Pleiotropy

Pleiotropy (from Greek πλείων pleion, 'more', and τρόπος tropos, 'way') is a phenomenom in genetics where a single gene or genetic variant influences multiple phenotypic traits. A gene that has such multiple effects is referred to as a pleiotropic gene. Mutations in pleiotropic genes can impact several traits simultaneously, often because the gene product is used in various cells and affects different biological targets through shared signaling pathways.

Pleiotropy can result from several distinct but potentially overlapping mechanisms, including gene pleiotropy, developmental pleiotropy, and selectional pleiotropy. Gene pleiotropy occurs when a gene product interacts with multiple proteins or catalyzes different reactions. Developmental pleiotropy refers to mutations that produce several phenotypic effects during development. Selectional pleiotropy occurs when a single phenotype influences evolutionary fitness in multiple ways (depending on factors such as age and sex).^[1]

There are also three main types of genetic pleiotropic effects when a variant or gene is associated with more than one trait:

• Biological pleiotropy, where a genetic variant directly affects multiple traits through biological pathways.
• Mediated pleiotropy, where a variant influences one trait, which in turn causes changes in a second trait, and
• Spurious pleiotropy, where statistical or methodological biases make it falsely appear as though a variant is associated with multiple traits.^[2]

A well- known example of pleiotropy is phenylketonuria (PKU), a genetic disorder caused by a mutation in a single gene on chromosome 12 that encodes the enzyme phenylalanine hydroxylase. This mutation leads to the accumulation of the amino acid phenylalanine in the body, affecting multiple systems, such as the nervous and integumentary system.^[3]

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. Pleiotropic mutations can sometimes be deleterious, especially when they negatively affect essential traits. Genetic correlations and responses to selection most often exemplify pleiotropy.

Pleiotropy is widespread in the genome, with many genes influencing biological traits and pathways. Understanding pleiotropy is crucial in genome- wide association studies (GWAS), where variants are often linked to multiple traits or diseases.