Developmental bias

In evolutionary biology, '''developmental bias''' refers to the production against or towards certain ontogenetic trajectories which ultimately influence the direction and outcome of evolutionary change by affecting the rates, magnitudes, directions and limits of trait evolution.<ref name=":0">{{Cite journal |author1=Maynard Smith, John |author1-link=John Maynard Smith |author2=Burian, R. |author3=Kauffman, S. |author4=Alberch, P. |author5=Campbell, J. |author6=Goodwin, B. |author7=Lande, R. |author8=Raup, D. |author9=Wolpert, L. |author9-link=Lewis Wolpert |date=1985 |title=Developmental constraints and evolution|journal=The Quarterly Review of Biology |volume=60 |issue=3 |pages=265–287 |doi=10.1086/414425 |s2cid=85201850 }}</ref><ref name=":1">{{Cite journal |last=Arthur |first=Wallace|date=2004|title=The effect of development on the direction of evolution: toward a twenty-first century consensus |journal=Evolution and Development |volume=6 |issue=4 |pages=282–288 |doi=10.1111/j.1525-142x.2004.04033.x |pmid=15230968 |issn=1520-541X |doi-access=free|hdl=10379/8840 |hdl-access=free }}</ref> Historically, the term was synonymous with developmental constraint,<ref name=":0" /><ref name=":2">{{Cite journal|last1=Gould|first1=S. J. |author1-link=Stephen Jay Gould |last2=Lewontin |first2=R. C. |date=1979|title=The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme |journal=Proceedings of the Royal Society of London B |volume=205 |issue=1161 |pages=581–598 |doi=10.1098/rspb.1979.0086 |issn=0080-4649 |pmid=42062 |bibcode=1979RSPSB.205..581G |s2cid=2129408 }}</ref><ref>{{Cite journal |last=Gould |first=Stephen Jay |author-link=Stephen Jay Gould |date=1989 |title=A Developmental Constraint in Cerion, with Comments of the Definition and Interpretation of Constraint in Evolution |journal=Evolution |volume=43 |issue=3 |pages=516–539 |doi=10.2307/2409056|pmid=28568388|jstor=2409056}}</ref> however, the latter has been more recently interpreted as referring solely to the negative role of development in evolution.<ref name=":3">{{Cite journal |last=Arthur |first=Wallace |date=2001|title=Developmental drive: an important determinant of the direction of phenotypic evolution |journal=Evolution and Development |volume=3 |issue=4 |pages=271–278 |doi=10.1046/j.1525-142x.2001.003004271.x |pmid=11478524 |s2cid=41698287 |issn=1520-541X}}</ref>

== The role of the embryo ==

thumb|Haeckel's drawings of "lower" (fish, salamander) and "higher" (tortoise, chick) vertebrates at comparable stages

In modern evolutionary biology, the idea of developmental bias is embedded into a current of thought called ''Structuralism'', which emphasizes the role of the organism as a ''causal'' force of evolutionary change.<ref name=":4">{{cite book |title=Homology, Genes, and Evolutionary Innovation |last=Wagner |first=Gunter P. |date=2014 |publisher=Princeton University Press |isbn=978-0-691-18067-0 |oclc=1005108561 |pages= }}{{pn|date=May 2023}}</ref>{{pn|date=May 2023}} In the Structuralist view, phenotypic evolution is the result of the action of natural selection on previously 'filtered' variation during the course of ontogeny.<ref name=":5">{{Cite journal |last=Alberch |first=Pere |author-link=Pere Alberch |date=1989 |title=The logic of monsters: Evidence for internal constraint in development and evolution |journal=Geobios |volume=22 |pages=21–57 |doi=10.1016/s0016-6995(89)80006-3 |bibcode=1989Geobi..22...21A |issn=0016-6995}}</ref><ref name=":6">{{Cite book |url=https://www.cambridge.org/core/books/biased-embryos-and-evolution/50D5C7174074E980B8A2AB4BC1A55819 |title=Biased Embryos and Evolution |last=Arthur |first=Wallace |date=2004 |publisher=Cambridge University Press |isbn=978-0-511-60683-0 |location=Cambridge |doi=10.1017/cbo9780511606830}}</ref> It contrasts with the ''Functionalist'' (also "adaptationist", "pan-selectionist" or "externalist") view in which phenotypic evolution results only from the interaction between the deterministic action of natural selection and variation caused by mutation.<ref name=":2" /><ref name=":5" />

The rationale behind the role of the organism, or more specifically the embryo, as a causal force in evolution and for the existence of bias is as follows: The traditional, neo-Darwinian, approach to explain the process behind evolutionary change is natural selection acting upon heritable variation caused by genetic mutations.<ref name=":13">{{Cite book|title=Evolution: Making sense of life |author=Zimmer, Carl. |author2=Emlen D. |author3=Perkins, Alison EH |publisher=Greenwood Village, CO: Roberts |year=2013 |isbn=978-1-319-20259-0 |oclc=1051973071}}</ref> However, natural selection acts on phenotypes and mutation does not in itself produce phenotypic variation, thus, there is a conceptual gap regarding the connection between a mutation and the potential change in phenotype.<ref name=":4" /> For a mutation to readily alter a phenotype, and hence be visible to natural selection, it has to modify the ontogenetic trajectory, a process referred to as ''developmental reprogramming''.<ref>{{Cite journal |last=Arthur |first=Wallace |date=2000 |title=The concept of developmental reprogramming and the quest for an inclusive theory of evolutionary mechanisms |journal=Evolution and Development |volume=2 |issue=1 |pages=49–57 |doi=10.1046/j.1525-142x.2000.00028.x |pmid=11256417 |s2cid=11972625 |issn=1520-541X}}</ref> Some kinds of reprogramming are more likely to occur than others given the nature of the genotype–phenotype map, which determines the propensity of a system to vary in a particular direction,<ref name=":6" /><ref name=":14">{{cite journal |last1=Wagner |first1=Günter P. |author1-link=Günter P. Wagner |last2=Altenberg |first2=Lee |date=1996 |journal=Evolution |volume=50 |issue=3 |pages=967–976 |doi=10.1111/j.1558-5646.1996.tb02339.x |pmid=28565291 |issn=0014-3820 |title=Perspective: Complex Adaptations and the Evolution of Evolvability |doi-access=free}}</ref> thus, creating a bias. In other words, the underlying architecture of the developmental systems influences the kinds of possible phenotypic outcomes.

However, developmental bias can evolve through natural selection, and both processes simultaneously influence phenotypic evolution. For example, developmental bias can affect the rate or path to an adaptive peak (high-fitness phenotype),<ref name=":3" /> and conversely, strong directional selection can modify the developmental bias to increase the phenotypic variation in the direction of selection.<ref name=":7">{{cite journal |last1=Uller |first1=Tobias |last2=Moczek |first2=Armin P. |last3=Watson |first3=Richard A. |last4=Brakefield |first4=Paul M. |last5=Laland |first5=Kevin N. |date=2018 |title=Developmental Bias and Evolution: A Regulatory Network Perspective |url=http://www.genetics.org/content/209/4/949 |journal=Genetics |volume=209|issue=4 |pages=949–966 |doi=10.1534/genetics.118.300995 |issn=0016-6731 |pmc=6063245|pmid=30049818}}</ref>

thumb|340x340px|Developmental bias for continuous characters. If the main axis of variation (red arrows) is orthogonal to the direction of selection (dashed line), trait covariation will constraint adaptive evolution. Conversely, if the main axis of variation is aligned with the direction of selection, trait covariation will facilitate adaptive evolution.

=== Types of bias ===

==== Developmental constraints ====

Developmental constraints are limitations on phenotypic variability (or absence of variation) caused by the inherent structure and dynamics of the developmental system.<ref name=":0" /> Constraints are a bias against a certain ontogenetic trajectory, and consequently are thought to limit adaptive evolution.<ref name=":7" /><ref>{{Cite journal |last1=Drost |first1=Hajk-Georg |last2=Janitza |first2=Philipp |last3=Grosse |first3=Ivo |last4=Quint |first4=Marcel | year=2017 |title=Cross-kingdom comparison of the developmental hourglass |journal=Current Opinion in Genetics & Development |volume=45 |pages=69–75 |doi=10.1016/j.gde.2017.03.003 |pmid=28347942 |doi-access=free}}</ref>

==== Developmental drive ====

Developmental drive is the inherent natural tendency of organisms and their ontogenetic trajectories to change in a particular direction (i.e. a bias towards a certain ontogenetic trajectory).<ref>{{cite book |last1=Altenberg |first1=L. |editor1-last=Banzhaf |editor2=Eeckman, F. H. |editor1-first=W. |title=Evolution and Biocomputation: Computational Models of Evolution |url=https://archive.org/details/evolutionbiocomp00banz |url-access=limited |chapter=Genome Growth and the Evolution of the Genotype-Phenotype Map |date=1995 |publisher=Springer |location=Berlin |isbn=978-3-540-49176-7 |pages=[https://archive.org/details/evolutionbiocomp00banz/page/n210 205]–259}}</ref><ref name=":3" /><ref name=":4" /> This type of bias is thought to facilitate adaptive evolution by aligning phenotypic variability with the direction of selection.<ref>{{cite book |last1=Altenberg |first1=L. |editor1=Callebaut, W. |editor2=Rasskin-Gutman, D. |editor3=Simon, Herbert A. |editor3-link=Herbert A. Simon |title=Modularity: Understanding the Development and Evolution of Natural Complex Systems |url=https://archive.org/details/modularityunders00call_111 |url-access=limited |chapter=Modularity in Evolution: Some Low-Level Questions |date=2005 |publisher=MIT Press |location=Cambridge, MA |isbn=978-0-262-03326-8 |pages=[https://archive.org/details/modularityunders00call_111/page/n115 99]–128}}</ref><ref name=":7" />

== Distribution of phenotypic variation ==

=== Morphospace === alt=|thumb|350x350px|Multidimensional representation of species in the morphospace. Each axis corresponds to a trait, and dots correspond to organisms with particular trait values combinations. In this case, the axes represent the form of the fish species. The morphospace is a quantitative representation of phenotypes in a multidimensional space, where each dimension corresponds to a trait. The phenotype of each organism or species is then represented as a point in that space that summarizes the combination of values or states at each particular trait.<ref name=":8">{{Cite journal|last1=Chartier|first1=Marion|last2=Jabbour|first2=Florian|last3=Gerber|first3=Sylvain|last4=Mitteroecker|first4=Philipp|last5=Sauquet|first5=Hervé|last6=von Balthazar|first6=Maria|last7=Staedler|first7=Yannick|last8=Crane|first8=Peter R.|last9=Schönenberger|first9=Jürg|date=2014|title=The floral morphospace - a modern comparative approach to study angiosperm evolution|journal=New Phytologist|volume=204|issue=4|pages=841–853|doi=10.1111/nph.12969|pmid=25539005|issn=0028-646X|pmc=5526441}}</ref> This approach is used to study the evolution of realized phenotypes compared to those that are theoretically possible but inexistent.<ref name=":8" /><ref name=":9">{{Cite journal|last=Gerber|first=Sylvain|date=2014|title=Not all roads can be taken: development induces anisotropic accessibility in morphospace|journal=Evolution & Development|language=en|volume=16|issue=6|pages=373–381|doi=10.1111/ede.12098|pmid=25212955|s2cid=21562182 |issn=1520-541X}}</ref>

=== Nonrandom (anisotropic) distribution of phenotypic variation === Describing and understanding the drivers of the distribution of phenotypic variation in nature is one of the main goals in evolutionary biology.<ref name=":1" /> One way to study the distribution of phenotypic variation is through depicting the volume of the morphospace occupied by a set of organisms or species. Theoretically, there can exist a natural process that generates an almost-evenly (quasi stochastic) distributed pattern of phenotypes in the morphospace, regarding that new species necessary tend to occupy a point in the morphospace that is close to those of its phylogenetic relatives.<ref>{{Cite book|title=The Origin of Higher Taxa: Palaeobiological, developmental and ecological perspectives|last=Kemp|first=T.S.|publisher=Oxford University Press|year=2016|isbn=978-0-19-969188-3|doi=10.1093/acprof:oso/9780199691883.001.0001}}</ref> However, it is now widely acknowledged that organisms are not evenly distributed along the morphospace, i.e. isotropic variation, but instead are nonrandomly distributed, i.e. anisotropic variation.<ref name=":9" /><ref name=":10">{{Cite journal|last=Jablonski|first=D.|date=2017|title=Approaches to Macroevolution: 1. General Concepts and Origin of Variation|journal=Evolutionary Biology|language=en|volume=44|issue=4|pages=427–450|doi=10.1007/s11692-017-9420-0|issn=0071-3260|pmc=5661017|pmid=29142333}}</ref> In other words, there exists a discordance between the apparent (or theoretical) possible phenotypes and their actual accessibility.<ref name=":9" /> thumb|Ontogenetically impossible creature Thus, some phenotypes are inaccessible (or impossible) due to the underlying architecture of the developmental trajectory, while others are accessible (or possible).<ref name=":11">{{Cite journal|last=Olson|first=M.E.|date=2012|title=The developmental renaissance in adaptationism|journal=Trends in Ecology & Evolution|volume=27|issue=5|pages=278–287|doi=10.1016/j.tree.2011.12.005|pmid=22326724|issn=0169-5347}}</ref> However, of the possible phenotypes, some are 'easier' or more probable to occur than others.<ref name=":6" /><ref name=":10" /> For example, a phenotype such as the classical figure of a dragon (i.e. a giant reptile-like creature with two pairs of limbs and an anterior pair of wings) may be ''impossible'' because in vertebrates the fore-limbs and the anterior pair of wings are homologous characters (e.g. birds and bats), and, thus, are mutually exclusive. On the other hand, if two phenotypes are possible (and equally fit), but one form of reprogramming requires only one mutation while the other requires two or more, the former will be more likely to occur (assuming that genetic mutations occur randomly).<ref name=":6" />

An important distinction between structuralism and functionalism regards primarily with the interpretation of the causes of the empty regions in the morphospace (that is, the inexistent phenotypes): Under the functionalist view, empty spaces correspond to phenotypes that are both ontogenetically possible and equally probable but are eliminated by natural selection due to their low fitness.<ref name=":11" /> In contrast, under the structuralist view, empty spaces correspond to ontogenetically impossible or improbable phenotypes,<ref name=":2" /><ref name=":11" /> thus, implying a bias in the types of phenotypes that can be produced assuming equal amounts of variation (genetic mutations) in both models.<ref name=":4" /><ref name=":6" />

=== Classical examples of anisotropic variation ===

thumb|287x287px|Shell variation in nature

In a classical natural example of bias it was shown that only a small proportion of all possible snail shell shapes was realized in nature and actual species were confined to discrete regions of the shell-morphospace rather than being continuously distributed.<ref name="Raup 1966">{{cite journal |last=Raup |first=David M. |date=1966 |title=Geometric Analysis of Shell Coiling: General Problems |journal=Journal of Paleontology |volume=40 |issue=5 |pages=1178–1190 |jstor=1301992}}</ref> In another natural example, it was shown that soil-dwelling centipedes have an enormous variation in the number of pairs of legs, the lowest being 27 and the highest 191 pairs; however, there are no species with an even number of leg pairs, which suggests that either these phenotypes are somehow restricted during development or that there is a developmental drive into odd numbers.<ref name="Arthur 2002">{{cite journal |last=Arthur |first=Wallace |date=2002 |title=The interaction between developmental bias and natural selection: from centipede segments to a general hypothesis |journal=Heredity |volume=89|issue=4 |pages=239–246 |doi=10.1038/sj.hdy.6800139 |pmid=12242638 |issn=0018-067X |doi-access=free}}</ref>

right|300px|Biased number of polydactylous toes in a Main Coon population

A study of the polydactyl toe counts of 375 Hemingway mutants of the Maine Coon cat showed that the number of additional toes was variable (plastic) and contained a bias. The Maine Coon cat (as the basic model of the Hemingway mutants) has 18 toes in the wild. Polydactyly occurred in some cases with an unchanged number of toes (18 toes), whereby the deviation consisted of a three-jointed thumb due to the extension of the first toe. However, 20 toes were found much more frequently and then 22, 24 or 26 toes with decreasing frequency. Odd total numbers of toes on the feet were less common. There is another bias between the number of toes on the front and rear feet, and a left-right asymmetry in the number of toes. Random bistability during the development process could explain the observed bias.<ref name="Lange Nemeschkal Müller 2014">{{cite journal |last=Lange |first=Axel |last2=Nemeschkal |first2=Hans L. |last3=Müller |first3=Gerd B. |title=Biased Polyphenism in Polydactylous Cats Carrying a Single Point Mutation: The Hemingway Model for Digit Novelty |journal=Evolutionary Biology |volume=41 |issue=2 |date=2014 |issn=0071-3260 |doi=10.1007/s11692-013-9267-y |pages=262–275}}</ref>

Conversely, developmental abnormalities (or teratologies) have been used to understand the logic behind the mechanisms that produce variation.<ref name=":12">{{cite book |last=Blumberg |first=M.S. |title=Freaks of Nature What Anomalies Tell Us About Development and Evolution|date=2009 |publisher=Oxford University Press |isbn=978-0-1997-5064-1 |oclc=1058406207}}</ref> For example, in a wide range of animals, from fish to humans, two-headed organisms are much more common than three-headed organisms; similarly, Siamese twins theoretically could 'fuse' through any region in the body but the fusion occurs more frequently in the abdominal region.<ref name=":5"/><ref name=":12"/> This trend was referred to as ''transpecific parallelism'', suggesting the existence of profound historical rules governing the expression of abnormal forms in distantly related species.<ref name=":5"/>

== Biased phenotypes I: Continuous variation ==

=== Developmental integration and the P-matrix === thumb|305x305px|Representation of the relationship between two traits. Left: No trait covariation. Each trait changes independently of the other. Right: Trait covariation causes a positive correlation between traits where increase in one trait is correlated with an increase in the other trait (covariation can also produce negative correlation). The red line within the ellipse represents the main eigenvector of the variance-covariance matrix. Integration or covariation among traits during development has been suggested to constrain phenotypic evolution to certain regions of the morphospace and limit adaptive evolution.<ref name=":15">{{Cite journal|last1=Goswami|first1=A.|last2=Smaers|first2=J. B.|last3=Soligo|first3=C.|last4=Polly|first4=P. D.|date=2014-08-19|title=The macroevolutionary consequences of phenotypic integration: from development to deep time|journal=Phil. Trans. R. Soc. B|language=en|volume=369|issue=1649|article-number=20130254|doi=10.1098/rstb.2013.0254|issn=0962-8436|pmc=4084539|pmid=25002699}}</ref> These allometric changes are widespread in nature and can account for a wide variety of realized morphologies and subsequent ecological and physiological changes.<ref>{{Cite journal|last=Gould|first=S.J.|date=1966|title=Allometry and Size in Ontogeny and Phylogeny.|journal=Biol. Rev.|volume=41|issue=4|pages=587–640|doi=10.1111/j.1469-185X.1966.tb01624.x|pmid=5342162|s2cid=28606846 }}</ref><ref>{{Cite journal|last=Emlen|first=Douglas J.|date=2001-02-23|title=Costs and the Diversification of Exaggerated Animal Structures|journal=Science|language=en|volume=291|issue=5508|pages=1534–1536|doi=10.1126/science.1056607|issn=0036-8075|pmid=11222856|bibcode=2001Sci...291.1534E|s2cid=24821274 }}</ref> Under this approach, phenotype is seen as an integrated system where each trait develops and evolves in concert with the other traits, and thus, a change in one trait affects the interacting parts in a correlated manner.<ref name=":15" /><ref>{{Cite journal|last=Pigliucci|first=M|date=2003|title=Phenotypic integration: studying the ecology and evolution of complex phenotypes|journal=Ecology Letters|language=en|volume=6|issue=3|pages=265–272|doi=10.1046/j.1461-0248.2003.00428.x|issn=1461-023X|url=https://philpapers.org/rec/PIGPIS|doi-access=free}}</ref> The correlation between traits is a consequence of the architecture of the genotype–phenotype map, particularly the pleiotropic effects of underlying genes.<ref name=":14" /> This correlated change between traits can be measured and analyzed through a phenotypic variance-covariance matrix (P-matrix) which summarizes the dimensions of phenotypic variability and the main axis of variation.<ref name=":15" />

=== Quantitative genetics and the G-matrix === Quantitative genetics is a statistical framework mainly concerned with modeling the evolution of continuous characters.<ref name=":13" /> Under this framework, correlation between traits could be the result of two processes: 1) natural selection acting simultaneously on several traits ensuring that they are inherited together (i.e. linkage disequilibrium),<ref>{{Cite journal|last1=Lande|first1=Russell|last2=Arnold|first2=Stevan J.|date=1983|title=The Measurement of Selection on Correlated Characters|journal=Evolution|volume=37|issue=6|pages=1210–1226|doi=10.1111/j.1558-5646.1983.tb00236.x|pmid=28556011|jstor=2408842|doi-access=}}</ref> or 2) natural selection acting on one trait causing correlated change in other traits due to pleiotropic effects of genes.<ref name=":14" /> For a set of traits, the equation that describe the variance among traits is the multivariate breeder's equation Δz = β x G, where Δz&nbsp;is the vector of differences in trait means, β&nbsp;is a vector of selection coefficients, and G is a matrix of the additive genetic variance and covariance between traits.<ref>{{Cite journal|last=Arnold|first=S.J.|date=1992|title=Constraints on phenotypic evolution|journal=The American Naturalist|volume=140|pages=S85–S107|doi=10.1086/285398|pmid=19426028|s2cid=5965825 }}</ref><ref name=":16">{{Cite journal |author=Steppan, Scott J. |author2=Patrick C. Phillips |author3=David Houle |date=2002|title=Comparative quantitative genetics: evolution of the G matrix |journal=Trends in Ecology & Evolution |language=en|volume=17|issue=7|pages=320–327|doi=10.1016/S0169-5347(02)02505-3|issn=0169-5347}}</ref> Thus, a population's immediate ability to respond to selection is determined by the G-matrix, in which the variance is a function of standing genetic variation, and the covariance arises from pleiotropy and linkage disequilibrium.<ref name=":16" /><ref name=":17">{{Cite journal|last1=Jones|first1=Adam G.|last2=Arnold|first2=Stevan J.|last3=Bürger|first3=Reinhard|date=2007|title=The Mutation Matrix and the Evolution of Evolvability |journal=Evolution |language=en |volume=61 |issue=4 |pages=727–745 |doi=10.1111/j.1558-5646.2007.00071.x |pmid=17439608 |issn=0014-3820|doi-access=}}</ref> Although the G-matrix is one of the most relevant parameters to study evolvability,<ref name=":7" /> the mutational matrix (M-matrix), also known as the distribution of mutational effects, has been shown to be of equivalent importance.<ref name=":17" /> The M-matrix describes the potential effects of new mutations on the existing genetic variances and covariances, and these effects will depend on the epistatic and pleiotropic interactions of the underlying genes.<ref name=":7" /><ref name=":17" /><ref>{{Cite journal|last=Cheverud|first=James M.|date=1984|title=Quantitative genetics and developmental constraints on evolution by selection |journal=Journal of Theoretical Biology |volume=110 |issue=2 |pages=155–171 |doi=10.1016/s0022-5193(84)80050-8 |pmid=6492829|bibcode=1984JThBi.110..155C |issn=0022-5193 }}</ref> In other words, the M-matrix determines the G-matrix, and thus, the response to selection of a population.<ref name=":17" /> Similarly to the P-matrix, the G-matrix describes the main axis of variation.

=== Paths of least resistance ===

thumb|325x325px|Morphospace and fitness landscape with a single fitness optimum. For a population undergoing directional selection, the main axis of variation (largest axis of the white ellipse) will bias the main direction of the trajectory toward the fitness optimum (arrow). The rate of morphological change will be inversely proportional to the angle (beta) formed between the direction of selection (dashed line) and the main axis of variation.

A general consequence of the P-matrices and G-matrices is that evolution will tend to follow the 'path of least resistance'. In other words, if the main axis of variation is aligned with the direction of selection, covariation (genetic or phenotypic) will facilitate the rate of adaptive evolution; however, if the main axis of variation is orthogonal to the direction of selection, covariation will constraint the rate of adaptive evolution.<ref name=":1" /><ref name=":7" /><ref name=":15" /> In general, for a population under the influence of a single fitness optimum, the rate of morphological divergence (from an ancestral to a new phenotype or between pairs of species) is inversely proportional to the angle formed by the main axis of variation and the direction of selection, causing a curved trajectory through the morphospace.<ref name=":18">{{Cite journal |last=Schluter |first=Dolph |author-link=Dolph Schluter |date=1996 |title=Adaptive Radiation Along Genetic Lines of Least Resistance |journal=Evolution |volume=50 |issue=5 |pages=1766–1774 |doi=10.2307/2410734 |pmid=28565589 |jstor=2410734}}</ref>

From the P-matrix for a set of characters, two broadly important measures of the propensity of variation can be extracted: 1) Respondability: ability of a developmental system to change in any direction, and 2) Evolvability: ability of a developmental system to change in the direction of natural selection.<ref name=":15" /> In the latter, the main axis of phenotypic variation is aligned with the direction of selection. Similarly, from the G-matrix, the most important parameter that describes the propensity of variation is the lead eigenvector of G (g_max), which describes the direction of greatest additive genetic variance for a set of continuous traits within populations.<ref name=":17" /><ref name=":18" /> For a population undergoing directional selection, g_max will bias the main direction of the trajectory.<ref name=":18" />

== Biased phenotypes II: Properties of gene regulatory networks ==

=== Hierarchy and optimal pleiotropy ===

[[File:Melanism in Panthera Onca.jpg|thumb|250x250px|Different vertebrate species have evolved melanic forms from parallel mutations at the ''mc1r'' gene.<ref>{{Cite journal |last=Hoekstra |first=H. E. |date=2006-07-05|title=Genetics, development and evolution of adaptive pigmentation in vertebrates |journal=Heredity |volume=97 |issue=3 |pages=222–234 |doi=10.1038/sj.hdy.6800861 |pmid=16823403|issn=0018-067X|doi-access=free}}</ref> ]]

GRNs are modular, multilayered, and semi-hierarchically systems of genes and their products: each transcription factor provides multiple inputs to other genes, creating a complex array of interactions,<ref name=":19">{{Cite journal|last1=Erwin|first1=Douglas H. |last2=Davidson|first2=Eric H.|date=2009 |title=The evolution of hierarchical gene regulatory networks |journal=Nature Reviews Genetics |volume=10 |issue=2 |pages=141–148|doi=10.1038/nrg2499|pmid=19139764 |s2cid=7613857 |issn=1471-0056 |url=https://authors.library.caltech.edu/14706/2/nrg2499-s1.pdf}}</ref> and information regarding the timing, place and amount of gene expression generally flows from few high-level control genes through multiple intermediate genes to peripheral gene batteries that ultimately determine the fate of each cell.<ref name=":10" /><ref name=":19" /> This type of architecture implies that high-level control genes tend to be more pleiotropic affecting multiple downstream genes, whereas intermediate and peripheral genes tend to have moderate to low pleiotropic effects, respectively.<ref name=":10" /><ref name=":19" />

In general, it is expected that newly arisen mutations with higher dominance and fewer pleiotropic and epistatic effects are more likely to be targets of evolution,<ref name=":20">{{Cite book |title=Evolution, development, & the predictable genome |last=Stern|first=D.L. |date=2011|publisher=Roberts and Company Publishers |isbn=978-1-936221-01-1 |location=Greenwood Village, Colorado |oclc=762460688}}</ref> thus, the hierarchical architecture of developmental pathways may bias the genetic basis of evolutionary change. For instance, genes within GRNs with "optimally pleiotropic" effects, that is, genes that have the most widespread effect on the trait under selection but few effects on other traits, are expected to accumulate a higher proportion of mutations that cause evolutionary change.<ref>{{Cite journal|last=Kopp|first=A.|date=2009 |title=Metamodels and phylogenetic replication: A systematic approach to the evolution of developmental pathways |journal=Evolution |volume=63 |issue=11|pages=2771–2789 |doi=10.1111/j.1558-5646.2009.00761.x |pmid=19545263 |doi-access=}}</ref> These strategically-positioned genes have the potential to filter random genetic variation and translate it to nonrandom functionally integrated phenotypes, making adaptive variants effectively accessible to selection,<ref name=":7" /> and, thus, many of the mutations contributing to phenotypic evolution may be concentrated in these genes.<ref name=":20" /><ref>{{Cite journal |last1=Stern |first1=D.L. |author2-link=Virginie Courtier-Orgogozo |last2=Orgogozo |first2=V. |date=2008 |title=The Loci of Evolution: How Predictable is Genetic Evolution? |journal=Evolution |language=en |volume=62 |issue=9 |pages=2155–2177 |doi=10.1111/j.1558-5646.2008.00450.x |issn=0014-3820 |pmc=2613234 |pmid=18616572}}</ref>

=== Neutral networks ===

The genotype–phenotype map perspective establishes that the way in which genotypic variation can be mapped to phenotypic variation is critical for the ability of a system to evolve.<ref name=":14" /> The prevalence of neutral mutations in nature implies that biological systems have more genotypes than phenotypes,<ref>{{Cite journal |last1=Schuster |first1=Peter |last2=Fontana |first2=Walter |last3=Stadler |first3=Peter F. |last4=Hofacker |first4=Ivo L. |date=1994|title=From sequences to shapes and back: a case study in RNA secondary structures |journal=Proceedings of the Royal Society of London B |volume=255 |issue=1344 |pages=279–284 |doi=10.1098/rspb.1994.0040 |issn=0962-8452 |pmid=7517565 |bibcode=1994RSPSB.255..279S |s2cid=12021473 }}</ref> and a consequence of this "many-to-few" relationship between genotype and phenotype is the existence of ''neutral networks''.<ref name=":4" /><ref name=":21">{{Cite journal |last=Wagner |first=Andreas |date=2011 |title=Genotype networks shed light on evolutionary constraints |journal=Trends in Ecology & Evolution |volume=26 |issue=11 |pages=577–584 |doi=10.1016/j.tree.2011.07.001 |pmid=21840080 |issn=0169-5347 |url=https://www.zora.uzh.ch/id/eprint/59829/1/Wagner_TrendsinEcologyandEvolution.pdf}}</ref> In development, neutral networks are clusters of GRNs that differ in only one interaction between two nodes (e.g. replacing transcription with suppression) and yet produce the same phenotypic outcome.<ref name=":4" /><ref name=":7" /> In this sense, an individual phenotype within a population could be mapped to several equivalent GRNs, that together constitute a neutral network. Conversely, a GRN that differs in one interaction and causes a different phenotype is considered non-neutral.<ref name=":4" /> Given this architecture, the probability of mutating from one phenotype to another will depend on the number of neutral-neighbors relative to non-neutral neighbors for a particular GRN,<ref name=":4" /><ref name=":7" /> and thus, phenotypic change will be influenced by the position of a GRN within the network and will be biased towards changes that require few mutations to reach a neighboring non-neutral GRN.<ref name=":7" /><ref name=":21" />

== See also ==

* Evolvability * Speciation

== References == {{Reflist}}

== Further reading == * ''Ontogeny and Phylogeny'' (Gould, 1977) * ''Biased Embryos and Evolution'' (Arthur, 2004) * ''Evolution: A developmental approach'' (Arthur, 2010) * ''Homology, Genes, and Evolutionary Innovation'' (Wagner, 2014) * ''Evolution, development, and the predictable genome'' (Stern, 2011)

Category:Developmental biology Category:Extended evolutionary synthesis