Heterozygote advantage
Encyclopedia
A heterozygote advantage (heterozygous advantage) describes the case in which the heterozygote
genotype has a higher relative fitness
than either the homozygote
dominant or homozygote recessive genotype
. The specific case of heterozygote advantage is due to a single locus
known as overdominance
.
Polymorphism
can be maintained by selection favoring the heterozygote, and this mechanism is used to explain the occurrence of some kinds of genetic variability
. A common example is the case where the heterozygote conveys both advantages and disadvantages while both homozygotes convey a disadvantage. A well-established case of heterozygote advantage is that of the gene involved in sickle cell anaemia
.
Often, the advantages and disadvantages conveyed are rather complicated, because more than one gene may influence a given trait or morph
. Major gene
s almost always have multiple effects (pleiotropism
), which can simultaneously convey separate advantageous traits and disadvantageous traits upon the same organism. In this instance, the state of the organism's environment will provide selection
, with a net effect either favoring or working in opposition to the gene, until an environmentally-determined equilibrium is reached.
Heterozygote advantage is a major underlying mechanism for heterosis
, or "hybrid vigor", which is the improved or increased function of any biological quality in a hybrid offspring.
. It is highly unlikely, however, that the same deleterious mutations will be prevalent in both populations after a long period of separation. Since loss-of-function mutations tend to be recessive (given that dominant mutations of this type generally prevent the organism from reproducing and thereby passing the gene on to the next generation), the result of any cross between the two populations will be fitter
than the parent.
This article deals with the specific case of fitness overdominance
, where the fitness advantage of the cross is caused by being heterozygous at one specific locus alone.
, a fruit fly that has been a model organism
for genetic research. In a classic study, Kalmus demonstrated how polymorphism
can persist in a population through heterozygote advantage.
Kalmus discovered a mutant allele
of an autosomal gene that expressed ebony body color and other selective advantages in a pattern that was autosomal dominant. The same allele also conveyed harsh disadvantages in a pattern that was completely recessive. When a fly inherited two copies of the mutation (homozygous), it expressed the dark ebony color, but it was also particularly weak, and was placed at a harsh reproductive disadvantage.
If weakness were the only effect of the mutant allele, so that it conveyed only disadvantages, natural selection would weed out this version of the gene until it became extinct from the population. However, the same mutation also conveyed advantages, providing improved viability for individuals that were heterozygotes. The heterozygote expressed none of the disadvantages of homozygotes, yet gained improved viability. The homozygote wild type
was perfectly healthy, but did not possess the improved viability of the heterozygote, and was thus at a disadvantage compared to the heterozygote in survival and reproduction.
This mutation, which at first glance appeared to be harmful, conferred enough of an advantage to heterozygotes to make it beneficial, so that it remained at dynamic equilibrium in the gene pool. Kalmus introduced flies with the ebony mutation to a wild-type population. The ebony allele persisted through many generations of flies in the study, at genotype frequencies that varied from 8% to 30%. In experimental populations, the ebony allele was more prevalent and therefore advantageous when flies were raised at low, dry temperatures, but less so in warm, moist environments.
(SCA) is a genetic disorder
that is caused by the presence of two incompletely recessive alleles. When a sufferer's red blood cell
s are exposed to low-oxygen
conditions, the cells lose their healthy round shape and become sickle-shaped. This deformation of the cells can cause them to become lodged in capillaries, depriving other parts of the body of precious oxygen. When untreated, a person with SCA may suffer from painful periodic bouts, often causing damage to internal organs, stroke
s, or anemia
. Typically the disease results in premature death.
Because the genetic disorder is incompletely recessive, a person with only one SCA allele and one unaffected allele will have a "mixed" phenotype
: The sufferer will not experience the ill effects of the disease, yet will still possess a sickle cell trait
, whereby some of the red blood cells undergo benign effects of SCA, but nothing severe enough to be harmful. Those afflicted with sickle-cell trait are also known as carriers: If two carriers have a child, there is a twenty-five percent chance that their child will have SCA, a fifty percent chance that their child will be a carrier, and a twenty-five percent chance that the child will neither have SCA nor be a carrier. Were the presence of the SCA allele to confer only negative traits, we would expect its allele frequency to decrease generation after generation, until its presence were completely eliminated by selection and by chance.
However, there is convincing evidence indicating that, in areas with persistent malaria outbreaks, individuals with the heterozygous state have a distinct advantage (and this is why individuals with heterozygous alleles are far more common in these areas). Those with the benign sickle trait possess a resistance to malarial infection. The pathogen that causes the disease spends part of its cycle in the red blood cells, and those with sickle cells effectively stop the pathogen in its tracks, until the immune system destroys the foreign bodies. These individuals have a great immunity to infection and have a greater chance of surviving outbreaks. However, those with two alleles for SCA may survive malaria but will typically die from their genetic disease unless they have access to advanced medical care. Those of the homozygous normal or wild-type case will have a greater chance of passing on their genes successfully, in that there is no chance of their offspring's suffering from SCA; yet, they are more susceptible to dying from malarial infection before they have a chance to pass on their genes.
This resistance to infection is the main reason that we still see the SCA allele and SCA disease. It is found in greatest frequency in populations where malaria was and often still is a serious problem. Approximately one in 375 African-Americans is a carrier, as their recent ancestry is from malaria-stricken regions, far fewer than in Central Africa. Other populations in Africa, India, the Mediterranean and the Middle East have higher allele frequencies as well. As effective anti-malarial treatment becomes increasingly available to malaria-stricken populations, we can expect the allele frequency for SCA to decrease, so long as SCA treatments are unavailable or only partially effective. If effective Sickle-cell anemia
treatments become available to the same degree, we can expect allele frequencies to remain at their present levels in these populations. In this context, 'treatment effectiveness' refers to the reproductive fitness that it grants, rather than the degree of suffering alleviation.
, or CF, is an autosomal recessive hereditary disease of the lungs, sweat gland
s and digestive system. The disorder is caused by the malfunction of the CFTR
protein, which controls inter-membrane transport
of chloride
ions, which is vital to maintaining equilibrium of water in the body. The malfunctioning protein causes viscous mucus to form in the lungs and intestinal tract. Before modern times, children born with CF would have a life expectancy of only a few years, but modern medicine has made it possible for these people to live into adulthood. However, even in these individuals, male and female, CF typically causes sterility
. It is the most common genetic disease among people of European
descent.
The presence of a single CF mutation may influence survivorship of people affected by diseases involving loss of body fluid, typically due to diarrhea. The most common of these maladies is cholera
, which throughout history has killed many Europeans. Those with cholera would often die of dehydration due to intestinal water losses. A mouse model of CF was used to study resistance to cholera, and the results were published in Science in 1994 (Gabriel, et al.). The heterozygote (carrier) mouse had less secretory diarrhea than normal, non-carrier mice. Thus it appeared for a time that resistance to cholera explained the selective advantage to being a carrier for CF and why the carrier state was so frequent.
This theory has been called into question. Hogenauer, et al. have challenged this popular theory with a human study. Prior data were based on solely on mouse experiments. These authors found that the heterozygote state was indistinguishable from the non-carrier state.
Another theory for the prevalence of the CF mutation is that it provides resistance to tuberculosis
. Tuberculosis was responsible for 20% of all European deaths between 1600 and 1900, so even partial protection against the disease could account for the current gene frequency.
As of 2007, the selective pressure for the high gene prevalence of CF mutations is still uncertain. Approximately 1 in 25 persons of European descent is a carrier of the disease, and 1 in 2500 to 3000 children born is affected by cystic fibrosis.
, the main pathway for cells to obtain energy metabolizing carbon sugar
s. In humans, certain mutations within this enzyme
which affect the dimerisation of this protein are causal for a rare disease, triosephosphate isomerase deficiency
. Other mutations, which inactivate the enzyme (= null allele
s) are lethal when inherited homozygous
ly (two defect copies of the TPI gene), but have no obvious effect as heterozygotes
(one defect and one normal copy). However, the frequency of heterozygous null-alleles is much higher than expected, indicating a heterozygous advantage for TPI null alleles as well. The reason is unknown, however, new scientific results are suggesting that cells having reduced TPI activity are more resistant against oxidative stress
PlosOne, Dec. 2006
loci. The reasons proposed for these findings are speculative, however, it has been argued that heterozygosity at MHC loci results in more alleles to fight against a wider variety of diseases, possibly increasing survival rates against a wider range of infectious diseases. The latter claim has been tested in an experiment, which showed that outbreeding mice to exhibit MHC heterozygosity enhanced their health and survival rates against multiple-strain infections.
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
genotype has a higher relative fitness
Fitness (biology)
Fitness is a central idea in evolutionary theory. It can be defined either with respect to a genotype or to a phenotype in a given environment...
than either the homozygote
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
dominant or homozygote recessive genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
. The specific case of heterozygote advantage is due to a single locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
known as overdominance
Overdominance
Overdominance is a condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents. Overdominance can also be described as heterozygote advantage, wherein heterozygous individuals have a higher fitness than homozygous individuals.An...
.
Polymorphism
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
can be maintained by selection favoring the heterozygote, and this mechanism is used to explain the occurrence of some kinds of genetic variability
Genetic variation
Genetic variation, variation in alleles of genes, occurs both within and among populations. Genetic variation is important because it provides the “raw material” for natural selection. Genetic variation is brought about by mutation, a change in a chemical structure of a gene. Polyploidy is an...
. A common example is the case where the heterozygote conveys both advantages and disadvantages while both homozygotes convey a disadvantage. A well-established case of heterozygote advantage is that of the gene involved in sickle cell anaemia
Sickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
.
Often, the advantages and disadvantages conveyed are rather complicated, because more than one gene may influence a given trait or morph
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
. Major gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s almost always have multiple effects (pleiotropism
Pleiotropy
Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously...
), which can simultaneously convey separate advantageous traits and disadvantageous traits upon the same organism. In this instance, the state of the organism's environment will provide selection
Selection
In the context of evolution, certain traits or alleles of genes segregating within a population may be subject to selection. Under selection, individuals with advantageous or "adaptive" traits tend to be more successful than their peers reproductively—meaning they contribute more offspring to the...
, with a net effect either favoring or working in opposition to the gene, until an environmentally-determined equilibrium is reached.
Heterozygote advantage is a major underlying mechanism for heterosis
Heterosis
Heterosis, or hybrid vigor, or outbreeding enhancement, is the improved or increased function of any biological quality in a hybrid offspring. The adjective derived from heterosis is heterotic....
, or "hybrid vigor", which is the improved or increased function of any biological quality in a hybrid offspring.
Heterozygote advantage in theory
When two populations of any sexual organism are separated and kept isolated from each other, the frequencies of deleterious mutations in the two populations will differ over time, by genetic driftGenetic drift
Genetic drift or allelic drift is the change in the frequency of a gene variant in a population due to random sampling.The alleles in the offspring are a sample of those in the parents, and chance has a role in determining whether a given individual survives and reproduces...
. It is highly unlikely, however, that the same deleterious mutations will be prevalent in both populations after a long period of separation. Since loss-of-function mutations tend to be recessive (given that dominant mutations of this type generally prevent the organism from reproducing and thereby passing the gene on to the next generation), the result of any cross between the two populations will be fitter
Fitness (biology)
Fitness is a central idea in evolutionary theory. It can be defined either with respect to a genotype or to a phenotype in a given environment...
than the parent.
This article deals with the specific case of fitness overdominance
Overdominance
Overdominance is a condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents. Overdominance can also be described as heterozygote advantage, wherein heterozygous individuals have a higher fitness than homozygous individuals.An...
, where the fitness advantage of the cross is caused by being heterozygous at one specific locus alone.
Experimental confirmation
Cases of heterozygote advantage have been demonstrated in several organisms, including humans. The first experimental confirmation of heterozygote advantage was with Drosophila melanogasterDrosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
, a fruit fly that has been a model organism
Model organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
for genetic research. In a classic study, Kalmus demonstrated how polymorphism
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
can persist in a population through heterozygote advantage.
Kalmus discovered a mutant allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
of an autosomal gene that expressed ebony body color and other selective advantages in a pattern that was autosomal dominant. The same allele also conveyed harsh disadvantages in a pattern that was completely recessive. When a fly inherited two copies of the mutation (homozygous), it expressed the dark ebony color, but it was also particularly weak, and was placed at a harsh reproductive disadvantage.
If weakness were the only effect of the mutant allele, so that it conveyed only disadvantages, natural selection would weed out this version of the gene until it became extinct from the population. However, the same mutation also conveyed advantages, providing improved viability for individuals that were heterozygotes. The heterozygote expressed none of the disadvantages of homozygotes, yet gained improved viability. The homozygote wild type
Wild type
Wild type refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard, "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele...
was perfectly healthy, but did not possess the improved viability of the heterozygote, and was thus at a disadvantage compared to the heterozygote in survival and reproduction.
This mutation, which at first glance appeared to be harmful, conferred enough of an advantage to heterozygotes to make it beneficial, so that it remained at dynamic equilibrium in the gene pool. Kalmus introduced flies with the ebony mutation to a wild-type population. The ebony allele persisted through many generations of flies in the study, at genotype frequencies that varied from 8% to 30%. In experimental populations, the ebony allele was more prevalent and therefore advantageous when flies were raised at low, dry temperatures, but less so in warm, moist environments.
Sickle-cell anemia
Sickle-cell anemiaSickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
(SCA) is a genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that is caused by the presence of two incompletely recessive alleles. When a sufferer's red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s are exposed to low-oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
conditions, the cells lose their healthy round shape and become sickle-shaped. This deformation of the cells can cause them to become lodged in capillaries, depriving other parts of the body of precious oxygen. When untreated, a person with SCA may suffer from painful periodic bouts, often causing damage to internal organs, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s, or anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. Typically the disease results in premature death.
Because the genetic disorder is incompletely recessive, a person with only one SCA allele and one unaffected allele will have a "mixed" phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
: The sufferer will not experience the ill effects of the disease, yet will still possess a sickle cell trait
Sickle cell trait
Sickle cell trait describes a condition in which a person has one abnormal allele of the hemoglobin beta gene , but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele...
, whereby some of the red blood cells undergo benign effects of SCA, but nothing severe enough to be harmful. Those afflicted with sickle-cell trait are also known as carriers: If two carriers have a child, there is a twenty-five percent chance that their child will have SCA, a fifty percent chance that their child will be a carrier, and a twenty-five percent chance that the child will neither have SCA nor be a carrier. Were the presence of the SCA allele to confer only negative traits, we would expect its allele frequency to decrease generation after generation, until its presence were completely eliminated by selection and by chance.
However, there is convincing evidence indicating that, in areas with persistent malaria outbreaks, individuals with the heterozygous state have a distinct advantage (and this is why individuals with heterozygous alleles are far more common in these areas). Those with the benign sickle trait possess a resistance to malarial infection. The pathogen that causes the disease spends part of its cycle in the red blood cells, and those with sickle cells effectively stop the pathogen in its tracks, until the immune system destroys the foreign bodies. These individuals have a great immunity to infection and have a greater chance of surviving outbreaks. However, those with two alleles for SCA may survive malaria but will typically die from their genetic disease unless they have access to advanced medical care. Those of the homozygous normal or wild-type case will have a greater chance of passing on their genes successfully, in that there is no chance of their offspring's suffering from SCA; yet, they are more susceptible to dying from malarial infection before they have a chance to pass on their genes.
This resistance to infection is the main reason that we still see the SCA allele and SCA disease. It is found in greatest frequency in populations where malaria was and often still is a serious problem. Approximately one in 375 African-Americans is a carrier, as their recent ancestry is from malaria-stricken regions, far fewer than in Central Africa. Other populations in Africa, India, the Mediterranean and the Middle East have higher allele frequencies as well. As effective anti-malarial treatment becomes increasingly available to malaria-stricken populations, we can expect the allele frequency for SCA to decrease, so long as SCA treatments are unavailable or only partially effective. If effective Sickle-cell anemia
Sickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
treatments become available to the same degree, we can expect allele frequencies to remain at their present levels in these populations. In this context, 'treatment effectiveness' refers to the reproductive fitness that it grants, rather than the degree of suffering alleviation.
Cystic fibrosis
Cystic fibrosisCystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
, or CF, is an autosomal recessive hereditary disease of the lungs, sweat gland
Sweat gland
Sweat glands, or sudoriferous glands, are small tubular structures of the skin that produce sweat. There are two kinds of sweat glands:...
s and digestive system. The disorder is caused by the malfunction of the CFTR
Cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator is a protein that in humans is encoded by the CFTR gene.CFTR is a ABC transporter-class ion channel that transports chloride and thiocyanate ions across epithelial cell membranes...
protein, which controls inter-membrane transport
Membrane transport
In cellular biology the term membrane transport refers to the collection of mechanisms that regulate the passage of solutes such as ions and small molecules through biological membranes namely lipid bilayers that contain proteins embedded in them...
of chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
ions, which is vital to maintaining equilibrium of water in the body. The malfunctioning protein causes viscous mucus to form in the lungs and intestinal tract. Before modern times, children born with CF would have a life expectancy of only a few years, but modern medicine has made it possible for these people to live into adulthood. However, even in these individuals, male and female, CF typically causes sterility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
. It is the most common genetic disease among people of European
European ethnic groups
The ethnic groups in Europe are the various ethnic groups that reside in the nations of Europe. European ethnology is the field of anthropology focusing on Europe....
descent.
The presence of a single CF mutation may influence survivorship of people affected by diseases involving loss of body fluid, typically due to diarrhea. The most common of these maladies is cholera
Cholera
Cholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission occurs primarily by drinking or eating water or food that has been contaminated by the diarrhea of an infected person or the feces...
, which throughout history has killed many Europeans. Those with cholera would often die of dehydration due to intestinal water losses. A mouse model of CF was used to study resistance to cholera, and the results were published in Science in 1994 (Gabriel, et al.). The heterozygote (carrier) mouse had less secretory diarrhea than normal, non-carrier mice. Thus it appeared for a time that resistance to cholera explained the selective advantage to being a carrier for CF and why the carrier state was so frequent.
This theory has been called into question. Hogenauer, et al. have challenged this popular theory with a human study. Prior data were based on solely on mouse experiments. These authors found that the heterozygote state was indistinguishable from the non-carrier state.
Another theory for the prevalence of the CF mutation is that it provides resistance to tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
. Tuberculosis was responsible for 20% of all European deaths between 1600 and 1900, so even partial protection against the disease could account for the current gene frequency.
As of 2007, the selective pressure for the high gene prevalence of CF mutations is still uncertain. Approximately 1 in 25 persons of European descent is a carrier of the disease, and 1 in 2500 to 3000 children born is affected by cystic fibrosis.
Triosephosphate isomerase
Triosephosphate isomerase (TPI) is a central enzyme of glycolysisGlycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
, the main pathway for cells to obtain energy metabolizing carbon sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
s. In humans, certain mutations within this enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
which affect the dimerisation of this protein are causal for a rare disease, triosephosphate isomerase deficiency
Triosephosphate isomerase deficiency
Triosephosphate isomerase deficiency is a rare autosomal recessive metabolic disorder which was initially described in 1965.It is a unique glycolytic enzymopathy that is characterized by chronic haemolytic anaemia, cardiomyopathy, susceptibility to infections, severe neurological dysfunction, and,...
. Other mutations, which inactivate the enzyme (= null allele
Null allele
A null allele is a mutant copy of a gene that completely lacks that gene's normal function. This can be the result of the complete absence of the gene product at the molecular level, or the expression of a non-functional gene product...
s) are lethal when inherited homozygous
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
ly (two defect copies of the TPI gene), but have no obvious effect as heterozygotes
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
(one defect and one normal copy). However, the frequency of heterozygous null-alleles is much higher than expected, indicating a heterozygous advantage for TPI null alleles as well. The reason is unknown, however, new scientific results are suggesting that cells having reduced TPI activity are more resistant against oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
PlosOne, Dec. 2006
Resistance to hepatitis C virus infection
There is evidence that genetic heterozygosity in humans provides increased resistance to certain viral infections. There is significantly lower proportions of HLA-DRB1 heterozygosity among HCV-infected than uninfected cases. The differences were more pronounced with alleles represented as functional supertypes (P = 1.05 x 10(-6)) than as low-resolution genotypes (P = 1.99 x 10(-3)). These findings constitute evidence that heterozygosity provides an advantage among carriers of different supertype HLA-DRB1 alleles against HCV infection progression to end-stage liver disease in a large-scale, long-term study population.MHC heterozygosity and human scent preferences
Multiple studies have shown that, in double-blind experiments, women prefer the scent of men who are heterozygous at all three MHCMajor histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
loci. The reasons proposed for these findings are speculative, however, it has been argued that heterozygosity at MHC loci results in more alleles to fight against a wider variety of diseases, possibly increasing survival rates against a wider range of infectious diseases. The latter claim has been tested in an experiment, which showed that outbreeding mice to exhibit MHC heterozygosity enhanced their health and survival rates against multiple-strain infections.
Ashkenazi Jewish intelligence
A more recent theory of heterozygote advantage detailed in the 2005 paper "Natural History of Ashkenazi Intelligence" proposes that Tay-Sachs, and the other lipid storage diseases that are prevalent in Ashkenazi Jews, reflect genes that enhance dendrite growth and promote higher intelligence in Ashkenazi Jews when present in carrier form.See also
- Balanced polymorphism
- Hybrid vigour
- OverdominanceOverdominanceOverdominance is a condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents. Overdominance can also be described as heterozygote advantage, wherein heterozygous individuals have a higher fitness than homozygous individuals.An...
- Polymorphism (biology)Polymorphism (biology)Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...