pleiotropism

The control by a single gene of several distinct and seemingly unrelated phenotypic effects.

[Greek pleiōn, more + -TROPISM.]

Pleiotropy is the phenomenon whereby a single gene has multiple consequences in numerous tissues. Pleiotropic effects stem from both normal and mutated genes, but those caused by mutations are often more noticeable and easier to study. Pleiotropy is actually more common than its opposite, since in a complex organism, a protein from a single gene is likely to be expressed in more than one tissue, and the cascade of problems caused by a mutation is likely to lead to numerous complications throughout the organism. Single-gene defects with effects in only one tissue are more common for nonessential features such as hair texture or eye color.

Sickle cell disease is a classic example of pleiotropy. This disease develops in persons carrying two defective alleles for a blood protein, beta-hemoglobin. Mutant beta-hemoglobins are misaligned inside a blood cell and cause misshapen red blood cells at low oxygen concentrations. Deformed blood cells impair circulation. Impaired circulation damages kidneys and bone. In this case, the gene defect itself only affects one tissue, the blood. The consequences of that defect are found in other tissues and organs.

One baby in three thousand to four thousand births is born with neurofibromatosis, an autosomal dominant disease caused by mutation in a tumor suppressor gene that helps regulate cell division and cell-cell contacts. A truncated version of the tumor suppression protein, neurofibromin (NF I) is implicated in the disease. This mutant protein can come from mis-sense or nonsense mutations, or from reading-frame shifts after a repetitive element called Alu is inserted upstream of the NF I reading frame (a reading frame is the DNA that codes for proteins). Because the mutant protein is unable to regulate cell division, tumors grow on the nerves throughout the body. The tumors produce collateral damage: low blood sugar, intestinal bleeding, café-au-lait spots on the skin, mental retardation, heart problems, high blood pressure, fractures, spinal cord lesions, blindness, aneurysms, arthritis, and respiratory distress.

Signaling Pathways

Many pleiotropic conditions arise from genes whose products are involved in signaling and regulation pathways. Because these proteins coordinate daily life in numerous tissues, defects in them have numerous consequences, as one breakdown leads to another.

Myotonic dystrophy is another autosomal dominant disorder. A gene for a protein—a kinase, involved in signalling and communication within the cell—is burdened with up to three thousand extra pieces of DNA. The extra DNA comes from trinucleotides (CTG)_n that are added by mistake during DNA duplication, both in germ line cells and during early cell divisions in the embryo. During transcription and translation, the kinase is not put together right, and the kinase's work in muscles goes badly. Muscles contract but cannot relax quickly. Young persons may have heart attacks, generalized muscle weakness, and loss of bulk. Swallowing and speech is hard, due to weak muscles in the tongue and neck. Other pleiotropic effects include baldness, cataracts, and changes in intelligence.

Pleiotropic outcomes are common with hormones. Hormones are signals that create multiple responses in tissues that carry receptors for them. The receptor binds to the hormone and triggers a cascade of reactions inside the cell. A defective receptor loses or misinterprets the signal. When the hormone insulin meets defective insulin receptors on an individual's cells, the person is more likely to develop type II diabetes. Cells do not open their gateways to let sugar in from the bloodstream, and the cells almost starve to death in the midst of plenty. Meanwhile, sugar accumulates in the blood and causes all sorts of ramifications for blood circulation, and it damages capillaries in all areas, from kidneys, to eyes, to feet. Gangrene, mental disturbances, kidney failure, and blindness can and do occur. Diminished give-and-take of sugar molecules across cell membranes leads to the multifaceted disease diabetes.

Bibliography

Solomon, Eldra Pearl, and Linda R. Berg. The World of Biology, 5th ed. Philadelphia:Saunders College Publishing, 1995.

Internet Resources

National Center for Biotechnology Information. www.ncbi.nlm.nih.gov.

United States National Library of Medicine. www.nlm.nih.gov.

—Susanne D. Dyby

Pleiotropy refers to a case where one gene may influence several other characteristics. An example of pleiotropy is sickle cell anemia, a disorder in which a single point mutation in the amino acid sequence for hemoglobin results in a spectrum of effects. Red blood cells produce abnormal hemoglobin molecules, which, because of their odd shape, tend to stick together and crystallize. Therefore, the normal disk shape of red blood cells changes to a sickle shape (hence the name of the disorder). Sickle-shaped red blood cells will clog small vessels, causing pain and the possibility of brain damage and heart failure. Since some of the hemoglobin in these cells is abnormal, there is less oxygen available, leading to physical weakness and anemia. If left untreated, the anemia can impair mental function.

The control by a single gene of several distinct and seemingly unrelated phenotypic effects.

This article includes a list of references or external links, but its sources remain unclear because it has insufficient inline citations. Please help to improve this article by introducing more precise citations where appropriate. (April 2009)

Pleiotropy occurs when a single gene influences multiple phenotypic traits. Consequently, a new mutation in the gene may have an effect on some or all traits simultaneously. This can become a problem when selection on one trait favors one specific version of the gene (allele), while the selection on the other trait favors another allele.

Contents 1 Etymology 2 Mechanism 3 Antagonistic pleiotropy 4 See also 5 References

Etymology

The term pleiotropy comes from the Greek πλείων pleion, meaning "more", and τρέπειν trepein, meaning "to turn, to convert". A common mistake is to use "pleiotrophic" instead of "pleiotropic"

Mechanism

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 PKU (phenylketonuria). 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 an enzyme (phenylalanine hydroxylase) that converts the amino acid phenylalanine to tyrosine, another amino acid. Depending on the mutation involved, this results in reduced or zero conversion of phenylalanine to tyrosine, and phenylalanine concentrations increase to toxic levels, causing damage at several locations in the body. PKU is totally benign if a diet free from phenylalanine is maintained.

Antagonistic pleiotropy

Antagonistic pleiotropy refers to the expression of a gene resulting in multiple competing effects, some beneficial but others detrimental to the organism.

This is central to a theory of aging first developed by G. C. Williams in 1957.^[1] Williams suggested that some genes responsible for increased fitness in the younger, fertile organism contribute to decreased fitness later in life. One such example in male humans is the gene for the hormone testosterone. In youth, testosterone has positive effects including reproductive fitness but, later in life, there are negative effects such as increased susceptibility to prostate cancer. Another example is the p53 gene which suppresses cancer, but also suppresses stem cells which replenish worn-out tissue^[2].

Whether or not pleiotropy is antagonistic may depend upon the environment; for instance, a bacterial gene that enhances glucose utilization efficiency at the expense of the ability to use other energy sources (such as lactose) has positive effects when there is plenty of glucose, but can be lethal if lactose is the only available food source.

See also

• Epistasis
• Metabolic network
• Metabolic supermice
• Enhancer (genetics)

References

1. ^ Williams, G.C. (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11: 398–411
2. ^ Rodier F, Campisi J, Bhaumik D (2007). "Two faces of p53: aging and tumor suppression". Nucleic Acids Res 35: 7475. doi:10.1093/nar/gkm744. PMID 17942417. 

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