Pleiotropy

Pleiotropic traits had been previously recognized in the scientific community but had not been experimented on until Gregor Mendel's 1866 pea plant experiment. 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 Festschrift, which was published in 1910. He originally defined pleiotropy as occurring when "several characteristics are dependent upon ... [inheritance]; these characteristics will then always appear together and may thus appear correlated". This definition is still used today. After Plate's definition, Hans Gruneberg was the first to study the mechanisms of pleiotropy. Through subsequent research, it has been established that Gruneberg's definition of "spurious" pleiotropy is what we now identify simply as "pleiotropy". This hypothesis shifted future research regarding pleiotropy towards how a single gene can produce various phenotypes. In the mid-1950s Richard Goldschmidt and Ernst Hadorn, through separate individual research, reinforced the faultiness of "genuine" pleiotropy. A few years later, Hadorn partitioned pleiotropy into a "mosaic" model (which states that one locus directly affects two phenotypic traits) and a "relational" model (which is analogous to "spurious" pleiotropy). These terms are no longer in use but have contributed to the current understanding of pleiotropy. Expanding on Fisher's work, Sewall Wright provided more evidence in his 1968 book Evolution and the Genetics of Populations: Genetic and Biometric Foundations by using molecular genetics to support the idea of "universal pleiotropy". The concepts of these various studies on evolution have seeded numerous other research projects relating to individual fitness. ==Mechanism==

Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. Recent genetic research distinguishes between three forms of pleiotropy: Biological pleiotropy Biological pleiotropy also known as horizontal pleiotropy is when a causal variant or gene has direct and independent effects on more than one phenotypes. There are two sub-types of biological pleiotropy, single-gene pleiotropy and multigene regulatory pleiotropy. Single-gene pleiotropy Causal risk variants can affect several traits by acting on a single gene that has many different effects. There are several ways that this kind of gene pleiotropy can happen, and these possibilities can overlap. For example, a gene might have more than one molecular function, be involved in several separate biological pathways or cellular processes, or be active in different organs, tissues, or times and places in the body, each influencing different traits. Also, one gene can produce different versions of a protein, called isoforms, which vary in structure and function and contribute to the gene's wide range of effects. Multigene regulatory pleiotropy Pleiotropy also occurs when a causal variant changes the expression of many genes. Every one of these genes may play a role in shaping different phenotypic outcomes. Regulatory pleiotropy can also arise from genetic influences on the 3D structure of chromosomes. Network pleiotropy Another model that has been proposed is network pleiotropy. In this model, a single causal variant influences several traits through one or more intermediate cell types within the same network. It may be especially useful for explaining multi-dimensional psychiatric disorders such as schizophrenia and bipolar disorder. == Polygenic risk scores and pleiotropy in complex traits ==

One of the key challenges is to figure out if a gene actually influences more than one trait. One reason is that it's not always clear how traits should be grouped or named when studying them. Another challenge is that many of the methods used to test for pleiotropy, do it in an indirect way. Usually, these methods start by assuming that a gene doesn't affect any traits, and then look for evidence to prove otherwise. To solve this, researchers have developed better ways to test if a gene affects several traits at the same time, using methods that don't rely on these indirect assumptions. Early genome-wide association studies (GWAS) that revealed links between many genetic loci and multiple traits were often described in terms of cross-phenotype (CP) associations. When such associations can be traced back to a shared biological mechanism at the causal locus, they can be more precisely defined as pleiotropic effects. Genome-wide association studies and machine learning analysis of large-scale genomic data have made it possible to develop SNP-based polygenic predictors for complex human traits. The goal of GWAS was to identify how strongly a specific genetic variant, typically a single-nucleotide polymorphism (SNP), is associated with a particular human trait. One way to quantify pleiotropy is by measuring the proportion of shared genetic variance between two complex traits. Analyses of hundreds of trait pairs have shown that often, the genomic regions involved are largely distinct, with only modest overlap. This suggests that, for the complex traits studied so far, pleiotropy is generally limited. Still, identifying genetic variants through GWAS and linking them to biological pathways offers valuable opportunities to improve diagnosis, develop new therapies, and better prevent diseases. Polygenic risk scores (PRS), built from these findings, holds promise for predicting individual risk for various conditions. However, while PRS has many strengths, their predictive power remains probabalistic. The accuracy and reliability of these scores are currently under scrutiny, emphasizing the need for cautious interpretation when applying them to clinical or public health contexts. == Models for the origin ==

One basic model of pleiotropy's origin describes a single gene locus that influences one trait. At first, this gene only affects the trait by changing how other genes are expressed. Over time, that locus would affect two traits by interacting with a second locus. If both traits are favored by natural selection at the same time, the connection between them becomes stronger. But, if only one trait is selected for, the connection weakens. Eventually, traits that underwent directional selection simultaneously were linked by a single gene, resulting in pleiotropy. The "pleiotropy-barrier" model proposes a logistic growth pattern for the increase of pleiotropy over time. This model differentiates between the levels of pleiotropy in evolutionarily younger and older genes subjected to natural selection. It suggests a higher potential for phenotypic innovation in evolutionarily newer genes due to their lower levels of 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. == Evolution ==

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 pleiotropyas the number of traits of an organism increases, the evolutionary rates of genes in the organism's population decrease. This relationship has not been clearly found in empirical studies for a long time. However, a study based on human disease genes revealed the evidence of lower evolutionary rate in genes with higher pleiotropy. 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 the result of selection on two independent genes, one that affects the signaling trait and one that affects the receptor trait. 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 beneficial 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. Pleiotropic genes act as an arbitrating force in speciation. William R. Rice and Ellen E. Hostert (1993) conclude that the observed prezygotic isolation in their studies is a product of pleiotropy's balancing role in indirect selection. By imitating the traits of all-infertile hybridized species, they noticed that the fertilization of eggs was prevented in all eight of their separate studies, a likely effect of pleiotropic genes on speciation. Likewise, pleiotropic gene's stabilizing selection allows for the allele frequency to be altered. 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. 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. This idea is central to the antagonistic pleiotropy hypothesis, which was 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 p53 gene, which suppresses cancer but also suppresses stem cells, which replenish worn-out tissue. Antagonistic pleiotropy can manifest in many ways, depending on the contexts in which its positive and negative effects occur. These effects may arise in different stages of an life. For example can certain alleles of ORL1 (lectin-like low-density lipoprotein receptor 1) enhance the immune defense in early life but also, increase the risk of cardiovascular disease later. It is also a possibility, that positive and negative effects can occur at the same time, for example some alleles of the androgen receptor (AR), which appears to lower the risk of getting breast cancer at the same time increasing the risk of ovarian cancer. 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 as sickle cell trait, while homozygotes have significantly lowered life expectancy—what is known as "heterozygote advantage". 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. == Examples ==

Human 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, thereby 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 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. Phenylketonuria (PKU) A common example of pleiotropy is the human disease phenylketonuria (PKU). This disease causes intellectual disability 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, this conversion 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. The most dangerous form of this is called classic PKU, which is common in infants. The baby seems normal at first but actually incurs permanent intellectual disability. This can cause symptoms such as intellectual disability, abnormal gait and posture, and delayed growth. Because tyrosine is used by the body to make melanin (a component of the pigment found in the hair and skin), failure to convert normal levels of phenylalanine to tyrosine can lead to fair hair and skin. Sickle cell anemia 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. It is caused by a change in one nucleotide, a point mutation in the HBB gene. The HBB gene encodes information to make the beta-globin subunit of hemoglobin, which is the protein red blood cells use to carry oxygen throughout the body. Sickle cell anemia occurs when the HBB gene mutation causes both beta-globin subunits of hemoglobin to change into hemoglobinS (HbS). Sickle cell anemia is a pleiotropic disease because the expression of a single mutated HBB gene produces numerous consequences throughout the body. The mutated hemoglobin forms polymers and clumps together causing the deoxygenated sickle red blood cells to assume the disfigured sickle shape. As a result, the cells are inflexible and cannot easily flow through blood vessels, increasing the risk of blood clots and possibly depriving vital organs of oxygen. Marfan syndrome Marfan syndrome (MFS) is an autosomal dominant disorder which affects 1 in 5–10,000 people. MFS arises from a mutation in the FBN1 gene, which encodes for the glycoprotein fibrillin-1, a major constituent of extracellular microfibrils which form connective tissues. This implies that, rather than these loci being associated with just one type of pain, many genetic loci contribute to susceptibility to various forms of pain, including headaches, muscle pain, and chronic pain. These pleiotropic loci were classified into four groups: loci associated with nearly all pain traits, loci associated with a specific type of pain, loci associated with multiple forms of musculoskeletal pain, and loci associated with headaches. Additionally, pleiotropy was not limited to different types of pain but also extended to psychiatric, metabolic, and immunological traits. Genetic correlations were found between pain susceptibility and conditions such as depression, increase of body mass index, asthma, and cardiovascular diseases. Animals Chickens 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. 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 two of the 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; those chickens who express higher levels of these two genes in bone tissue produce more eggs and display less egg incubation behavior. Pleiotropy in psychiatry Autism and schizophrenia Pleiotropy in genes has been linked between certain psychiatric disorders as well. Deletion in the 22q11.2 region of chromosome 22 has been associated with schizophrenia and autism. Schizophrenia and autism are linked to the same gene deletion but manifest very differently from each other. The resulting phenotype depends on the stage of life at which the individual develops the disorder. 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. Though the disorders are linked by genetics, there is no increased risk found for adult schizophrenia in patients who are autistic. These particular studies show clustering of these diseases within patients themselves or families. The estimated heritability of schizophrenia is 70% to 90%, therefore the pleiotropy of genes is crucial since it causes an increased risk for certain psychotic disorders and can aid psychiatric diagnosis. Through looping in three-dimensional space, distant non-coding regulatory elements, sometimes located several megabases away from gene promoters, can physically interact with and influence the expression of specific genes. For example, there is a genetic variant located upstream of the PCDH gene clusters that play a role in brain development and has been shown to impact the expression of several protocadherin genes. These genes have been linked to schizophrenia and major depressive disorder. The mini-muscle allele shows a mendelian recessive behavior. Cellular functions and DNA repair DNA repair proteins DNA repair pathways that repair damage to cellular DNA use many different proteins. These proteins often have other functions in addition to DNA repair. In humans, defects in some of these multifunctional proteins can cause widely differing clinical phenotypes. Mutations in ERCC6 are associated with disorders of the eye (retinal dystrophy), heart (cardiac arrhythmias), and immune system (lymphocyte immunodeficiency). == See also ==