Pleiotropy
Pleiotropy (from Greek πλείων pleion, 'more', and τρόπος tropos, 'way') occurs when one gene influences two or more seemingly unrelated phenotypic traits.
[1] An example of pleiotropy is phenylketonuria, an inherited disorder that affects the level of phenylalanine, an amino acid that can be obtained from food, in the human body.
[3] 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.
[3] 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 mathematical model illustrates how evolutionary fitness depends on the independence of phenotypic variation from random changes (that is, mutations).
[1] 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.
Knowing this, Williams argued that if only close linkage was present, then beneficial traits will occur both before and after reproduction due to natural selection.
In this context pleiotropy refers to the influence that a specific genetic variant, e.g., a single nucleotide polymorphism or SNP, has on two or more distinct traits.
Genome-wide association studies (GWAS) and machine learning analysis of large genomic datasets have led to the construction of SNP based polygenic predictors for human traits such as height, bone density, and many disease risks.
It suggests a higher potential for phenotypic innovation in evolutionarily newer genes due to their lower levels of pleiotropy.
William R. Rice and Ellen E. Hostert (1993) conclude that the observed prezygotic isolation in their studies is a product of pleiotropy's balancing role in indirect selection.
By imitating the traits of all-infertile hybridized species, they noticed that the fertilization of eggs was prevented in all eight of their separate studies, a likely effect of pleiotropic genes on speciation.
[13] Unfortunately, the process of antagonistic pleiotropy may result in an altered evolutionary path with delayed adaptation, in addition to effectively cutting the overall benefit of any alleles by roughly half.
Since both of these states are linked to the same mutated gene, large populations today are susceptible to sickle cell despite it being a fitness-impairing genetic disorder.
[26] The estimated heritability of schizophrenia is 70% to 90%,[27] therefore the pleiotropy of genes is crucial since it causes an increased risk for certain psychotic disorders and can aid psychiatric diagnosis.
Unconverted phenylalanine builds up in the bloodstream and can lead to levels that are toxic to the developing nervous system of newborn and infant children.
The HBB gene encodes information to make the beta-globin subunit of hemoglobin, which is the protein red blood cells use to carry oxygen throughout the body.
[31] Sickle cell anemia is a pleiotropic disease because the expression of a single mutated HBB gene produces numerous consequences throughout the body.
[31] Some complications associated with sickle cell anemia include pain, damaged organs, strokes, high blood pressure, and loss of vision.
[34] MFS arises from a mutation in the FBN1 gene, which encodes for the glycoprotein fibrillin-1, a major constituent of extracellular microfibrils which form connective tissues.
[34] Over 1,000 different mutations in FBN1 have been found to result in abnormal function of fibrillin, which consequently relates to connective tissues elongating progressively and weakening.
[34] Without medical intervention, prognosis of Marfan syndrome can range from moderate to life-threatening, with 90% of known causes of death in diagnosed patients relating to cardiovascular complications and congestive cardiac failure.
[9] In addition to smaller hindlimb muscle mass, the mutant mice exhibit lower heart rates during physical activity, and a higher endurance.
[36] In the context of pain, pleiotropy refers to the ability of a single gene or genomic region to influence multiple pain-related traits.
A study that conducted a genome-wide association joint analysis of 17 pain-related traits revealed that many of the 99 identified risk loci are pleiotropic.
Genetic correlations were found between pain susceptibility and conditions such as depression, increase of body mass index, asthma, and cardiovascular diseases.
[38] As an example, mutations in the XPB gene that encodes the largest subunit of the basal Transcription factor II H have several pleiotropic effects.
[39] Mutations in ERCC6 are associated with disorders of the eye (retinal dystrophy), heart (cardiac arrhythmias), and immune system (lymphocyte immunodeficiency).
This gene seems to pleiotropically lead to other abnormalities like increased metabolism, higher food consumption, accelerated heart rate, and delayed sexual maturity.
[41] Domesticated chickens underwent a rapid selection process that led to unrelated phenotypes having high correlations, suggesting pleiotropic, or at least close linkage, effects between comb mass and physiological structures related to reproductive abilities.
