevention of malaria in heterozygous individual although they posses normal RBCs also??
Leah Lefler (author) from Western New York on April 28, 2012:
The heterozygote advantage does explain why so many recessive genetic diseases remain in the population in decently high numbers - sickle cell disease is the classic example of this phenomenon with its resistance to malaria, but many other genetic diseases have a similar advantage in carriers.
Kelley Marks from Sacramento, California on April 28, 2012:
Genetics is a very interesting subject, though a bit daunting. It's also fascinating reading about people's resistance to some disease when they carry only one recessive gene, rather than two, which would give them the disease. Thanks. Later!