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Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits, an example being phenylketonuria, which is a human disease that affects multiple systems but is caused by one gene defect. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously. Pleiotropic gene action can limit the rate of multivariate evolution when natural selection, sexual selection or artificial selection on one trait favours one specific version of the gene (allele), while selection on other traits favors a different allele. The underlying mechanism of pleiotropy in most cases is the effect of a gene on metabolic pathways that contribute to different phenotypes. Genetic correlations and hence correlated responses to selection most often exemplify pleiotropy.
The term "pleiotropie" was coined in a 1910 Festschrift written by the German geneticist Ludwig Plate, a former student of Ernst Haeckel. The term "polyphaeon" was also suggested in 1925 by Haeckel but did not persist. Even before the term was proposed there were examples of distinct traits that seemed to be inherited together. In his classic 1866 paper, Gregor Mendel listed his trait number three in peas as having brown seed coat, violet flowers, and axial spots.
Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. The underlying mechanism is that the gene codes for a product that is, for example, used by various cells, or has a signaling function on various targets.
A classic example of pleiotropy is the human disease phenylketonuria (PKU). This disease can cause mental retardation and reduced hair and skin pigmentation, and can be caused by any of a large number of mutations in a single gene that codes for the enzyme phenylalanine hydroxylase, which converts the amino acid phenylalanine to tyrosine, another amino acid. Depending on the mutation involved, conversion of phenylalanine to tyrosine is reduced or ceases entirely. Unconverted phenylalanine concentrates in the bloodstream and can rise to levels that are toxic to the developing nervous system of newborn and infant children and which can cause effects such as mental retardation and abnormal gait and posture.
Because tyrosine is used by the body to make melanin (an important component of the pigment found in hair and skin) the failure to convert normal levels of phenylalanine to tyrosine results in less pigmentation being produced causing the fair hair and skin typically associated with phenylketonuria.
By excluding phenylalanine from the diet until adulthood, it is possible to avoid injury to the developing nervous system, neutralizing the particular effects that can result from toxic levels of phenylalanine, without having any effect on the low pigmentation production caused by the reduced levels of tyrosine.
A gene recently discovered in laboratory house mice, termed "mini-muscle," causes a 50% reduction in hindlimb muscle mass as its primary effect (the phenotypic effect by which it was originally identified:), in addition to various effects on behavior, skeletal morphology, relative size of internal organs, and metabolism. The mini-muscle allele behaves as a Mendelian recessive. Perhaps surprisingly, the mutation is a single nucleotide polymorphism (SNP) in an intron of the Myosin heavy polypeptide 4 gene.
This is central to the antagonistic pleiotropy hypothesis, 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. An example is the p53 gene, which suppresses cancer, but also suppresses stem cells, which replenish worn-out tissue.
Pleiotropy affects the evolutionary rate of genes and allele frequencies. Traditionally, it has been expected that evolutionary rate of genes is related negatively with pleiotropy. However, this has not been clearly found in empirical studies. Contrary to this traditional expectation, it has been theoretically demonstrated that evolutionary rate should be positively related with pleiotropy by itself as the square root of gene pleiotropy; however, other effects of pleiotropy may explain why a clear relationship between evolutionary rate and gene pleiotropy has not been found at the genomic scale.
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