Pleiotropy

Pleiotropy (from Greek πλείων pleion, 'more', and τρόπος tropos, 'way') occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. 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. Pleiotropy (from Greek πλείων pleion, 'more', and τρόπος tropos, 'way') occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. 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. Pleiotropy can arise from several distinct but potentially overlapping mechanisms, such as gene pleiotropy, developmental pleiotropy, and selectional pleiotropy. Gene pleiotropy occurs when a gene product interacts with multiple other proteins or catalyzes multiple reactions. Developmental pleiotropy occurs when mutations have multiple effects on the resulting phenotype. Selectional pleiotropy occurs when the resulting phenotype has many effects on fitness (depending on factors such as age and gender). An example of pleiotropy is phenylketonuria, an inherited disorder that affects the level of phenylalanine in the human body. Phenylalanine is an amino acid that can be obtained from food. Phenylketonuria causes this amino acid to increase in amount 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 enzyme phenylalanine hydroxylase, 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 mice have 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 allele, while selection on other traits favors a different allele. Some gene evolution is harmful to an organism. Genetic correlations and responses to selection most often exemplify 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 ... ; 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. In 1938 Gruneberg published an article dividing pleiotropy into two distinct types: 'genuine' and 'spurious' pleiotropy. 'Genuine' pleiotropy is when two distinct primary products arise from one locus. 'Spurious' pleiotropy, on the other hand, is either when one primary product is utilized in different ways or when one primary product initiates a cascade of events with different phenotypic consequences. Gruneberg came to these distinctions after experimenting on rats with skeletal mutations. He recognized that 'spurious' pleiotropy was present in the mutation, while 'genuine' pleiotropy was not, thus partially invalidating his own original theory. Through subsequent research, it has been established that Gruneberg's definition of 'spurious' pleiotropy is what we now identify simply as 'pleiotropy'. In 1941 American geneticists George Beadle and Edward Tatum further invalidated Gruneberg's definition of 'genuine' pleiotropy, advocating instead for the 'one gene-one enzyme' hypothesis that was originally introduced by French biologist Lucien Cuénot in 1903. 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. By accepting the one gene-one enzyme hypothesis, scientists instead focused on how uncoupled phenotypic traits can be affected by genetic recombination and mutations, applying it to populations and evolution. This view of pleiotropy, 'universal pleiotropy', defined as locus mutations being capable of affecting essentially all traits, was first implied by Ronald Fisher's Geometric Model in 1930. This mathematical model illustrates how evolutionary fitness depends on the independence of phenotypic variation from random changes (that is, mutations). It theorizes that an increasing phenotypic independence corresponds to a decrease in the likelihood that a given mutation will result in an increase in fitness. 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.