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Pleiotropy (from Greek πλείων pleion, "more", and τρόπος tropos, "way") occurs when one gene influences two or more seemingly unrelated phenotypic traits. Therefore, a mutation in a pleiotropic gene may have an effect on several traits simultaneously due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.

An example of pleiotropy is phenylketonuria, which is a human disease caused by a defect in a single gene on chromosome 12 that affects multiple systems, such as the nervous and integumentary system. Other examples of pleiotropy are albinism, sickle cell anemia, and certain forms of autism and schizophrenia. Pleiotropy not only affects humans, but also animals, such as chickens and laboratory house mice, where the laboratory house mice have found to exhibit the "mini-muscle" allele.

Pleiotropic gene action can limit the rate of multivariate evolution when natural selection, sexual selection or artificial selection on one trait favors one specific version of the gene (allele), while selection on other traits favors a different allele, which shows how evolution is negatively related with pleiotropy. Although some of the evolution in genes can be beneficial, some gene evolution is harmful to an organism. Genetic correlations and responses to selection most often exemplify pleiotropy.

Contents

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• 1History
• 2Mechanism
• 3Models for the origin
• 4Evolution
  • 4.1Antagonistic pleiotropy
• 5Examples
  • 5.1Albinism
  • 5.2Autism and schizophrenia
  • 5.3Phenylketonuria (PKU)
  • 5.4Sickle cell anemia
  • 5.5"Mini-muscle" allele
  • 5.6Chickens
• 6Current research
• 7Practical applications
• 8See also
• 9References
• 10External links

History[edit | edit source]

Pleiotropy was recognized even before it was formally named. Gregor Mendel recognized that certain pea plant traits (seed coat color, flower color, and axial spots) seemed to be inherited together, however their correlation to a single gene has never been proven. The term "pleiotropie" was first coined by Ludwig Plate in his 1910 Festschrift.^[1] He originally defined pleiotropy as when "several characteristics are dependent upon it [inheritence]; these characteristics will then always appear together and may thus appear correlated."^[1] The first experimental investigation into the mechanism behind pleiotropy was conducted by Hans Gruneberg in 1938 on rats. He recognized two different versions of pleiotropy: genuine pleiotropy where a single gene codes for two different products and spurious pleiotropy where a gene codes for a single product that has a variety of uses. Since then much more research has been conducted, however many questions such as the universality of pleiotropy and certain aspects of the mechanism are still not answered. (insert citation)

Mechanism[edit | edit source

Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. The underlying mechanism is genes codes for a product that is either used by various cells or has a signaling function affecting various targets, similar to a cascade.

A common example of pleiotropy is the human disease phenylketonuria (PKU). This disease causes mental retardation and reduced hair and skin pigmentation, and can be caused by any of a large number of mutations in the single gene on chromosome 12 that codes for the enzyme phenylalanine hydroxylase, which converts the amino acid phenylalanine to tyrosine. Depending on the mutation involved, conversion of phenylalanine to tyrosine is reduced or ceases entirely. Unconverted phenylalanine builds up in the bloodstream and can lead to levels that are toxic to the developing nervous system of newborn and infant children. This can cause, mental retardation, abnormal gait and posture, and delayed growth. Because tyrosine is used by the body to make melanin (a component of the pigment found in hair and skin), failure to convert normal levels of phenylalanine to tyrosine, leading to fair hair and skin.

Models for the origin[edit | edit source]

One basic model of pleiotropy's origin describes a single gene locus to the expression of a certain trait. The locus affects the expressed trait only through changing the expression of other loci. Over time, that locus would affect two traits by interacting with more loci. Directional selection for both traits during the same time period would increase the positive correlation between the traits, while selection on only one trait would decrease the positive correlation between the two traits. Eventually, traits that underwent directional selection simultaneously were linked by a single gene, resulting in pleiotropy.

Other more complex models compensate for some of the basic model's oversights, such as multiple traits or assumptions about how the loci affect the traits. They also propose the idea that pleiotropy increases the phenotypic variation of both traits since a single mutation on a gene would have twice the effect.^[6]

Evolution[edit | edit source]

Pleiotropy can have an effect on the evolutionary rate of genes and allele frequencies. Traditionally, models of pleiotropy have predicted that evolutionary rate of genes is related negatively with pleiotropy – as the number of traits of an organism increases, the evolutionary rates of genes in the organism's population decrease.^[7]However, this relationship has not been clearly found in empirical studies.^[8][9]

In mating for many animals, the signals and receptors of sexual communication may have evolved simultaneously as the expression of a single gene, instead of as the result of selection on two independent genes, one that affects the signaling trait and one that affects the receptor trait.^[10] In such a case, pleiotropy would facilitate mating and survival. However, pleiotropy can act negatively as well. A study on seed beetles found that intralocus sexual conflict arises when selection for certain alleles of a gene that are benefical for one sex causes expression of potentially harmful traits by the same gene in the other sex, especially if the gene is located on an autosomal chromosome.^[11]

Pleiotropic genes act as an arbitrating force in speciation. Rice and Hostert(1993) concludes that the observed prezygotic isolation in their studies is a product of pleiotropy's balancing role in indirect selection. By imitating the traits of an all-infertile hybridized species, they noticed that the fertilization of eggs was prevented in all eight of eight separate studies, a likely effect of pleiotropic genes on speciation.^[12] Likewise, pleiotropic gene's stabilizing selection allows for the allele frequency to be altered.^[13]

Studies on fungal evolutionary genomics have shown pleiotropic traits that simultaneously affect adaptation and reproductive isolation, converting adaptations directly to speciation. A particularly telling case of this effect is host specificity in pathogenic ascomycetes and specifically, in venturia, the fungus responsible for apple scab. These parasitic fungi each adapts to a host, and are only able to mate within a shared host after obtaining resources.^[14] Since a single toxin gene or virulence allele can grant the ability to colonize the host, adaptation and reproductive isolation are instantly facilitated, and in turn, pleiotropically causes adaptive speciation. The studies on fungal evolutionary genomics will further elucidate the earliest stages of divergence as a result of gene flow, and provide insight into pleiotropically induced adaptive divergence in other eukaryotes.^[14]

Antagonistic pleiotropy[edit | edit source]

Main article: Antagonistic pleiotropy hypothesis

Sometimes, a pleiotropic gene may be both harmful and beneficial to an organism, which is referred to as antagonistic pleiotropy. This may occur when the trait is beneficial for the organism's early life, but not its late life. Such "trade-offs" are possible since natural selection affects traits expressed earlier in life, when most organisms are most fertile, more than traits expressed later in life.^[15]

This idea is central to the antagonistic pleiotropy hypothesis, first developed by G.C. Williams in 1957. Williams suggested that some genes responsible for increased fitness in the younger, fertile organism contribute to decreased fitness later in life, which may give an evolutionary explanation for senescence. An example is the p53gene, which suppresses cancer, but also suppresses stem cells, which replenish worn-out tissue.^[10]

Unfortunately, the process of antagonistic pleiotropy may result in an altered evolutionary path with delayed adaptation, in addition to effectively cutting the overall benefit of any alleles by roughly half. However, antagonistic pleiotropy also lends a greater amount of evolutionary "staying power" to genes controlling beneficial traits, since an organism with a mutation to those genes would have a decreased chance of successfully reproducing, as multiple traits would be affected, potentially for the worse.^[16]

Sickle cell anemia is a classic example of the mixed benefit given by the staying power of pleiotropic genes, as the mutation to Hb-S provides the fitness benefit of malaria resistance to heterozygotes, while homozygotes have significantly lowered life expectancy. Since both of these states are linked to the same mutated gene, large populations today are susceptible to sickle cell despite it being a fitness-impairing genetic disorder.^[17]

Examples[edit | edit source]

Peacock with albinism

Albinism[edit | edit source]

Main article: Albinism

Albinism is the mutation of the TYR gene, also termed tyrosinase, this mutation causes the most common form of albinism. The mutation alters the production of melanin and leads to phenotypic traits throughout the organism. Melanin is a substance made by the body that is used to absorb light and also provides coloration to the skin. Indications of albinism are the absence of color in an organism's eyes, hair, and skin, due to the lack of melanin. Some forms of albinism are also known to have symptoms that manifest themselves through rapid-eye movement, light sensitivity, and strabismus.^[18]

Autism and schizophrenia[edit | edit source]

Main articles: Autism and Schizophrenia

Pleiotropy in genes has been linked between certain psychological disorders as well. Deletion in the 22q11.2 region of chromosome 22 has been associated with schizophrenia and autism.^[2] Schizophrenia and autism are caused by the same gene deletion, but manifest very differently from each other, depending on the stage of life the individual develops the disorder in. Childhood manifestation of the gene deletion is typically associated with autism, while adolescent and later expression of the gene deletion often manifests in schizophrenia or other psychotic disorders.^[19] Though the disorders are linked by genetics, there is no increased risk found for adult schizophrenia in patients who experienced autism in childhood.^[20]

A February 2013 study also genetically linked five psychiatric disorders, including schizophrenia and autism. The link was a single nucleotide polymorphism of two genes involved in calcium channel signaling with neurons. One of these genes, CACNA1C, has been found to influence cognition and has been associated with autism, as well as linked in studies to schizophrenia and bipolar disorder.^[21] These particular studies instead show clustering of these diseases within patients themselves or families.^[22] With the estimated heritability of schizophrenia being 70% to 90%,^[23] pleiotropy of genes proves important to psychiatric diagnosis and increased risk for certain psychotic disorders.

Phenylketonuria (PKU)[edit | edit source]

Main article: Phenylketonuria

Sickle cell anemia[edit | edit source]

Main article: Sickle-cell disease

Sickle cell anemia is a genetic disease that causes deformed red blood cells with a rigid, crescent shape instead of the normal flexible, round shape.^[24] Point mutation, a change in only one nucleotide,^[25] in the HBB gene causes sickle cell anemia. The HBB gene encodes information to make the beta-globin subunit of hemoglobin, which is the protein molecule of red blood cells that carries oxygen throughout the body. Sickle cell anemia occurs when the HBB gene mutation causes both beta-globin subunits of hemoglobin to change into hemoglobin S (HbS).^[26]

Sickle cell anemia is a pleiotropic disease because the expression of a single mutated HBB gene produces numerous consequences throughout the body. When deoxygenated, sickle red blood cells assume the disfigured sickle shape because the mutated hemoglobin forms polymers and clumps together.^[27] As a result, the deformed sickle cells are inflexible and cannot easily flow through blood vessels, increasing the risk of blood clots and possibly depriving vital organs of oxygen.^[26]Some complications associated with sickle cell anemia include immense pain, damaged organs, strokes, high blood pressure, and vision loss. Sickle red blood cells also have a shortened lifespan and die prematurely, which leads to anemia because of the decreased number of red blood cells in the body.^[28]

"Mini-muscle" allele[edit | edit source]

A gene recently discovered in laboratory house mice, termed "mini-muscle", causes a 50% reduction in hindlimb muscle mass as its primary effect (the phenotypic effect by which it was originally identified:^[3]). In addition it has various effects on behavior, skeletal morphology, relative size of internal organs, and metabolism. The mini-muscle allele behaves as a Mendelian recessive.^[4] The mutation is a single nucleotide polymorphism (SNP) in an intron of the Myosin heavy polypeptide 4 gene.^[5]

Chickens[edit | edit source]

Chickens exhibit various traits affected by pleiotropic genes.  Some chickens exhibit frizzle feather trait, where their feathers all curl outward and upward rather than lying flat against the body.  Frizzle feather was found to stem from a deletion in the genomic region coding for α-Keratin.  This gene seems to pleiotropically lead to other abnormalities like increased metabolism, higher food consumption, accelerated heart rate, and delayed sexual maturity.^[29]

Domesticated chickens underwent a rapid selection process that led to unrelated phenotypes having high correlations, suggesting pleiotropic, or at least close linkage, effects between comb mass and physiological structures related to reproductive abilities.  Both males and females with larger combs have higher bone density and strength, which allows females to deposit more calcium into eggshells.  This linkage is further evidenced by the fact that 2 genes, HAO1 and BMP2 affecting medullary bone (the part of the bone that transfers calcium into developing eggshells) are located at the same locus as the gene affecting comb mass.  HAO1 and BMP2 also display pleiotropic effects with commonly desired domestic chicken behavior, with chickens who express higher levels of these two genes in bone tissue producing more eggs and displaying less egg incubation behavior.^[30]