Editing Pleiotropy

{{short description|Influence of a single gene on multiple phenotypic traits}}
{{About|genetic pleiotropy|drug pleiotropy|Pleiotropy (drugs)}}
[[File:SimpleGenotypePhenotypeMap.jpg|thumb|Simple genotype–phenotype map that only shows additive pleiotropy effects. G1, G2, and G3 are different genes that contribute to phenotypic traits P1, P2, and P3.]]

'''Pleiotropy''' ({{etymology|grc|''{{wikt-lang|grc|πλείων}}'' ({{grc-transl|πλείων}})|more||''{{wikt-lang|grc|τρόπος}}'' ({{grc-transl|τρόπος}})|turn, way, manner, style}}) is a condition in which a single [[gene]] or genetic variant influences multiple [[phenotypic trait]]s. A gene that has such multiple effects is referred to as a ''pleiotropic gene''. [[Mutation]]s in pleiotropic genes can impact several traits simultaneously, often because the gene product is used in various [[cell (biology)|cells]] and affects different biological targets through shared signaling pathways. 

Pleiotropy can result from several distinct but potentially overlapping mechanisms, including [[gene]] pleiotropy, [[developmental biology|developmental]] pleiotropy, and selectional pleiotropy. Gene pleiotropy occurs when a gene product interacts with multiple [[protein]]s or catalyzes different reactions. Developmental pleiotropy refers to [[mutation]]s that produce several [[phenotype|phenotypic]] effects during development. Selectional pleiotropy occurs when a single phenotype influences evolutionary [[fitness (biology)|fitness]] in multiple ways (depending on factors such as age and sex).<ref name="Paaby 66–73">{{Cite journal|last1=Paaby|first1=Annalise B.|last2=Rockman|first2=Matthew V.|date=2016-11-15|title=The many faces of pleiotropy |journal=Trends in Genetics|volume=29 |issue=2|pages=66–73 |doi=10.1016/j.tig.2012.10.010 |pmc=3558540|pmid=23140989}}</ref>

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.<ref>{{Cite journal |last1=Solovieff |first1=Nadia |last2=Cotsapas |first2=Chris |last3=Lee |first3=Phil H. |last4=Purcell |first4=Shaun M. |last5=Smoller |first5=Jordan W. |date=July 2013 |title=Pleiotropy in complex traits: challenges and strategies |journal=Nature Reviews Genetics |language=en |volume=14 |issue=7 |pages=483–495 |doi=10.1038/nrg3461 |issn=1471-0056 |pmc=4104202 |pmid=23752797}}</ref>

A well- known example of pleiotropy is [[phenylketonuria|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]].<ref name="National Center for Biotechnology Information-1998">{{cite book |chapter=Phenylketonuria |title=Genes and Disease |date=1998 |publisher=National Center for Biotechnology Information |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK22253/ }}</ref>

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 correlation]]s 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 catalog|GWAS)]], where variants are often linked to multiple traits or diseases.

==History==
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;<ref name="Stearns-2016">{{Cite journal|last=Stearns|first=Frank W.|date=2016-11-15|title=One Hundred Years of Pleiotropy: A Retrospective |journal=Genetics |volume=186 |issue=3 |pages=767–773 |doi=10.1534/genetics.110.122549 |pmc=2975297 |pmid=21062962}}</ref> however, their [[Correlation and dependence|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.<ref name="Stearns-2016">{{Cite journal|last=Stearns|first=Frank W.|date=2016-11-15|title=One Hundred Years of Pleiotropy: A Retrospective |journal=Genetics |volume=186 |issue=3 |pages=767–773 |doi=10.1534/genetics.110.122549 |pmc=2975297 |pmid=21062962}}</ref> He originally defined pleiotropy as occurring when "several characteristics are dependent upon&nbsp;... [inheritance]; these characteristics will then always appear together and may thus appear correlated".<ref>{{Cite journal|last=McKusick|first=V A |date=1976-05-01 |title=Letter: Pleiotropism.|journal=American Journal of Human Genetics|volume=28|issue=3|pages=301–302 |pmc=1685011|pmid=1266859}}</ref> This definition is still used today.

After Plate's definition, [[Hans Grüneberg|Hans Gruneberg]] was the first to study the [[Mechanism (biology)|mechanisms]] of pleiotropy.<ref name="Stearns-2016" /> 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 (genetics)|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 [[Phenotype|phenotypic]] consequences. Gruneberg came to these distinctions after experimenting on rats with skeletal [[mutation]]s. He recognized that "spurious" pleiotropy was present in the mutation, while "genuine" pleiotropy was not, thus partially invalidating his own original [[theory]].<ref>Gruneberg, H., 1938 An analysis of the "pleiotropic" effects of a new lethal mutation in the rat (Mus norvegicus). Proc. R. Soc. Lond. B 125: 123–144.</ref> Through subsequent [[research]], it has been established that Gruneberg's definition of "spurious" pleiotropy is what we now identify simply as "pleiotropy".<ref name="Stearns-2016" />

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|"one gene-one enzyme" hypothesis]] that was originally introduced by French biologist [[Lucien Cuénot]] in 1903.<ref name="Stearns-2016" /><ref>{{cite journal |last1=Beadle |first1=G. W. |last2=Tatum |first2=E. L. |title=Genetic Control of Biochemical Reactions in Neurospora |journal=Proceedings of the National Academy of Sciences |date=15 November 1941 |volume=27 |issue=11 |pages=499–506 |doi=10.1073/pnas.27.11.499 |pmid=16588492 |pmc=1078370 |bibcode=1941PNAS...27..499B |doi-access=free }}</ref> 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 (which states that one locus directly affects two phenotypic traits) and a "relational" model (which is analogous to "spurious" pleiotropy). These terms are no longer in use but have contributed to the current understanding of pleiotropy.<ref name="Stearns-2016" />

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 [[Population biology|populations]] and [[evolution]].<ref name="Stearns-2016" /> This view of pleiotropy, "universal pleiotropy", defined as locus mutations being capable of affecting essentially all traits, was first implied by [[Ronald Fisher]]'s [[Fisher's geometric model|Geometric Model]] in 1930. This mathematical model illustrates how evolutionary [[Fitness (biology)|fitness]] depends on the independence of phenotypic variation from random changes (that is, 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.<ref>{{Cite journal |last=Edwards |first=A W |date=2016-11-15 |title=The genetical theory of natural selection |journal=Genetics |volume=154 |issue=4 |pages=1419–1426 |doi=10.1093/genetics/154.4.1419 |pmc=1461012 |pmid=10747041}}</ref> 

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.<ref name="Paaby 66–73" />

In 1957 evolutionary biologist [[George C. Williams (biologist)|George C. Williams]] theorized that antagonistic effects will be exhibited during an organism's [[Biological life cycle|life cycle]] if it is closely linked and pleiotropic. [[Natural selection]] favors genes that are more beneficial prior to [[reproduction]] than after (leading to an increase in [[reproductive success]]). Knowing this, Williams argued that if only close [[Genetic linkage|linkage]] was present, then beneficial traits will occur both before and after reproduction due to natural selection. This, however, is not observed in nature, and thus [[Antagonistic pleiotropy hypothesis|antagonistic pleiotropy]] contributes to the slow deterioration with age ([[senescence]]).<ref>{{cite journal | last1 = Williams | first1 = G. C. | year = 1957 | title = Pleiotropy, natural selection, and the evolution of senescence | journal = Evolution | volume = 11 | issue = 4| pages = 398–411 | doi=10.2307/2406060| jstor = 2406060 }}</ref>

==Mechanism==
Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. Recent genetic research distinguishes between three forms of pleiotropy: 

=== Biological pleiotropy ===
Biological pleiotropy also known as horizontal pleiotropy is when a causal variant or gene has direct and independent effects on more than one phenotypes. There are two sub- types og biological pleiotropy, single- gene pleiotropy and [[Gene family|multigene]] regulatory pleiotropy. 

==== Single- gene pleiotropy ====
Causal risk variants can affect several traits by acting on a single gene that has many different effects. There are several ways that this kind of gene pleiotropy can happen, and these possibilities can overlap. For example, a gene might have more than one molecular function, be involved in several separate biological pathways or cellular processes, or be active in different organs, tissues, or times and places in the body, each influencing different traits. Also, one gene can produce different versions of a protein, called [[Protein isoform|isoforms]], which vary in strucure and function and contribute to the gene's wide range of effects.<ref name=":1">{{Cite journal |last1=Lee |first1=Phil H |last2=Feng |first2=Yen- Chen A. |last3=Smoller |first3=Jordan W |date=Jan 1, 2021 |title=Pleiotropy and Cross-Disorder Genetics Among Psychiatric Disorders |url=https://www.biologicalpsychiatryjournal.com/article/S0006-3223(20)31987-9/abstract |journal=Biological Psychiatry |volume=89 |pages=20–31|doi=10.1016/j.biopsych.2020.09.026 |pmid=33131714 |pmc=7898275 }}</ref>

==== Multigene regulatory pleiotropy ====
Pleiotropy also occurs when a causal variant changes the expression of many genes. Every one of these genes may play a role in shaping different phenotypic outcomes. Regulatory pleiotropy can also arise from genetic influences on the 3D structure of chromosomes.<ref name=":1" />

=== Mediated pleiotropy ===
Also known as vertical pleiotropy and happens when a causal variant effect on one trait which itself causes effect on a different trait. An example of mediated pleiotropy is that gene variants that affect low-density lipoprotein (LDF) also affect coronary artery disease. <ref name=":1" />

=== Spurious pleiotropy ===
Sometimes, what looks like pleiotropy can be caused by problems in how the study is designed or how risk genes and traits are defined, leading to incorrect conclusions about pleiotropy. Spurious pleiotropy occures when there is a misclassification either at the genomic level or  the phenotypic level. At the genomic level, this might happen when a region of the [[genome]] linked to a special trait includes causal variants that are related. When this is the case, variants that influence different phenotypes through separate biological mechanisms may wrongly appear as a single pleiotropic locus. <ref name=":1" />

=== Other ===

==== Polygenicity- induced horizontal pleiotropy ====
There has been introduced a fourth type, polygenicity- induced horizontal pleiotropy, where several genetic loci with causal effects could be linked to multiple phenotypic traits. <ref name=":2">{{Cite journal |last=Fisch |first=Gene S. |date=2022-08-01 |title=Associating complex traits with genetic variants: polygenic risk scores, pleiotropy and endophenotypes |url=https://link.springer.com/article/10.1007/s10709-021-00138-2 |journal=Genetica |language=en |volume=150 |issue=3 |pages=183–197 |doi=10.1007/s10709-021-00138-2 |pmid=34677750 |issn=1573-6857|url-access=subscription }}</ref>

==== Network pleiotropy ====
Another model that has been proposed is network pleiotropy. In this model, a single causal variant influences several traits through one or more intermediate cell types within the same network. It may be especially useful for explaining multi-dimensional psyciatric disorders such as [[Schizophrenia|schizofrenia]] and [[bipolar disorder]].<ref name=":2" />

== Polygenic risk scores and pleiotropy in complex traits ==
One of the key challenges is to figure out if a gene actually influences more than one trait. One reason is that it's not always clear how traits should be grouped or named when studying them. Another challenge is that many of the methods used to test for pleiotropy, do it in an indirect way. Usually, these methods start by assuming that a gene doesn't affect any traits, and then look for evidence to prove otherwise. To solve this, researchers have developed better ways to test if a gene affects several traits at the same time, using methods that don't rely on these indirect assumptions. <ref name=":2" />

Early [[Genome-wide association study|genome- wide association studies (GWAS)]] that revealed links between many genetic loci and multiple traits were often described in terms of cross- phenotype (CP) associations. When such associations can be traced back to a shared biological mechanism at the causal locus, they can be more precisely defined as pleiotropic effects. <ref name=":2" />

[[Genome-wide association study|Genome-wide association studies]] (GWAS) and machine learning analysis of large- scale genomic data have made it possible to develop SNP- based polygenic predictors for complex human traits. The goal of GWAS was to identify how strongly a specific genetic variant, typically a [[SNP genotyping|single- nucleotide polymorphism (SNP]]), is associated with a particular human trait. <ref name=":2" />  

One way to quantify pleiotropy is by measuring the proportion of shared genetic variance between two complex traits. Analyses of hundreds of trait pairs have shown that often, the genomic regions involved are largely distinct, with only modest overlap. This suggests that, for the complex traits studied so far, pleiotropy is generally limited. Still, identifying genetic variants through GWAS and linking them to biological pathways offers valuable opportunities to improve diagnosis, develop new therapies, and better prevent diseases. 

[[Polygenic score|Polygenic risk scores]] (PRS), buildt from these findings, holds promise for predicting individual risk for various conditions. However, while PRS has many strengths, their predictive power remains probalistic. The accuracy and reliability of these scores are currently under scrutiny, emphasizing the need for cautious interpretation when applying them to clinical or public health contexts.<ref name=":2" /> 

== Models for the origin ==
One basic model of pleiotropy's origin describes a single gene [[Locus (genetics)|locus]] that influences one trait. At first, this gene only affects the trait by changing how other genes are expressed. Over time, that locus would affect two traits by interacting with a second locus. If both traits are favored by [[natural selection]] at the same time, the connection between them becomes stronger. But, if only one trait is selected for, the connection weakens. Eventually, traits that underwent directional selection simultaneously were linked by a single gene, resulting in pleiotropy. 

The "pleiotropy-barrier" model proposes a logistic growth pattern for the increase of pleiotropy over time.<ref>{{Cite journal |last1=Chen |first1=Jian-Hai |last2=Landback |first2=Patrick |last3=Arsala |first3=Deanna |last4=Guzzetta |first4=Alexander |last5=Xia |first5=Shengqian |last6=Atlas |first6=Jared |last7=Sosa |first7=Dylan |last8=Zhang |first8=Yong E. |last9=Cheng |first9=Jingqiu |last10=Shen |first10=Bairong |last11=Long |first11=Manyuan |date=2025-03-01 |title=Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection |url=https://genome.cshlp.org/content/35/3/379 |journal=Genome Research |language=en |volume=35 |issue=3 |pages=379–392 |doi=10.1101/gr.279498.124 |issn=1088-9051 |pmid=39952680|pmc=11960464 }}</ref> This model differentiates between the levels of pleiotropy in evolutionarily younger and older genes subjected to natural selection. It suggests a higher potential for phenotypic innovation in evolutionarily newer genes due to their lower levels of pleiotropy.

Other more complex models compensate for some of the basic model's oversights, such as multiple traits or assumptions about how the loci affect the traits. They also propose the idea that pleiotropy increases the [[phenotypic variation]] of both traits since a single mutation on a gene would have twice the effect.<ref name="Pavlicev">{{Cite journal |last1=Pavlicev |first1=Mihaela |last2=Cheverud |first2=James |title=Constraints Evolve: Context Dependency of Gene Effects Allows Evolution of Pleiotropy|year=2015|journal=Annual Review of Ecology, Evolution, and Systematics|volume=46|doi=10.1146/annurev-ecolsys-120213-091721|pages=413–434|s2cid=85813898 |doi-access=free}}</ref>

== Evolution ==
Pleiotropy can have an effect on the evolutionary rate of [[gene]]s and [[Allele frequency|allele frequencies]]. Traditionally, models of pleiotropy have predicted that evolutionary rate of genes is related negatively with pleiotropy{{snd}}as the number of traits of an organism increases, the evolutionary rates of genes in the organism's population decrease.<ref name="Wang">{{Cite journal|last1=Wang|first1=Zhi|last2=Liao|first2=Ben-Yang|last3=Zhang |first3=Jianzhi |date=2010-10-19 |title=Genomic patterns of pleiotropy and the evolution of complexity |journal=Proceedings of the National Academy of Sciences |volume=107 |issue=42 |pages=18034–18039|doi=10.1073/pnas.1004666107 |pmc=2964231|pmid=20876104|doi-access=free}}</ref> This relationship has not been clearly found in [[Empirical research|empirical studies]] for a long time.<ref name="Pál">{{cite journal |last1=Pál |first1=Csaba |last2=Papp |first2=Balázs |last3=Hurst |first3=Laurence D |title=Highly Expressed Genes in Yeast Evolve Slowly |journal=Genetics |date=1 June 2001 |volume=158 |issue=2 |pages=927–931 |doi=10.1093/genetics/158.2.927 |pmid=11430355 |pmc=1461684 }}</ref><ref>{{cite journal |last1=Camps |first1=Manel |last2=Herman |first2=Asael |last3=Loh |first3=Ern |last4=Loeb |first4=Lawrence A. |title=Genetic Constraints on Protein Evolution |journal=Critical Reviews in Biochemistry and Molecular Biology |date=January 2007 |volume=42 |issue=5 |pages=313–326 |doi=10.1080/10409230701597642 |pmid=17917869 |pmc=3825456 }}</ref> However, a study based on human disease genes revealed the evidence of lower evolutionary rate in genes with higher pleiotropy.  

In mating, for many animals the signals and receptors of sexual communication may have evolved simultaneously as the expression of a single gene, instead of the result of selection on two independent genes, one that affects the signaling trait and one that affects the [[Receptor (biochemistry)|receptor]] trait.<ref name=Singh>{{cite journal |last1=Singh |first1=Nadia D. |last2=Shaw |first2=Kerry L. |title=On the scent of pleiotropy |journal=Proceedings of the National Academy of Sciences |date=3 January 2012 |volume=109 |issue=1 |pages=5–6 |doi=10.1073/pnas.1118531109 |pmid=22198765 |pmc=3252949 |bibcode=2012PNAS..109....5S |doi-access=free }}</ref> In such a case, pleiotropy would facilitate mating and survival. However, pleiotropy can act negatively as well. A study on seed beetles found that [[intralocus sexual conflict]] arises when selection for certain alleles of a gene that are beneficial for one sex causes expression of potentially harmful traits by the same gene in the other sex, especially if the gene is located on an [[Autosome|autosomal chromosome]].<ref>{{cite journal |last1=Berger |first1=David |last2=Berg |first2=Elena C. |last3=Widegren |first3=William |last4=Arnqvist |first4=Göran |last5=Maklakov |first5=Alexei A. |title=Multivariate intralocus sexual conflict in seed beetles |journal=Evolution |date=December 2014 |volume=68 |issue=12 |pages=3457–3469 |doi=10.1111/evo.12528 |pmid=25213393 |s2cid=12606026 }}</ref>

Pleiotropic genes act as an arbitrating force in [[speciation]]. William R. Rice and Ellen E. Hostert (1993) conclude that the observed [[Reproductive isolation|prezygotic]] isolation in their studies is a product of pleiotropy's balancing role in indirect selection. By imitating the traits of all-infertile [[Hybridisation (biology)|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.<ref>{{cite journal |last1=Kirkpatrick |first1=Mark |last2=Ravigné |first2=Virginie |title=Speciation by Natural and Sexual Selection: Models and Experiments |journal=The American Naturalist |date=March 2002 |volume=159 |issue=S3 |pages=S22–S35 |doi=10.1086/338370 |pmid=18707367 |bibcode=2002ANat..159S..22K |s2cid=16516804 }}</ref> Likewise, pleiotropic gene's [[stabilizing selection]] allows for the allele frequency to be altered.<ref>{{cite journal |last1=Pavličev |first1=Mihaela |last2=Cheverud |first2=James M. |title=Constraints Evolve: Context Dependency of Gene Effects Allows Evolution of Pleiotropy |journal=Annual Review of Ecology, Evolution, and Systematics |date=4 December 2015 |volume=46 |issue=1 |pages=413–434 |doi=10.1146/annurev-ecolsys-120213-091721 |s2cid=85813898 |doi-access=free }}</ref>

Studies on [[Fungus|fungal]] [[Genomics|evolutionary genomics]] have shown pleiotropic traits that simultaneously affect [[adaptation]] and [[reproductive isolation]], converting adaptations directly to [[speciation]]. A particularly telling case of this effect is host specificity in pathogenic [[Ascomycota|ascomycetes]] and specifically, in ''[[Venturia (fungus)|venturia]]'', the fungus responsible for [[apple scab]]. These [[Parasitism|parasitic]] fungi each adapts to a host, and are only able to mate within a shared host after obtaining resources.<ref name="Gladieux 753–773">{{cite journal |last1=Gladieux |first1=Pierre |last2=Ropars |first2=Jeanne |last3=Badouin |first3=Hélène |last4=Branca |first4=Antoine |last5=Aguileta |first5=Gabriela |last6=Vienne |first6=Damien M. |last7=Rodríguez de la Vega |first7=Ricardo C. |last8=Branco |first8=Sara |last9=Giraud |first9=Tatiana |title=Fungal evolutionary genomics provides insight into the mechanisms of adaptive divergence in eukaryotes |journal=Molecular Ecology |date=February 2014 |volume=23 |issue=4 |pages=753–773 |doi=10.1111/mec.12631 |pmid=24341913 |s2cid=120555 |doi-access=free |bibcode=2014MolEc..23..753G |hdl=10230/58707 |hdl-access=free }}</ref> Since a single toxin gene or [[virulence]] allele can grant the ability to colonize the host, adaptation and [[reproductive isolation]] are instantly facilitated, and in turn, pleiotropically causes adaptive speciation. The studies on fungal evolutionary genomics will further elucidate the earliest stages of divergence as a result of gene flow, and provide insight into pleiotropically induced adaptive divergence in other [[eukaryote]]s.<ref name="Gladieux 753–773"/>

=== Antagonistic pleiotropy ===
{{Main|Antagonistic pleiotropy hypothesis}}
Sometimes, a pleiotropic gene may be both harmful and beneficial to an organism, which is referred to as ''antagonistic pleiotropy''. This may occur when the trait is beneficial for the organism's early life, but not its late life. Such "trade-offs" are possible since [[natural selection]] affects traits expressed earlier in life, when most organisms are most fertile, more than traits expressed later in life.<ref>{{Cite journal |last1=Lemaître |first1=Jean-François |last2=Berger |first2=Vérane |last3=Bonenfant |first3=Christophe |last4=Douhard |first4=Mathieu |last5=Gamelon |first5=Marlène |last6=Plard |first6=Floriane |last7=Gaillard |first7=Jean-Michel |date=2015-05-07 |title=Early-late life trade-offs and the evolution of ageing in the wild |journal=Proc. R. Soc. B |volume=282 |issue=1806 |pages=20150209 |doi=10.1098/rspb.2015.0209 |pmc=4426628 |pmid=25833848}}</ref>

This idea is central to the [[antagonistic pleiotropy hypothesis]], which was first developed by [[George C. Williams (biologist)|G.{{nbsp}}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, which may give an evolutionary explanation for [[senescence]]. An example is the [[p53]] gene, which suppresses [[cancer]] but also suppresses [[stem cell]]s, which replenish worn-out tissue.<ref name=Singh/>

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 [[allele]]s by roughly half. However, antagonistic pleiotropy also lends greater evolutionary "staying power" to genes controlling beneficial traits, since an organism with a mutation to those genes would have a decreased chance of successfully reproducing, as multiple traits would be affected, potentially for the worse.<ref>{{Cite journal|last=Society|first=The Royal|date=2004-04-07|title=Two steps forward, one step back: the pleiotropic effects of favoured alleles|journal=Proceedings of the Royal Society of London B: Biological Sciences |volume=271|issue=1540|pages=705–714|doi=10.1098/rspb.2003.2635 |pmc=1691650|pmid=15209104}}</ref>

Antagonistic pleiotropy can manifest in many ways, depending on the contexts in which its positive and negative effects occur. These effects may arise in different stages of an life. For example can certain alleles of ORL1 (lectin-like low-density lipoprotein receptor 1) enhance the immune defense in early life but also, increase the risk of [[cardiovascular disease]] later. It is also a possibility, that positive and negative effects can occur at the same time, for example some alleles of the androgen receptor (AR), which appears to lower the risk of getting [[breast cancer]] at the same time increasing the risk of [[ovarian cancer]].<ref>{{Cite journal |last1=Gems |first1=David |last2=Kern |first2=Carina C |date=28 September 2024 |title=Biological constraint, evolutionary spandrels and antagonistic pleiotropy |url=https://www.sciencedirect.com/science/article/pii/S1568163724003453 |journal=Ageing Research Reviews |volume=101 |doi=10.1016/j.arr.2024.102527 |pmid=39374830 |via=Elsevier|doi-access=free }}</ref>

[[Sickle-cell disease|Sickle cell anemia]] is a classic example of the mixed benefit given by the staying power of pleiotropic genes, as the mutation to Hb-S provides the fitness benefit of [[malaria]] resistance to [[Zygosity|heterozygotes]] as [[sickle cell trait]], while [[Zygosity|homozygotes]] have significantly lowered life expectancy—what is known as "[[heterozygote advantage]]". 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.<ref>{{Cite journal|last1=Carter|first1=Ashley JR|last2=Nguyen|first2=Andrew Q.|date=2011-01-01|title=Antagonistic pleiotropy as a widespread mechanism for the maintenance of polymorphic disease alleles |journal=BMC Medical Genetics |volume=12 |pages=160|doi=10.1186/1471-2350-12-160 |pmc=3254080|pmid=22151998 |doi-access=free }}</ref>

== Examples ==
[[File:Pavo cristatus -Southwicks Zoo, Massachusetts, USA -albino-8a (1).jpg|thumb|Peacock with albinism]]

=== Human ===

==== Albinism ====
{{Main|Albinism}}Albinism is the mutation of the [[Tyrosinase|TYR gene]], also termed tyrosinase. This mutation causes the most common form of albinism. The mutation alters the production of [[melanin]], thereby affecting melanin-related and other dependent traits throughout the organism. Melanin is a substance made by the body that is used to absorb light and provides coloration to the skin. Indications of albinism are the absence of color in an organism's eyes, hair, and skin, due to the lack of melanin. Some forms of albinism are also known to have symptoms that manifest themselves through rapid-eye movement, light sensitivity, and [[strabismus]].<ref>{{MedlinePlusEncyclopedia|001479|Albinism}}</ref>

==== Phenylketonuria (PKU) ====
{{Main|Phenylketonuria}}
[[File:Phenylketonuria testing.jpg|thumb|The blood of a two-week-old infant is collected for a PKU screening.]]

A common example of pleiotropy is the human disease [[phenylketonuria]] (PKU). This disease causes [[mental retardation]] and reduced [[hair]] and [[skin pigmentation]], and can be caused by any of a large number of mutations in the single gene on chromosome 12 that codes for the [[enzyme]] [[phenylalanine hydroxylase]], which converts the [[amino acid]] [[phenylalanine]] to [[tyrosine]]. Depending on the mutation involved, this conversion is reduced or ceases entirely. 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 most dangerous form of this is called classic PKU, which is common in infants. The baby seems normal at first but actually incurs permanent intellectual disability. This can cause symptoms such as mental retardation, abnormal gait and posture, and delayed growth. Because tyrosine is used by the body to make [[melanin]] (a component of the pigment found in the hair and skin), failure to convert normal levels of phenylalanine to tyrosine can lead to fair hair and skin.<ref name="National Center for Biotechnology Information-1998" />
The frequency of this disease varies greatly. Specifically, in the United States, PKU is found at a rate of nearly 1 in 10,000 births. Due to newborn screening, doctors are able to detect PKU in a baby sooner. This allows them to start treatment early, preventing the baby from suffering from the severe effects of PKU. PKU is caused by a mutation in the PAH gene, whose role is to instruct the body on how to make phenylalanine hydroxylase. Phenylalanine hydroxylase is what converts the phenylalanine, taken in through diet, into other things that the body can use. The mutation often decreases the effectiveness or rate at which the hydroxylase breaks down the phenylalanine. This is what causes the phenylalanine to build up in the body.<ref>{{cite web|publisher=MedlinePlus, US National Library of Medicine |title=Phenylketonuria |url=https://medlineplus.gov/genetics/condition/phenylketonuria/|date=25 April 2023|accessdate=17 August 2023}}</ref>

==== Sickle cell anemia ====
{{Main|Sickle cell disease|Sickle cell trait}}
[[File:Red Blood Cells in Sickle Cell Disease.jpg|thumb|Photomicrograph of normal-shaped and sickle-shape red blood cells from a patient with [[sickle cell disease]]]]

Sickle cell anemia is a genetic disease that causes deformed red blood cells with a rigid, crescent shape instead of the normal flexible, round shape.<ref>{{cite web |url=https://www.nhlbi.nih.gov/health/sickle-cell-disease |title=What Is Sickle Cell Disease?|website=[[National Heart, Lung, and Blood Institute|NHLBI]] |access-date=2024-08-05}}</ref> It is caused by a change in one nucleotide, a [[point mutation]]<ref>{{cite web |url=http://genetics.thetech.org/about-genetics/mutations-and-disease |title=Mutations and Disease |website=[[The Tech Interactive]] |archive-url=https://web.archive.org/web/20120511202928/https://genetics.thetech.org/about-genetics/mutations-and-disease |archive-date=2012-05-11}}</ref> in the [[HBB|HBB gene]]. 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. Sickle cell anemia occurs when the HBB gene mutation causes both beta-globin subunits of hemoglobin to change into hemoglobin{{nbsp}}S (HbS).<ref name="Reference">{{cite web |url=https://medlineplus.gov/genetics/condition/sickle-cell-disease/ |title=Sickle cell disease |website=[[MedlinePlus]] |access-date=2024-08-05}}</ref>

Sickle cell anemia is a pleiotropic disease because the expression of a single mutated HBB gene produces numerous consequences throughout the body. The mutated hemoglobin forms polymers and clumps together causing the deoxygenated sickle red blood cells to assume the disfigured sickle shape.<ref>{{cite web |url=http://sickle.bwh.harvard.edu/scd_background.html |title=How Does Sickle Cell Cause Disease? |last=Bridges |first=Kenneth R. |website=[[Brigham and Women's Hospital]] |access-date=2024-08-05}}</ref> As a result, the cells are inflexible and cannot easily flow through blood vessels, increasing the risk of [[Thrombus|blood clots]] and possibly depriving vital organs of oxygen.<ref name="Reference" /> Some complications associated with sickle cell anemia include pain, damaged organs, [[stroke]]s, [[Hypertension|high blood pressure]], and loss of vision. Sickle red blood cells also have a shortened lifespan and die prematurely.<ref>{{cite web |url=https://www.cdc.gov/sickle-cell/complications/ |title=Complications of Sickle Cell Disease |website=[[Centers for Disease Control and Prevention|CDC]] |date=22 May 2024 |access-date=2024-08-05}}</ref>

==== Marfan syndrome ====
{{Main|Marfan syndrome}}
[[File:Marfan Patient.jpeg|thumb|Patient with Marfan Syndrome]]
Marfan syndrome (MFS) is an [[Autosome|autosomal]] [[Dominance (genetics)|dominant disorder]] which affects 1 in 5–10,000 people.<ref name=NORD2017>{{cite web|title=Marfan Syndrome|url=http://rarediseases.org/rare-diseases/marfan-syndrome/|website=National Organization for Rare Disorders|access-date=5 November 2016|date=2017}}</ref> MFS arises from a mutation in the [[FBN1]] gene, which encodes for the [[glycoprotein]] fibrillin-1, a major constituent of extracellular [[microfibril]]s which form [[connective tissue]]s.<ref name=NORD2017/>  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. Because these fibers are found in tissues throughout the body, mutations in this gene can have a widespread effect on certain systems, including the [[Skeleton|skeletal]], [[Circulatory system|cardiovascular]], and [[nervous system]], as well as the eyes and lungs.<ref name=NORD2017/>

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 [[Heart failure|congestive cardiac failure]].  Other characteristics of MFS include an increased arm span and decreased upper to lower body ratio.<ref name=NORD2017/>

==== Pain susceptibility ====
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 study|genome-wide association]] joint analysis of 17 [[pain]]-related traits revealed that many of the 99 identified risk [[Locus (genetics)|loci]] are pleiotropic.<ref>{{Cite journal |last1=Mocci |first1=Evelina |last2=Ward |first2=Kathryn |last3=Perry |first3=James A. |last4=Starkweather |first4=Angela |last5=Stone |first5=Laura S. |last6=Schabrun |first6=Siobhan M. |last7=Renn |first7=Cynthia |last8=Dorsey |first8=Susan G. |last9=Ament |first9=Seth A. |date=2023-10-16 |title=Genome wide association joint analysis reveals 99 risk loci for pain susceptibility and pleiotropic relationships with psychiatric, metabolic, and immunological traits |journal=PLOS Genetics |language=en |volume=19 |issue=10 |pages=e1010977 |doi=10.1371/journal.pgen.1010977 |doi-access=free |issn=1553-7404 |pmc=10602383 |pmid=37844115}}</ref> This implies that, rather than these loci being associated with just one type of pain, many genetic loci contribute to susceptibility to various forms of pain, including [[Headache|headaches]], [[Myalgia|muscle pain]], and [[chronic pain]].

These pleiotropic loci were classified into four groups: loci associated with nearly all pain traits, loci associated with a specific type of pain, loci associated with multiple forms of [[Musculoskeletal disorder|musculoskeletal pain]], and loci associated with [[Headache|headaches]].

Additionally, pleiotropy was not limited to different types of pain but also extended to psychiatric, metabolic, and immunological traits. [[Genetic correlation|Genetic correlations]] were found between pain susceptibility and conditions such as [[Depression (mood)|depression]], increase of body mass index, [[asthma]], and cardiovascular diseases.

=== Animals ===

==== Chickens ====
[[File:Salon agriculture 2009 - Padoue frisée blanche.jpg|thumb|upright|Chicken exhibiting the frizzle feather trait]]
Chickens exhibit various traits affected by pleiotropic genes. Some chickens exhibit [[Frizzle (chicken plumage)|frizzle feather trait]], where their feathers all curl outward and upward rather than lying flat against the body. Frizzle feather was found to stem from a deletion in the genomic region coding for α-Keratin. This gene seems to pleiotropically lead to other abnormalities like increased [[metabolism]], higher food consumption, accelerated heart rate, and delayed sexual maturity.<ref>{{Cite journal|last1=Ng|first1=Chen Siang|last2=Wu |first2=Ping|last3=Foley |first3=John |last4=Foley |first4=Anne |last5=McDonald|first5=Merry-Lynn|last6=Juan|first6=Wen-Tau|last7=Huang |first7=Chih-Jen|last8=Lai|first8=Yu-Ting|last9=Lo |first9=Wen-Sui|date=2012-07-19 |title=The Chicken Frizzle Feather Is Due to an α-Keratin (KRT75) Mutation That Causes a Defective Rachis |journal=PLOS Genetics|volume=8 |issue=7 |doi=10.1371/journal.pgen.1002748 |pmc=3400578|pmid=22829773|pages=e1002748 |doi-access=free }}</ref>

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 [[Physiology|physiological]] structures related to [[Reproduction|reproductive]] abilities. Both males and females with larger combs have higher bone density and strength, which allows females to deposit more [[calcium]] into eggshells. This linkage is further evidenced by the fact that two of the genes, [[Hydroxyacid oxidase (glycolate oxidase) 1|HAO1]] and BMP2, affecting medullary bone (the part of the bone that transfers calcium into developing eggshells) are located at the same locus as the gene affecting comb mass. HAO1 and BMP2 also display pleiotropic effects with commonly desired domestic chicken behavior; those chickens who express higher levels of these two genes in bone tissue produce more eggs and display less [[egg incubation]] behavior.<ref>{{Cite journal|last1=Johnsson|first1=Martin|last2=Gustafson|first2=Ida|last3=Rubin|first3=Carl-Johan|last4=Sahlqvist|first4=Anna-Stina|last5=Jonsson|first5=Kenneth B.|last6=Kerje|first6=Susanne |last7=Ekwall |first7=Olov|last8=Kämpe|first8=Olle|last9=Andersson|first9=Leif|date=2012-08-30|title=A Sexual Ornament in Chickens Is Affected by Pleiotropic Alleles at HAO1 and BMP2, Selected during Domestication|journal=PLOS Genetics|volume=8|issue=8|doi=10.1371/journal.pgen.1002914 |pmc=3431302 |pmid=22956912 |pages=e1002914 |doi-access=free }}</ref>

=== Pleiotropy in psychiatry ===

==== Autism and schizophrenia ====
{{Main|Autism|Schizophrenia}}
Pleiotropy in genes has been linked between certain [[Mental disorder|psychiatric disorders]] as well. Deletion in the [[22q11.2]] region of [[Chromosome 22 (human)|chromosome 22]] has been associated with [[schizophrenia]] and [[autism]].<ref name=":0">{{cite journal |last1=Vorstman |first1=Jacob A.S. |last2=Breetvelt |first2=Elemi J. |last3=Thode |first3=Kirstin I. |last4=Chow |first4=Eva W.C. |last5=Bassett |first5=Anne S. |date=January 2013 |title=Expression of autism spectrum and schizophrenia in patients with a 22q11.2 deletion |journal=Schizophrenia Research |volume=143 |issue=1 |pages=55–59 |doi=10.1016/j.schres.2012.10.010 |pmid=23153825 |s2cid=20964079}}</ref> Schizophrenia and autism are linked to the same gene deletion but manifest very differently from each other. The resulting phenotype depends on the stage of life at which the individual develops the disorder. Childhood manifestation of the gene deletion is typically associated with autism, while adolescent and later expression of the gene deletion often manifests in schizophrenia or other psychotic disorders.<ref>{{Cite news |date=2016-10-18 |title=Same DNA deletion paves paths to autism, schizophrenia {{!}} Spectrum |url=https://spectrumnews.org/opinion/viewpoint/dna-deletion-paves-paths-autism-schizophrenia/ |access-date=2016-11-13 |newspaper=Spectrum}}</ref> Though the disorders are linked by genetics, there is no increased risk found for adult schizophrenia in patients who are autistic.<ref name=":0" />

A 2013 study also genetically linked five psychiatric disorders, including schizophrenia and autism. The link was a [[Single-nucleotide polymorphism|single nucleotide polymorphism]] of two genes involved in [[Calcium channel|calcium channel signaling]] with [[neuron]]s. One of these genes, [[Cav1.2|CACNA1C]], has been found to influence [[cognition]]. It has been associated with autism, as well as linked in studies to schizophrenia and [[bipolar disorder]].<ref>{{Cite journal |last1=Roussos |first1=Panos |last2=McClure |first2=Margaret M. |last3=Hazlett |first3=Erin A. |last4=New |first4=Antonia S. |last5=Siever |first5=Larry J. |last6=Bitsios |first6=Panos |last7=Giakoumaki |first7=Stella G. |date=2013-03-30 |title=CACNA1C as a risk factor for schizotypal personality disorder and schizotypy in healthy individuals |journal=Psychiatry Research |volume=206 |issue=1 |pages=122–123 |doi=10.1016/j.psychres.2012.08.039 |pmc=4176879 |pmid=22985546}}</ref> These particular studies show clustering of these diseases within patients themselves or families.<ref>{{Cite web |title=Pleiotropy of psychiatric disorders will reinvent DSM |url=http://www.mdedge.com/currentpsychiatry/article/65079/practice-management/pleiotropy-psychiatric-disorders-will-reinvent#bib1 |access-date=2016-11-13 |website=www.mdedge.com}}</ref> The estimated [[heritability]] of schizophrenia is 70% to 90%,<ref>{{Cite journal |last1=Sullivan |first1=Patrick F. |last2=Kendler |first2=Kenneth S. |last3=Neale |first3=Michael C. |date=2003-12-01 |title=Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies |journal=Archives of General Psychiatry |volume=60 |issue=12 |pages=1187–1192 |doi=10.1001/archpsyc.60.12.1187 |pmid=14662550 |doi-access=}}</ref> therefore the pleiotropy of genes is crucial since it causes an increased risk for certain psychotic disorders and can aid psychiatric diagnosis.

Through looping in three-dimensional space, distant non-coding regulatory elements, sometimes located several megabases away from gene promoters, can physically interact with and influence the expression of specific genes. For example, there is a genetic variant located upstream of the PCDH gene clusters that play a role in brain development and has  been shown to impact the expression of several [[protocadherin]] genes. These genes have been linked to schizophrenia (SCZ) and major depressive disorder (MDD).<ref name=":1" />

=== Model organisms ===

==== "Mini-muscle" allele ====
A gene recently discovered in laboratory [[house mice]], termed "mini-muscle", causes, when mutated, a 50% reduction in hindlimb muscle mass as its primary effect (the phenotypic effect by which it was originally identified).<ref name="Pavlicev" /> In addition to smaller hindlimb muscle mass, the mutant mice exhibit lower heart rates during physical activity, and a higher endurance. Mini Muscle Mice also exhibit larger kidneys and livers. All of these morphological deviations influence the behavior and [[metabolism]] of the mouse. For example, mice with the Mini Muscle mutation were observed to have a higher per-gram aerobic capacity.<ref>{{cite journal |last1=Garland |first1=Theodore |last2=Morgan |first2=Martin T. |last3=Swallow |first3=John G. |last4=Rhodes |first4=Justin S. |last5=Girard |first5=Isabelle |last6=Belter |first6=Jason G. |last7=Carter |first7=Patrick A. |date=June 2002 |title=Evolution of a small-muscle polymorphism in lines of house mice selected for high activity levels |journal=Evolution |volume=56 |issue=6 |pages=1267–1275 |doi=10.1111/j.0014-3820.2002.tb01437.x |pmid=12144025 |s2cid=14217517 |doi-access=free}}</ref> The mini-muscle allele shows a [[Mendelian inheritance|mendelian recessive]] behavior.<ref name="Wang" /> The mutation is a single nucleotide polymorphism ([[Single-nucleotide polymorphism|SNP]]) in an [[intron]] of the [[myosin]] heavy polypeptide{{nbsp}}4 gene.<ref>{{Cite journal |last1=Kelly |first1=Scott A. |last2=Bell |first2=Timothy A. |last3=Selitsky |first3=Sara R. |last4=Buus |first4=Ryan J. |last5=Hua |first5=Kunjie |last6=Weinstock |first6=George M. |last7=Garland |first7=Theodore |last8=Pardo-Manuel de Villena |first8=Fernando |last9=Pomp |first9=Daniel |date=2013-12-01 |title=A novel intronic single nucleotide polymorphism in the myosin heavy polypeptide 4 gene is responsible for the mini-muscle phenotype characterized by major reduction in hind-limb muscle mass in mice |journal=Genetics |volume=195 |issue=4 |pages=1385–1395 |doi=10.1534/genetics.113.154476 |pmc=3832280 |pmid=24056412}}</ref>

=== Cellular functions and DNA- repair ===

==== DNA repair proteins ====
[[DNA repair]] pathways that repair damage to cellular DNA use many different proteins.  These proteins often have other functions in addition to DNA repair.<ref name="Lehmann1998">{{cite journal |last1=Lehmann |first1=AR |date=February 1998 |title=Dual functions of DNA repair genes: molecular, cellular, and clinical implications |journal=BioEssays |volume=20 |issue=2 |pages=146–55 |doi=10.1002/(SICI)1521-1878(199802)20:2<146::AID-BIES7>3.0.CO;2-R |pmid=9631660 |s2cid=25183408}}</ref> In humans, defects in some of these multifunctional proteins can cause widely differing clinical phenotypes.<ref name="Lehmann1998" />  As an example, mutations in the [[XPB]] gene that encodes the largest subunit of the basal [[Transcription factor II H]] have several pleiotropic effects.  XPB mutations are known to be deficient in [[nucleotide excision repair]] of DNA and in the quite separate process oDf gene [[transcription (biology)|transcription]].<ref name="Lehmann1998" />   In humans, ''XPB'' [[mutation]]s can give rise to the cancer-prone disorder [[xeroderma pigmentosum]] or the noncancer-prone multisystem disorder [[trichothiodystrophy]]. Another example in humans is the ''[[ERCC6]]'' gene, which encodes a protein that mediates DNA repair, [[Transcription (biology)|transcription]], and other cellular processes throughout the body.<ref>{{Cite web |title=ERCC6 gene: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/gene/ercc6/ |access-date=2021-06-02 |website=medlineplus.gov |language=en}}</ref> Mutations in ''[[ERCC6]]'' are associated with disorders of the eye ([[Retinal disease|retinal dystrophy]]), heart (cardiac [[Arrhythmia|arrhythmias]]), and immune system (lymphocyte [[immunodeficiency]]).<ref>{{cite journal |last1=Forrest |first1=Iain S. |last2=Chaudhary |first2=Kumardeep |last3=Vy |first3=Ha My T. |last4=Bafna |first4=Shantanu |last5=Kim |first5=Soyeon |last6=Won |first6=Hong-Hee |last7=Loos |first7=Ruth J.F. |last8=Cho |first8=Judy |last9=Pasquale |first9=Louis R. |last10=Nadkarni |first10=Girish N. |last11=Rocheleau |first11=Ghislain |last12=Do |first12=Ron |date=August 2021 |title=Genetic pleiotropy of ERCC6 loss-of-function and deleterious missense variants links retinal dystrophy, arrhythmia, and immunodeficiency in diverse ancestries |journal=Human Mutation |volume=42 |issue=8 |pages=969–977 |doi=10.1002/humu.24220 |pmc=8295228 |pmid=34005834}}</ref>

== See also ==
{{colbegin}}
* [[cis-regulatory element]]
* [[Enhancer (genetics)]]
* [[Epistasis]]
* [[Genetic correlation]]
* [[Metabolic network]]
* [[Metabolic supermice]]
* [[Polygene]]
{{colend}}

==References==
{{Reflist|30em}}

==External links==
* [http://pleiotropy.fieldofscience.com/2010/12/pleiotropy-is-100-years-old.html? Pleiotropy is 100 years old]

{{Genarch}}
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[[Category:Evolutionary developmental biology]]
[[Category:Genetics concepts]]