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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 when "several characteristics are dependent upon it [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. 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 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 which 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 (states that one locus directly affects two phenotypic traits) and a “relational” model (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 (i.e. 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.

In 1957, evolutionary biologist George C. Williams theorized that antagonistic effects will be exhibited during an organism’s life cycle if it is closely linked and pleiotropic. Natural selection favors genes that are more beneficial prior to reproduction than after (i.e. increase in reproductive success). Knowing this, Williams argued that if only close linkage was present, beneficial traits will occur both before and after reproduction due to natural selection. This, however, is not observed in nature and antagonistic pleiotropy contributes to the slow deterioration with age (senescence).