Pleiotropy (from Greek pleion , “more”, and tropos , ” way”) occurs when a gene affects two or more disjointed phenotypic traits . A gene that exhibits multiple phenotypic expressions is called a pleiotropic gene. Mutations in pleiotropic genes can have an effect on multiple traits at once, as genes coding for a product used by numerous cells or distinct targets with similar signaling function.
Pleiotropy can arise from several different but potentially overlapping mechanisms, such as gene pleiotropy, developmental pleiotropy, and selective pleiotropy. Gene pleiotropy occurs when a gene product interacts with several other proteins or catalyzes multiple reactions. Developmental pleiotropy occurs when mutations result in multiple effects on the phenotype . Selective pleiotropy occurs when the resulting phenotype has multiple effects on fitness (depending on factors such as age and sex). [1]
An example of pleiotropy is phenylketonuria , an inherited disorder that affects levels of phenylalanine , an amino acid that can be obtained from food, in the human body. Phenylketonuria causes this amino acid to increase in amounts in the body, which can be very dangerous. The disease is caused by a defect in a single gene on chromosome 12 that codes for the enzyme phenylalanine hydroxylase , which affects multiple systems, such as the nervous and integumentary systems . [2] Pleiotropy affects not only humans, but also animals, such as chickens and laboratory house mice, where mice carry the “mini-muscle” allele .
G1, G2, and G3 are distinct genes that contribute to the phenotypic traits P1, P2 and P3.
Pleiotropic gene action can limit the rate of multivariate evolution when natural selection , sexual selection or artificial selection on one trait favors one allele, while selection on other traits favors a different allele. Some gene development is harmful to an organism. Genetic correlation and responses to selection often exemplify pleiotropy.
History
Pleiotropic traits were first recognized in the scientific community, but were not used until Gregor Mendel ‘s 1866 experiment with the pea plant. Mendel assumed that some characteristics of the pea plant (seed coat color, flower color and axillary spots) appear to be inherited together; However, their association with a single gene has never been proven. The term “pleiotropy” was first coined by Ludwig Plate in his Festschrift , published in 1910. [3] He originally defined pleiotropy as occurring when “many characteristics depend on … [inheritance]; then these characteristics will always appear together and thus may appear correlated”. [4]This definition is still used today.
Following the definition of plate, Hans Grüneberg was the first to study the mechanism of pleiotropy . [3] In 1938 Grüneberg published an article dividing pleiotropy into two distinct types: “real” and “spurious” pleiotropy. “True” pleiotropy occurs when two different elementary products are produced from the same location . “Spurious” pleiotropy, on the other hand, occurs either when a primary product is used in different ways or when a primary product initiates a cascade of events with different phenotypic consequences. of skeletal mutationsGrüneberg came across these distinctions after experimenting with rats. He assumed that “fake” pleurisy was present in the mutation, while “real” pleurisy was not, thus partially invalidating his original theory . [5] Through subsequent research , it has been established that Grüneberg’s definition of “spurious” pleiotropy is what we now recognize only as “pleiotropy”. [3]
In 1941 the American geneticists George Beadle and Edward Tatum further invalidated Grüneberg’s definition of “real” pleiotropy, instead advocating the “one gene-one enzyme” hypothesis , originally introduced by French biologist Lucien Cunot in 1903. it was done . [3] [6] This hypothesis moved future research about pleiotropy into how a single gene can produce different phenotypes.
In the mid-1950s Richard Goldschmidt and Ernst Hadorn solidified the mistake of “real” pleiotropy through separate individual research. A few years later, Hadorn divided pleiotropy into a “mosaic” model (which states that a locus directly affects two phenotypic traits) and a “relational” model (which is similar to “spurious” pleiotropy). These terms are no longer in use but have contributed to the current understanding of pleiotropy.
By accepting the one gene-one enzyme hypothesis, scientists instead focused on how unrelated phenotypic traits could be affected by genetic recombination and mutation, applying it to populations and evolution. [3] This view of pleiotropy, “universal pleiotropy”, defined as a locus mutation capable of affecting essentially all traits, was first implied by Ronald Fisher’s geometric model in 1930. had gone . This mathematical model shows how evolutionary fitness depends on the degree of freedom. Phenotypic variation from random changes (ie mutations). It theorizes that an increased phenotypic independence corresponds to a decrease in the likelihood that a given mutation will result in an increase in fitness.[7] Extending Fisher’s work, Sewall Wright provided more evidence using molecular genetics to support the idea of ”universal pleiotropy” in his 1968 book Evolution and the Genetics of Populations: Genetic and Biometric Foundations . . The concepts of these various studies on development have given rise to many other research projects related to personal fitness. [1]
In 1957 evolutionary biologist George C. Williams theorized that opposing effects would appear during the life cycle of an organism if it was closely related and pleiotropic. Natural selection favors genes that are more beneficial before breeding than later (leading to increased reproductive success). Knowing this, Williams argued that if only close relationships were present, natural selection would cause beneficial traits to arise before and after reproduction. This, however, has not been observed in nature, and thus anti-pleurisy contributes to the slow decline with age (senility). [8]
Mechanism
Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. The underlying mechanism is genes that code for a product that is either used by different cells or has a cascade-like signaling function that affects different targets.
Model for original
A basic model of the origin of pleiotropy describes a single gene locus for the expression of a specific trait. The locus affects the expressed trait only by changing the expression of other loci. Over time, that locus will interact with the other locus to affect the two traits. Directional selection for both traits during the same time period would increase the positive correlation between traits, whereas selection on only one trait would decrease the positive correlation between the two traits. Eventually, traits undergoing simultaneous directional selection were linked to the same gene, resulting in pleiotropy.
Other more complex models compensate for oversight of some basic model, such as multiple traits or assumptions about how loci affect traits. They also propose the idea that pleiotropy increases the phenotypic variation of both traits because the effect of a single mutation on the gene would be double. [9]
Continuous improvement
Pleiotropy can influence the evolutionary rate of genes and allele frequencies. Traditionally, models of pleiotropy have predicted that the evolutionary rate of genes is negatively correlated with pleiotropy – as the number of traits of an organism increases, the growth rate of genes in the population of the organism decreases. [10] However, this relationship has not been clearly found in empirical studies. [11] [12]
In mating, signals and receptors for sexual communication for many animals may have evolved simultaneously as the expression of a single gene, rather than the result of selection on two independent genes, one that affects the signaling trait and one that affects the receptor trait. affects. [13] In such a case, pleiotropy would facilitate mating and survival. However, pleiotropy can also act negatively. A study on seed beetles found that intrauterine sexual conflict arises when selection for certain alleles of a gene that is beneficial for one sex causes the expression of potentially harmful traits by the same gene in the other sex, Especially if the gene is located on an autosomal chromosome.
Pleiotropic genes act as a mediator in force speciation. William R. Rice and Allen E. Hostert (1993) concluded that the prezygotic isolation observed in their study is a product of the balancing role of pleiotropy in indirect selection. By mimicking the traits of all-infertile hybrid species, they observed that fertilization of the eggs was prevented in all eight of their separate studies, a possible effect of pleiotropic genes on the species. [15] Similarly, stabilizing selection of pleiotropic genes allows the allele frequency to change. [16]
Studies on fungal evolutionary genomics have shown pleiotropic traits that simultaneously affect adaptation and reproductive isolation, converting adaptation directly into speciation. A particularly telling case of this effect is host specificity in pathogenic Ascomycetes and, in particular, in venturia , the fungus responsible for apple scab. These parasitic fungi are each adapted to a single host, and are able to mate only within a shared host after obtaining a resource. [17]Since a single toxin gene or virulence allele can confer the ability to colonize the host, adaptation and reproductive isolation are immediately facilitated, and in turn, lead to pleiotropically adaptive species. Studies on fungal evolutionary genomics will further elucidate the early stages of divergence as a result of gene flow, and provide insight into pleiotropically induced adaptive divergence in other eukaryotes. [17]
Anti pulmonary
Sometimes, a pleiotropic gene can be both harmful and beneficial to an organism, which is called antagonistic pleiotropy . This can happen if the trait is beneficial for the organism’s early life, but not for its later life. Such “trade-offs” are possible because natural selection affects traits expressed earlier in life, when most organisms are most fertile, than traits expressed later in life. [18]
This idea is central to the anti-pleiotropy hypothesis, which was first developed by G. C. Williams. Williams in 1957 suggested that certain genes responsible for increased fitness in young, fertile organisms contribute, the latter to decreased fitness. in life, which could give an evolutionary explanation for old age. An example is the p53 gene, which suppresses cancer but also suppresses stem cells, which repair damaged tissue.
Unfortunately, the process of opposing pleiotropy can result in an altered evolutionary path with delayed adaptation, in addition to effectively cutting the overall advantage of either allele by about half. However, antagonism pleiotropy gives more evolutionary “staying power” to genes controlling beneficial traits, as an organism with mutations in those genes will be less likely to reproduce successfully, as many traits will be affected, potentially worse. For. [19]
Sickle cell anemia is a classic example of the compound advantage given by the staying power of pleiotropic genes, as mutation of Hb-S confers fitness advantage to malaria resistance to malaria, whereas homozygotes have significantly reduced life expectancy. Since these two states are linked by the same mutated gene, today a large population is susceptible to sickle cell, although it is a fitness-impairing genetic disorder. [20]
Example
Colorlessness
Albinism is a mutation of the TYR gene, also known as tyrosinase. This mutation causes the most common form of albinism. The mutation alters the production of melanin, affecting melanin-related and other dependent traits throughout the organism. Melanin is a substance made by the body that is used to absorb light and provide color to the skin. The absence of color in an organism’s eyes, hair and skin due to a lack of melanin are signs of albinism. Some forms of albinism are also known to have symptoms that manifest through rapid eye movements, light sensitivity, and strabismus. [21]
Autism and schizophrenia
Pleiotropy in genes has also been linked to some mental disorders. Deletion in the 22q11.2 region of chromosome 22 is associated with schizophrenia and autism. [22] [23] Schizophrenia and autism have been linked to the same gene deletion but manifest themselves in very different ways. The resulting phenotype depends on the stage of life at which the individual develops the disorder. Childhood expression of gene deletions is commonly associated with autism, whereas adolescent and later expression of gene deletions often manifest in schizophrenia or other psychiatric disorders. [24] Although the disorders are linked to genetics, no increased risk for adult schizophrenia has been found in patients who experienced autism in childhood. [25]
A 2013 study also linked five psychiatric disorders genetically, 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 affect cognition. It has been associated with autism, as well as schizophrenia and bipolar disorder in studies. [26] These specific studies suggest that these diseases tend to cluster in the patients themselves or in families. [27] Schizophrenia has an estimated heritability of 70% to 90%, [28] so pleiotropy of the gene is important because it causes an increased risk for certain psychiatric disorders and may aid in psychiatric diagnosis.
Phenylketonuria (PKU)
A common example of pleiotropy is the human disease phenylketonuria (PKU). The disease causes mental retardation and reduced pigmentation of hair and skin, and may be caused by a large number of mutations in a single gene on chromosome 12 that codes for the enzyme phenylalanine hydroxylase, which cleaves the amino acid phenylalanine. Converts to tyrosine. Depending on the mutation involved, this conversion is reduced or eliminated entirely. Unchanged phenylalanine builds up in the bloodstream and can lead to levels that are toxic to the developing nervous system of newborns and infants. Its most dangerous form is called classic PKU, which is common in infants. The child seems normal at first but actually suffers from permanent intellectual disability. This mental retardation, abnormal gait and posture, and can cause symptoms such as delayed development. Because tyrosine is used by the body to make melanin (a component of a pigment found in hair and skin), failure to convert normal levels of phenylalanine into tyrosine can lead to fair hair and skin.[2] The frequency of this disease varies greatly. Specifically, in the United States, PKU is found at a rate of about 1 in 10,000 births. Newborn screening allows doctors to detect PKU early in the baby. This allows them to start treatment early, to prevent the child from suffering the severe effects of PKU. PKU is caused by a mutation in the PAH gene, whose role is to instruct the body to make phenylalanine hydroxylase. Phenylalanine hydroxylase is what converts phenylalanine taken through the diet into other things the body can use. Mutations often reduce the effectiveness or rate at which the hydroxylase breaks down phenylalanine. This is the reason why phenylalanine builds up in the body. [29]The way to treat PKU is to manage your diet. Phenylalanine is ingested through food, so the diet should reduce foods that contain high amounts of phenylalanine. Foods with high levels of protein should be avoided. These include breast milk, eggs, chicken, beef, pork, fish, nuts and other foods. A special PKU formula can be obtained for having protein in the body. [30]
Sickle cell anemia
Photomicrograph of normal size and sickle-shaped red blood cells from a patient with sickle cell disease
Sickle cell anemia is a genetic disease that causes deformed red blood cells to have a rigid, crescent-shaped shape instead of the normal flexible, round shape. [31] It is caused by a change in a nucleotide, a point mutation [32] in the HbB gene. The HbB gene encodes information for making the beta-globin subunit of hemoglobin, a protein red blood cells use to carry oxygen throughout the body. Sickle cell anemia occurs when the Hbb gene mutation causes the conversion of both beta-globin subunits of hemoglobin to hemoglobin S (HbS). [33]
Sickle cell anemia is a pulmonary disease because expression of a single mutated HbB gene produces multiple consequences throughout the body. The mutated hemoglobin forms polymers and clumps together causing deoxygenated sickle red blood cells to assume a distorted sickle shape. [34] As a result, cells are inflexible and cannot flow easily through blood vessels, increasing the risk of blood clots and possibly depriving vital organs of oxygen. [33] Some of the complications associated with sickle cell anemia include pain, damaged limbs, stroke, high blood pressure, and loss of vision. Sickle red blood cells also have a short life span and die prematurely. [35]
Marfan syndrome
Marfan syndrome (MFS) is an autosomal dominant disorder that affects 1 in 5–10,000 people. [36] MFS results from a mutation in the FBN1 gene, which encodes for the glycoprotein fibrillin-1, a major component of the extracellular microfibrils that make up connective tissue. [36] More than 1,000 different mutations in FBN1 have been found to result in abnormal function of fibrillin, which results in connective tissues that progressively grow and weaken. Since these fibers are found throughout the body’s tissues, mutations in this gene can have widespread effects on the skeletal, cardiovascular and nervous systems as well as some systems including the eyes and lungs. [36]
Without medical intervention, the prognosis of Marfan syndrome can range from moderate to life-threatening, with 90% of known causes of death in diagnosed patients related to cardiac complications and congestive cardiac failure. Other features of MFS include an increased arm span and decreased upper to lower body ratio. [36]
“Mini-muscle” allele
A gene recently discovered in laboratory house mice, termed “mini-muscle”, when mutated, has as its primary effect a 50% reduction in hindlimb muscle mass (the phenotypic effect by which it was originally identified). had gone). [9] In addition to smaller hindlimb muscle mass, mutant mice have a lower heart rate during physical activity, and a higher endurance. Mini Muscle mice also display larger kidneys and livers. All these morphological deviations affect the behavior and metabolism of the mouse. For example, mice with the mini muscle mutation have higher aerobic capacity per gram. [37] The mini-muscle allele shows a Mendelian recessive behavior. [10]The mutation is a single nucleotide polymorphism (SNP) in an intron of the myosin heavy polypeptide 4 gene. [38]
DNA repair protein
DNA repair pathways that repair damage to cellular DNA use many different proteins. These proteins often have other functions in addition to DNA repair. [39] In humans, defects in some of these multifunctional proteins can cause widely varying clinical phenotypes. [39] As an example, mutations in the XPB gene that encodes the largest subunit of basal transcription factor II H have several pleiotropic effects. XPB mutations are known to impair DNA’s nucleotide excision repair and a completely different process of gene transcription. [39] In humans, XPBMutations can lead to the cancer-prone disorder xeroderma pigmentosum or the non-cancer-prone multisystem disorder trichothiodystrophy. Another example in humans is the ERCC6 gene, which encodes a protein that mediates DNA repair, transcription and other cellular processes throughout the body. [40] Mutations in ERCC6 are associated with disorders of the eye (retinal dystrophy), heart (cardiac arrhythmias), and immune system (lymphocyte immunodeficiency). [41]
Chicken’s
Chickens exhibit various traits influenced by pleiotropic genes. Some chickens display the feature of curly plumage, where their feathers curl outwards and upwards instead of lying flat against the body. The frizzle feather was found to stem from a deletion in the genomic region coding for α-keratin. This gene seems to be pleiotropically giving rise to other abnormalities such as increased metabolism, high food consumption, accelerated heart rate and delayed sexual maturation. [42]
Domesticated chickens underwent a rapid selection process, which led to high correlations in unrelated phenotypes, suggesting a pleiotropic, or at least close relationship, effect between comb mass and anatomical structures related to reproductive abilities. Both males and females with larger combs have higher bone density and strength, which allows females to store more calcium in the eggshell. This association is further substantiated by the fact that two genes, HAO1 and BMP2, affecting the medullary bone (the part of the bone that transports calcium to the developing testicle) are located in the same locus where the gene Affects the comb mass. HAO1 and BMP2 also exhibit pleiotropic effects with commonly desired domestic chicken behavior; Chickens that express high levels of these two genes in bone tissue,
