evolutionary developmental biology

{{Short description|Comparison of organism developmental processes}}

File:Genes hox.jpeg Hox genes in such different animals as insects and vertebrates control embryonic development and hence the form of adult bodies. These genes have been highly conserved through hundreds of millions of years of evolution.]]

Evolutionary developmental biology, informally known as evo-devo, is a field of biological research that compares the developmental processes of different organisms to infer how developmental processes evolved.

The field grew from 19th-century beginnings, where embryology faced a mystery: zoologists did not know how embryonic development was controlled at the molecular level. Charles Darwin noted that having similar embryos implied common ancestry, but little progress was made until the 1970s. Then, recombinant DNA technology at last brought embryology together with molecular genetics. A key early discovery was that of homeotic genes that regulate development in a wide range of eukaryotes.

The field is composed of multiple core evolutionary concepts. One is deep homology, the finding that dissimilar organs such as the eyes of insects, vertebrates and cephalopod molluscs, long thought to have evolved separately, are controlled by similar genes such as pax-6, from the evo-devo gene toolkit. These genes are ancient, being highly conserved among phyla; they generate the patterns in time and space which shape the embryo, and ultimately form the body plan of the organism. Another is that species do not differ much in their structural genes, such as those coding for enzymes; what does differ is the way that gene expression is regulated by the toolkit genes. These genes are reused, unchanged, many times in different parts of the embryo and at different stages of development, forming a complex cascade of control, switching other regulatory genes as well as structural genes on and off in a precise pattern. This multiple pleiotropic reuse explains why these genes are highly conserved, as any change would have many adverse consequences which natural selection would oppose.

New morphological features and ultimately new species are produced by variations in the toolkit, either when genes are expressed in a new pattern, or when toolkit genes acquire additional functions. Another possibility is the neo-Lamarckian theory that epigenetic changes are later consolidated at gene level, something that may have been important early in the history of multicellular life.

History

=Early theories=

Philosophers began to think about how animals acquired form in the womb in classical antiquity. Aristotle asserts in his Physics treatise that according to Empedocles, order "spontaneously" appears in the developing embryo. In his The Parts of Animals treatise, he argues that Empedocles' theory was wrong. In Aristotle's account, Empedocles stated that the vertebral column is divided into vertebrae because, as it happens, the embryo twists about and snaps the column into pieces. Aristotle argues instead that the process has a predefined goal: that the "seed" that develops into the embryo began with an inbuilt "potential" to become specific body parts, such as vertebrae. Further, each sort of animal gives rise to animals of its own kind: humans only have human babies.{{Cite book |last=Leroi |first=Armand Marie |author-link=Armand Marie Leroi |title=The Lagoon: How Aristotle Invented Science |title-link=Aristotle's Lagoon |date=2014 |publisher=Bloomsbury |isbn=978-1-4088-3622-4 |pages=181–182}}

=Recapitulation=

File:Haeckel vs von Baer.svg, who argued for recapitulation{{harvnb|Richardson|Keuck|2002|p=516}} of evolutionary development in the embryo, and Karl Ernst von Baer's epigenesis ]]

A recapitulation theory of evolutionary development was proposed by Étienne Serres in 1824–26, echoing the 1808 ideas of Johann Friedrich Meckel. They argued that the embryos of 'higher' animals went through or recapitulated a series of stages, each of which resembled an animal lower down the great chain of being. For example, the brain of a human embryo looked first like that of a fish, then in turn like that of a reptile, bird, and mammal before becoming clearly human. The embryologist Karl Ernst von Baer opposed this, arguing in 1828 that there was no linear sequence as in the great chain of being, based on a single body plan, but a process of epigenesis in which structures differentiate. Von Baer instead recognized four distinct animal body plans: radiate, like starfish; molluscan, like clams; articulate, like lobsters; and vertebrate, like fish. Zoologists then largely abandoned recapitulation, though Ernst Haeckel revived it in 1866.{{Cite web |last=O'Connell |first=Lindsey |date=10 July 2013 |title=The Meckel-Serres Conception of Recapitulation |url=https://embryo.asu.edu/pages/meckel-serres-conception-recapitulation |access-date=10 October 2016 |website=The Embryo Project Encyclopedia}}{{Cite book |last=Desmond |first=Adrian J. |author-link=Adrian Desmond |url=https://archive.org/details/politicsofevolut00adri/page/53 |title=The politics of evolution: morphology, medicine, and reform in radical London |publisher=University of Chicago Press |year=1989 |isbn=978-0-226-14374-3 |location=Chicago |pages=[https://archive.org/details/politicsofevolut00adri/page/53 53–53, 86–88, 337–340, 490–491] |url-access=registration}}{{harvnb|Secord|2003|pp=252–253}}{{Cite book |last=Bowler |first=Peter J. |url=https://archive.org/details/evolutionhistory0000bowl_n7y8/page/120 |title=Evolution: the history of an idea |publisher=University of California Press |year=2003 |isbn=978-0-520-23693-6 |location=Berkeley |pages=[https://archive.org/details/evolutionhistory0000bowl_n7y8/page/120 120–128, 190–191, 208]}}{{harvnb|Secord|2003|pp=424, 512}}

=Evolutionary morphology=

File:Comparison of Three Invertebrate Chordates.svg (a chordate), B. Larval tunicate, C. Adult tunicate. Kowalevsky saw that the notochord (1) and gill slits (5) are shared by tunicates and vertebrates.]]

From the early 19th century through most of the 20th century, embryology faced a mystery. Animals were seen to develop into adults of widely differing body plan, often through similar stages, from the egg, but zoologists knew almost nothing about how embryonic development was controlled at the molecular level, and therefore equally little about how developmental processes had evolved.{{Cite web |last=Carroll |first=Sean B. |author-link=Sean B. Carroll |title=The Origins of Form |url=http://www.naturalhistorymag.com/features/061488/the-origins-of-form |access-date=9 October 2016 |website=Natural History |quote=Biologists could say, with confidence, that forms change, and that natural selection is an important force for change. Yet they could say nothing about how that change is accomplished. How bodies or body parts change, or how new structures arise, remained complete mysteries.}} Charles Darwin argued that a shared embryonic structure implied a common ancestor. For example, Darwin cited in his 1859 book On the Origin of Species the shrimp-like larva of the barnacle, whose sessile adults looked nothing like other arthropods; Linnaeus and Cuvier had classified them as molluscs.{{Cite journal |last=Gilbert |first=Scott F. |author-link=Scott F. Gilbert |date=2003 |title=The morphogenesis of evolutionary developmental biology |url=http://www.chd.ucsd.edu/_files/fall2008/Gilbert.2003.IJDB.pdf |journal=International Journal of Developmental Biology |volume=47 |issue=7–8 |pages=467–477 |pmid=14756322}}{{Cite book |last=Darwin |first=Charles |author-link=Charles Darwin |url=http://darwin-online.org.uk/content/frameset?viewtype=text&itemID=F373&pageseq=457 |title=On the Origin of Species |publisher=John Murray |year=1859 |isbn=978-0-8014-1319-3 |location=London |pages=439–440 |quote=Cirripedes afford a good instance of this: even the illustrious Cuvier did not perceive that a barnacle was, as it certainly is, a crustacean; but a glance at the larva shows this to be the case in an unmistakeable manner.}} Darwin also noted Alexander Kowalevsky's finding that the tunicate, too, was not a mollusc, but in its larval stage had a notochord and pharyngeal slits which developed from the same germ layers as the equivalent structures in vertebrates, and should therefore be grouped with them as chordates.{{Cite web |last=Richmond |first=Marsha |date=January 2007 |title=Darwin's Study of the Cirripedia |url=http://darwin-online.org.uk/EditorialIntroductions/Richmond_cirripedia.html |access-date=9 October 2016 |publisher=Darwin Online}}

19th century zoology thus converted embryology into an evolutionary science, connecting phylogeny with homologies between the germ layers of embryos. Zoologists including Fritz Müller proposed the use of embryology to discover phylogenetic relationships between taxa. Müller demonstrated that crustaceans shared the Nauplius larva, identifying several parasitic species that had not been recognized as crustaceans. Müller also recognized that natural selection must act on larvae, just as it does on adults, giving the lie to recapitulation, which would require larval forms to be shielded from natural selection. Two of Haeckel's other ideas about the evolution of development have fared better than recapitulation: he argued in the 1870s that changes in the timing (heterochrony) and changes in the positioning within the body (heterotopy) of aspects of embryonic development would drive evolution by changing the shape of a descendant's body compared to an ancestor's. It took a century before these ideas were shown to be correct.{{Cite journal |last=Hall |first=B. K. |date=2003 |title=Evo-Devo: evolutionary developmental mechanisms |journal=International Journal of Developmental Biology |volume=47 |issue=7–8 |pages=491–495 |pmid=14756324}}{{Cite book |last=Ridley |first=Mark |author-link=Mark Ridley (zoologist) |url=http://www.blackwellpublishing.com/ridley/ |title=Evolution |publisher=Wiley-Blackwell |year=2003 |isbn=978-1-4051-0345-9}}{{sfn|Gould|1977|pp=221–222}}

File:Giant Pufferfish skin pattern detail.jpg, may arise, without molecular evidence.]]

In 1917, D'Arcy Thompson wrote a book on the shapes of animals, showing with simple mathematics how small changes to parameters, such as the angles of a gastropod's spiral shell, can radically alter an animal's form, though he preferred a mechanical to evolutionary explanation.{{Cite journal |last=Ball |first=Philip |author-link=Philip Ball |date=7 February 2013 |title=In retrospect: On Growth and Form |journal=Nature |volume=494 |issue=32–33 |pages=32–33 |bibcode=2013Natur.494...32B |doi=10.1038/494032a |s2cid=205076253 |doi-access=free}}{{Cite web |last=Shalizi |first=Cosma |title=Review: The Self-Made Tapestry by Philip Ball |url=http://bactra.org/reviews/self-made-tapestry/ |access-date=14 October 2016 |publisher=University of Michigan}} But without molecular evidence, progress stalled.

In 1952, Alan Turing published his paper "The Chemical Basis of Morphogenesis", on the development of patterns in animals' bodies. He suggested that morphogenesis could be explained by a reaction–diffusion system, a system of reacting chemicals able to diffuse through the body.{{Cite journal |last=Turing |first=Alan M. |author-link=Alan Turing |date=14 August 1952 |title=The Chemical Basis of Morphogenesis |journal=Philosophical Transactions of the Royal Society of London B |volume=237 |pages=37–72 |bibcode=1952RSPTB.237...37T |doi=10.1098/rstb.1952.0012 |s2cid=120437796 |number=641}} He modelled catalysed chemical reactions using partial differential equations, showing that patterns emerged when the chemical reaction produced both a catalyst (A) and an inhibitor (B) that slowed down production of A. If A and B then diffused at different rates, A dominated in some places, and B in others. The Russian biochemist Boris Belousov had run experiments with similar results, but was unable to publish them because scientists thought at that time that creating visible order violated the second law of thermodynamics.{{Cite book |last=Gribbin |first=John |author-link=John Gribbin |title=Deep Simplicity |publisher=Random House |year=2004 |page=126}}

=The modern synthesis of the early 20th century=

In the so-called modern synthesis of the early 20th century, between 1918 and 1930 Ronald Fisher brought together Darwin's theory of evolution, with its insistence on natural selection, heredity, and variation, and Gregor Mendel's laws of genetics into a coherent structure for evolutionary biology. Biologists assumed that an organism was a straightforward reflection of its component genes: the genes coded for proteins, which built the organism's body. Biochemical pathways (and, they supposed, new species) evolved through mutations in these genes. It was a simple, clear and nearly comprehensive picture: but it did not explain embryology.{{Cite journal |last=Bock |first=Walter J. |date=July 1981 |title=Reviewed Work: The Evolutionary Synthesis. Perspectives on the Unification of Biology |journal=The Auk |volume=98 |issue=3 |pages=644–646 |jstor=4086148}} Sean B. Carroll has commented that had evo-devo's insights been available, embryology would certainly have played a central role in the synthesis.

The evolutionary embryologist Gavin de Beer anticipated evolutionary developmental biology in his 1930 book Embryos and Ancestors,{{Cite book |last=Held |first=Lewis I. |author-link=Lewis I. Held |title=How the Snake Lost its Legs. Curious Tales from the Frontier of Evo-Devo |title-link=How the Snake Lost its Legs |date=2014 |publisher=Cambridge University Press |isbn=978-1-107-62139-8 |page=67}} by showing that evolution could occur by heterochrony,{{harvnb|Gould|1977|pp=221–222}} such as in the retention of juvenile features in the adult. This, de Beer argued, could cause apparently sudden changes in the fossil record, since embryos fossilise poorly. As the gaps in the fossil record had been used as an argument against Darwin's gradualist evolution, de Beer's explanation supported the Darwinian position.{{Cite journal |last=Brigandt |first=Ingo |year=2006 |title=Homology and heterochrony: the evolutionary embryologist Gavin Rylands de Beer (1899-1972) |url=https://www.ualberta.ca/~brigandt/de_Beer.pdf |journal=Journal of Experimental Zoology |volume=306B |issue=4 |pages=317–328 |bibcode=2006JEZB..306..317B |doi=10.1002/jez.b.21100 |pmid=16506229}} However, despite de Beer, the modern synthesis largely ignored embryonic development to explain the form of organisms, since population genetics appeared to be an adequate explanation of how forms evolved.{{Cite journal |last=Gilbert |first=S. F. |last2=Opitz |first2=J. M. |last3=Raff |first3=R. A. |date=1996 |title=Resynthesizing evolutionary and developmental biology |journal=Developmental Biology |volume=173 |issue=2 |pages=357–372 |doi=10.1006/dbio.1996.0032 |pmid=8605997 |doi-access=free}}{{Cite book |last=Adams, M. |title=New Perspectives in Evolution |date=1991 |publisher=Liss/Wiley |editor-last=Warren, L. |pages=37–63 |chapter=Through the looking glass: The evolution of Soviet Darwinism |editor-last2=Koprowski, H.}}{{efn|Though C. H. Waddington had called for embryology to be added to the synthesis in his 1953 paper "Epigenetics and Evolution".{{harvnb|Smocovitis|1996|page=153}}}}

=The lac operon=

File:Lac Operon.svg. Top: repressed. Bottom: active. (1) RNA Polymerase, (2) Repressor, (3) Promoter, (4) Operator, (5) Lactose, (6–8) protein-encoding genes, controlled by the switch, that cause lactose to be digested.]]

In 1961, Jacques Monod, Jean-Pierre Changeux and François Jacob discovered the lac operon in the bacterium Escherichia coli. It was a cluster of genes, arranged in a feedback control loop so that its products would only be made when "switched on" by an environmental stimulus. One of these products was an enzyme that splits a sugar, lactose; and lactose itself was the stimulus that switched the genes on. This was a revelation, as it showed for the first time that genes, even in organisms as small as a bacterium, are subject to precise control. The implication was that many other genes were also elaborately regulated.{{Cite journal |last=Monod |first=Jacques |author-link=Jacques Monod |last2=Changeux |first2=J.P. |last3=Jacob |first3=François |author-link3=François Jacob |year=1963 |title=Allosteric proteins and cellular control systems |journal=Journal of Molecular Biology |volume=6 |issue=4 |pages=306–329 |doi=10.1016/S0022-2836(63)80091-1 |pmid=13936070}}

=The birth of evo-devo and a second synthesis=

In 1977, a revolution in thinking about evolution and developmental biology began, with the arrival of recombinant DNA technology in genetics, the book Ontogeny and Phylogeny by Stephen J. Gould and the paper "Evolution and Tinkering"{{Cite journal |last=Jacob |first=François |date=10 June 1977 |title=Evolution and Tinkering |journal=Science |volume=196 |issue=4295 |pages=1161–1166 |bibcode=1977Sci...196.1161J |doi=10.1126/science.860134 |pmid=860134}} by François Jacob. Gould laid to rest Haeckel's interpretation of evolutionary embryology, while Jacob set out an alternative theory.

This led to a second synthesis,{{Cite journal |last=Gilbert |first=S.F. |last2=Opitz |first2=J.M. |last3=Raff |first3=R.A. |date=1996 |title=Resynthesizing Evolutionary and Developmental Biology |journal=Developmental Biology |volume=173 |issue=2 |pages=357–372 |doi=10.1006/dbio.1996.0032 |pmid=8605997 |doi-access=free}}{{Cite journal |last=Müller |first=G. B. |author-link=Gerd B. Müller |date=2007 |title=Evo–devo: extending the evolutionary synthesis |journal=Nature Reviews Genetics |volume=8 |issue=12 |pages=943–949 |doi=10.1038/nrg2219 |pmid=17984972 |s2cid=19264907}} at last including embryology as well as molecular genetics, phylogeny, and evolutionary biology to form evo-devo.{{Cite journal |last=Goodman |first=C. S. |last2=Coughlin |first2=B. C. |year=2000 |editor2-last=Coughlin B. S. |title=Special feature: The evolution of evo-devo biology |journal=Proceedings of the National Academy of Sciences |volume=97 |issue=9 |pages=4424–4456 |bibcode=2000PNAS...97.4424G |doi=10.1073/pnas.97.9.4424 |pmc=18255 |pmid=10781035 |doi-access=free |editor1=Goodman, C. S.}}{{Cite journal |last=Müller GB and Newman SA (Eds.) |year=2005 |title=Special issue: Evolutionary Innovation and Morphological Novelty |url=http://www3.interscience.wiley.com/cgi-bin/jissue/112149101 |journal=Journal of Experimental Zoology Part B |volume=304B |issue=6 |pages=485–631 |doi=10.1002/jez.b.21080 |pmid=16252267 |archive-url=https://archive.today/20121211055145/http://www3.interscience.wiley.com/cgi-bin/jissue/112149101 |archive-date=2012-12-11|url-access=subscription }} In 1978, Edward B. Lewis discovered homeotic genes that regulate embryonic development in Drosophila fruit flies, which like all insects are arthropods, one of the major phyla of invertebrate animals.{{Cite journal |last=Palmer |first=R.A. |year=2004 |title=Symmetry breaking and the evolution of development |journal=Science |volume=306 |issue=5697 |pages=828–833 |bibcode=2004Sci...306..828P |citeseerx=10.1.1.631.4256 |doi=10.1126/science.1103707 |pmid=15514148 |s2cid=32054147}}

Bill McGinnis quickly discovered homeotic gene sequences, homeoboxes, in animals in other phyla, in vertebrates such as frogs, birds, and mammals; they were later also found in fungi such as yeasts, and in plants.{{Cite web |last=Bürglin |first=Thomas R. |title=The Homeobox Page |url=http://homeobox.biosci.ki.se/ |access-date=13 October 2016 |publisher=Karolinska Institutet}} There were evidently strong similarities in the genes that controlled development across all the eukaryotes.{{Cite journal |last=Holland |first=P.W. |date=2013 |title=Evolution of homeobox genes |journal=Wiley Interdiscip Rev Dev Biol |volume=2 |issue=1 |pages=31–45 |doi=10.1002/wdev.78 |pmid=23799629 |s2cid=44396110 |quote=Homeobox genes are found in almost all eukaryotes, and have diversified into 11 gene classes and over 100 gene families in animal evolution, and 10 to 14 gene classes in plants.}}

In 1980, Christiane Nüsslein-Volhard and Eric Wieschaus described gap genes which help to create the segmentation pattern in fruit fly embryos;{{Cite journal |last=Nüsslein-Volhard, C. |last2=Wieschaus, E. |date=October 1980 |title=Mutations affecting segment number and polarity in Drosophila |journal=Nature |volume=287 |issue=5785 |pages=795–801 |bibcode=1980Natur.287..795N |doi=10.1038/287795a0 |pmid=6776413 |s2cid=4337658}}{{Cite journal |last=Arthur |first=Wallace |date=14 February 2002 |title=The emerging conceptual framework of evolutionary developmental biology |journal=Nature |volume=415 |issue=6873 |pages=757–764 |bibcode=2002Natur.415..757A |doi=10.1038/415757a |pmid=11845200 |s2cid=4432164}} they and Lewis won a Nobel Prize for their work in 1995.{{Cite journal |last=Winchester |first=Guil |year=2004 |title=Edward B. Lewis 1918-2004 |url=http://www.cell.com/current-biology/pdf/S0960-9822(04)00683-9.pdf |publication-date=Sep 21, 2004 |volume=14 |issue=18 |pages=R740–742 |doi=10.1016/j.cub.2004.09.007 |pmid=15380080 |s2cid=32648995 |doi-access=free |periodical=Current Biology}}{{Cite web |title=Eric Wieschaus and Christiane Nüsslein-Volhard: Collaborating to Find Developmental Genes |url=https://www.ibiology.org/ibiomagazine/eric-wieschaus-and-christiane-nusselin-volhard.html |url-status=dead |archive-url=https://web.archive.org/web/20161013223611/https://www.ibiology.org/ibiomagazine/eric-wieschaus-and-christiane-nusselin-volhard.html |archive-date=13 October 2016 |access-date=13 October 2016 |publisher=iBiology}}

Later, more specific similarities were discovered: for example, the distal-less gene was found in 1989 to be involved in the development of appendages or limbs in fruit flies,{{Cite journal |last=Cohen, S. M. |last2=Jurgens, G. |date=1989 |title=Proximal-distal pattern formation in Drosophila: cell autonomous requirement for Distal-less activity in limb development |journal=EMBO J. |volume=8 |issue=7 |pages=2045–2055 |doi=10.1002/j.1460-2075.1989.tb03613.x |pmc=401088 |pmid=16453891}} the fins of fish, the wings of chickens, the parapodia of marine annelid worms, the ampullae and siphons of tunicates, and the tube feet of sea urchins. It was evident that the gene must be ancient, dating back to the last common ancestor of bilateral animals (before the Ediacaran Period, which began some 635 million years ago). Evo-devo had started to uncover the ways that all animal bodies were built during development.{{Cite book |last=Carroll |first=Sean B. |author-link=Sean B. Carroll |title=Endless Forms Most Beautiful: The New Science of Evo Devo and the Making of the Animal Kingdom |title-link=Endless Forms Most Beautiful (book) |date=2006 |publisher=Weidenfeld & Nicolson [Norton] |isbn=978-0-297-85094-6 |pages=63–70 |orig-date=2005}}{{Cite journal |last=Panganiban |first=G. |last2=Irvine |first2=S. M. |last3=Lowe |first3=C. |last4=Roehl |first4=H. |last5=Corley |first5=L. S. |last6=Sherbon |first6=B. |last7=Grenier |first7=J. K. |last8=Fallon |first8=J. F. |last9=Kimble |first9=J. |last10=Walker |first10=M. |last11=Wray |first11=G. A. |last12=Swalla |first12=B. J. |last13=Martindale |first13=M. Q. |last14=Carroll |first14=S. B. |year=1997 |title=The origin and evolution of animal appendages |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=94 |issue=10 |pages=5162–5166 |bibcode=1997PNAS...94.5162P |doi=10.1073/pnas.94.10.5162 |pmc=24649 |pmid=9144208 |doi-access=free}}

The control of body structure

=Deep homology=

Roughly spherical eggs of different animals give rise to unique morphologies, from jellyfish to lobsters, butterflies to elephants. Many of these organisms share the same structural genes for body{{hyp}}building proteins like collagen and enzymes, but biologists had expected that each group of animals would have its own rules of development. The surprise of evo-devo is that the shaping of bodies is controlled by a rather small percentage of genes, and that these regulatory genes are ancient, shared by all animals. The giraffe does not have a gene for a long neck, any more than the elephant has a gene for a big body. Their bodies are patterned by a system of switching which causes development of different features to begin earlier or later, to occur in this or that part of the embryo, and to continue for more or less time.

The puzzle of how embryonic development was controlled began to be solved using the fruit fly Drosophila melanogaster as a model organism. The step-by-step control of its embryogenesis was visualized by attaching fluorescent dyes of different colours to specific types of protein made by genes expressed in the embryo. A dye such as green fluorescent protein, originally from a jellyfish, was typically attached to an antibody specific to a fruit fly protein, forming a precise indicator of where and when that protein appeared in the living embryo.{{Cite web |date=2015 |title=Fluorescent Probes |url=https://www.thermofisher.com/uk/en/home/life-science/protein-biology/protein-biology-learning-center/protein-biology-resource-library/pierce-protein-methods/fluorescent-probes.html# |access-date=12 October 2016 |publisher=ThermoFisher Scientific}}

File:PAX6 Phenotypes Washington etal PLoSBiol e1000247.png gene controls development of eyes of different types across the animal kingdom.]]

Using such a technique, in 1994 Walter Gehring found that the pax-6 gene, vital for forming the eyes of fruit flies, exactly matches an eye-forming gene in mice and humans. The same gene was quickly found in many other groups of animals, such as squid, a cephalopod mollusc. Biologists including Ernst Mayr had believed that eyes had arisen in the animal kingdom at least 40 times, as the anatomy of different types of eye varies widely. For example, the fruit fly's compound eye is made of hundreds of small lensed structures (ommatidia); the human eye has a blind spot where the optic nerve enters the eye, and the nerve fibres run over the surface of the retina, so light has to pass through a layer of nerve fibres before reaching the detector cells in the retina, so the structure is effectively "upside-down"; in contrast, the cephalopod eye has the retina, then a layer of nerve fibres, then the wall of the eye "the right way around".{{Cite journal |last=Land |first=M. F. |last2=Fernald |first2=R. D. |year=1992 |title=The evolution of eyes |journal=Annual Review of Neuroscience |volume=15 |pages=1–29 |doi=10.1146/annurev.ne.15.030192.000245 |pmid=1575438}} The evidence of pax-6, however, was that the same genes controlled the development of the eyes of all these animals, suggesting that they all evolved from a common ancestor. Ancient genes had been conserved through millions of years of evolution to create dissimilar structures for similar functions, demonstrating deep homology between structures once thought to be purely analogous.{{Cite journal |last=Pichaud |first=Franck |last2=Desplan |first2=Claude |date=August 2002 |title=Pax genes and eye organogenesis |journal=Current Opinion in Genetics & Development |volume=12 |issue=4 |pages=430–434 |doi=10.1016/S0959-437X(02)00321-0 |pmid=12100888}} This notion was later extended to the evolution of embryogenesis{{Cite journal |last=Drost |first=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}} and has caused a radical revision of the meaning of homology in evolutionary biology.{{Cite journal |last=Tomarev |first=Stanislav I. |last2=Callaerts |first2=Patrick |last3=Kos |first3=Lidia |last4=Zinovieva |first4=Rina |last5=Halder |first5=Georg |last6=Gehring |first6=Walter |last7=Piatigorsky |first7=Joram |year=1997 |title=Squid Pax-6 and eye development |journal=Proceedings of the National Academy of Sciences |volume=94 |issue=6 |pages=2421–2426 |bibcode=1997PNAS...94.2421T |doi=10.1073/pnas.94.6.2421 |pmc=20103 |pmid=9122210 |doi-access=free}}

=Gene toolkit=

File:Hoxgenesoffruitfly.svg in the fruit fly]]

A small fraction of the genes in an organism's genome control the organism's development. These genes are called the developmental-genetic toolkit. They are highly conserved among phyla, meaning that they are ancient and very similar in widely separated groups of animals. Differences in deployment of toolkit genes affect the body plan and the number, identity, and pattern of body parts. Most toolkit genes are parts of signalling pathways: they encode transcription factors, cell adhesion proteins, cell surface receptor proteins and signalling ligands that bind to them, and secreted morphogens that diffuse through the embryo. All of these help to define the fate of undifferentiated cells in the embryo. Together, they generate the patterns in time and space which shape the embryo, and ultimately form the body plan of the organism. Among the most important toolkit genes are the Hox genes. These transcription factors contain the homeobox protein-binding DNA motif, also found in other toolkit genes, and create the basic pattern of the body along its front-to-back axis.

Hox genes determine where repeating parts, such as the many vertebrae of snakes, will grow in a developing embryo or larva. Pax-6, already mentioned, is a classic toolkit gene.{{Cite journal |last=Xu, P.X. |last2=Woo, I. |last3=Her, H. |last4=Beier, D. R. |last5=Maas, R. L. |year=1997 |title=Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for expression in lens and nasal placode |journal=Development |volume=124 |issue=1 |pages=219–231 |doi=10.1242/dev.124.1.219 |pmid=9006082}} Although other toolkit genes are involved in establishing the plant bodyplan,{{Cite journal |last=Quint |first=Marcel |last2=Drost |first2=Hajk-Georg |last3=Gabel |first3=Alexander |last4=Ullrich |first4=Kristian Karsten |last5=Bönn |first5=Markus |last6=Grosse |first6=Ivo |date=2012-10-04 |title=A transcriptomic hourglass in plant embryogenesis |journal=Nature |volume=490 |issue=7418 |pages=98–101 |bibcode=2012Natur.490...98Q |doi=10.1038/nature11394 |issn=0028-0836 |pmid=22951968 |s2cid=4404460}} homeobox genes are also found in plants, implying they are common to all eukaryotes.{{Cite journal |last=Mukherjee |first=K. |last2=Brocchieri, L. |last3=Bürglin, T.R. |date=December 2009 |title=A comprehensive classification and evolutionary analysis of plant homeobox genes |journal=Molecular Biology and Evolution |volume=26 |issue=12 |pages=2775–94 |doi=10.1093/molbev/msp201 |pmc=2775110 |pmid=19734295}}{{Cite journal |last=Bürglin, T.R. |date=November 1997 |title=Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals |journal=Nucleic Acids Research |volume=25 |issue=21 |pages=4173–80 |doi=10.1093/nar/25.21.4173 |pmc=147054 |pmid=9336443}}{{Cite journal |last=Derelle |first=R. |last2=Lopez, P. |last3=Le Guyader, H. |last4=Manuel, M. |year=2007 |title=Homeodomain proteins belong to the ancestral molecular toolkit of eukaryotes |journal=Evolution & Development |volume=9 |issue=3 |pages=212–9 |doi=10.1111/j.1525-142X.2007.00153.x |pmid=17501745 |s2cid=9530210}}

=The embryo's regulatory networks=

{{Further|Regulation of gene expression|Transcriptional regulation}}

File:Gene Regulatory Network.jpg]]

The protein products of the regulatory toolkit are reused not by duplication and modification, but by a complex mosaic of pleiotropy, being applied unchanged in many independent developmental processes, giving pattern to many dissimilar body structures. The loci of these pleiotropic toolkit genes have large, complicated and modular cis-regulatory elements. For example, while a non-pleiotropic rhodopsin gene in the fruit fly has a cis-regulatory element just a few hundred base pairs long, the pleiotropic eyeless cis-regulatory region contains 6 cis-regulatory elements in over 7000 base pairs. The regulatory networks involved are often very large. Each regulatory protein controls "scores to hundreds" of cis-regulatory elements. For instance, 67 fruit fly transcription factors controlled on average 124 target genes each. All this complexity enables genes involved in the development of the embryo to be switched on and off at exactly the right times and in exactly the right places. Some of these genes are structural, directly forming enzymes, tissues and organs of the embryo. But many others are themselves regulatory genes, so what is switched on is often a precisely-timed cascade of switching, involving turning on one developmental process after another in the developing embryo.

File:Drosophila early embryo protein gradients.svg]]

Such a cascading regulatory network has been studied in detail in the development of the fruit fly embryo. The young embryo is oval in shape, like a rugby ball. A small number of genes produce messenger RNAs that set up concentration gradients along the long axis of the embryo. In the early embryo, the bicoid and hunchback genes are at high concentration near the anterior end, and give pattern to the future head and thorax; the caudal and nanos genes are at high concentration near the posterior end, and give pattern to the hindmost abdominal segments. The effects of these genes interact; for instance, the Bicoid protein blocks the translation of caudal{{'s}} messenger RNA, so the Caudal protein concentration becomes low at the anterior end. Caudal later switches on genes which create the fly's hindmost segments, but only at the posterior end where it is most concentrated.{{Cite book |last=Russel |first=Peter |title=iGenetics: a molecular approach |publisher=Pearson Education |year=2010 |isbn=978-0-321-56976-9 |pages=564–571}}{{Cite journal |last=Rivera-Pomar |first=Rolando |last2=Jackle, Herbert |year=1996 |title=From gradients to stripes in Drosophila embryogenesis: Filling in the gaps |journal=Trends in Genetics |volume=12 |issue=11 |pages=478–483 |doi=10.1016/0168-9525(96)10044-5 |pmid=8973159}}

File:Gap gene expression.svgs in the fruit fly are switched on by genes such as bicoid, setting up stripes across the embryo which start to pattern the body's segments.]]

The Bicoid, Hunchback and Caudal proteins in turn regulate the transcription of gap genes such as giant, knirps, Krüppel, and tailless in a striped pattern, creating the first level of structures that will become segments. The proteins from these in turn control the pair-rule genes, which in the next stage set up 7 bands across the embryo's long axis. Finally, the segment polarity genes such as engrailed split each of the 7 bands into two, creating 14 future segments.

This process explains the accurate conservation of toolkit gene sequences, which has resulted in deep homology and functional equivalence of toolkit proteins in dissimilar animals (seen, for example, when a mouse protein controls fruit fly development). The interactions of transcription factors and cis-regulatory elements, or of signalling proteins and receptors, become locked in through multiple usages, making almost any mutation deleterious and hence eliminated by natural selection.

The mechanism that sets up every animal's front-back axis is the same, implying a common ancestor. There is a similar mechanism for the back-belly axis for bilaterian animals, but it is reversed between arthropods and vertebrates.{{Cite journal |last=De Robertis |first=Eddy |last2=Sasai |first2=Yoshiki |year=1996 |title=A common plan for dorsoventral patterning in Bilateria |journal=Nature |volume=380 |issue=6569 |pages=37–40 |bibcode=1996Natur.380...37D |doi=10.1038/380037a0 |pmid=8598900 |s2cid=4355458}} Another process, gastrulation of the embryo, is driven by Myosin II molecular motors, which are not conserved across species. The process may have been started by movements of sea water in the environment, later replaced by the evolution of tissue movements in the embryo.{{Cite journal |last=Farge |first=Emmanuel |year=2003 |title=Mechanical induction of twist in the Drosophila foregut/stomodeal primordium |journal=Current Biology |volume=13 |issue=16 |pages=1365–1377 |doi=10.1016/s0960-9822(03)00576-1 |pmid=1293230 |doi-access=free}}{{Cite journal |last=Nguyen |first=Ngoc-Minh |last2=Merle |first2=Tatiana |display-authors=etal |year=2022 |title=Mechano-biochemical marine stimulation of inversion, gastrulation, and endomesoderm specification in multicellular Eukaryota |journal=Frontiers in Cell and Developmental Biology |volume=10 |page=992371 |doi=10.3389/fcell.2022.992371 |pmc=9754125 |pmid=36531949 |doi-access=free}}

The origins of novelty

Among the more surprising and, perhaps, counterintuitive (from a neo-Darwinian viewpoint) results of recent research in evolutionary developmental biology is that the diversity of body plans and morphology in organisms across many phyla are not necessarily reflected in diversity at the level of the sequences of genes, including those of the developmental genetic toolkit and other genes involved in development. Indeed, as John Gerhart and Marc Kirschner have noted, there is an apparent paradox: "where we most expect to find variation, we find conservation, a lack of change".{{Cite book |last=Gerhart |first=John |title=Cells, Embryos and Evolution |last2=Kirschner |first2=Marc |publisher=Blackwell Science |year=1997 |isbn=978-0-86542-574-3}} So, if the observed morphological novelty between different clades does not come from changes in gene sequences (such as by mutation), where does it come from? Novelty may arise by mutation-driven changes in gene regulation.{{Cite journal |last=Carroll |first=Sean B. |author-link=Sean B. Carroll |date=2008 |title=Evo-Devo and an Expanding Evolutionary Synthesis: A Genetic Theory of Morphological Evolution |journal=Cell |volume=134 |issue=1 |pages=25–36 |doi=10.1016/j.cell.2008.06.030 |pmid=18614008 |s2cid=2513041 |doi-access=free}}{{Cite book |last=Carroll |first=Sean B. |author-link=Sean B. Carroll |title=From DNA to Diversity: Molecular Genetics and the Evolution of Animal Design — Second Edition |last2=Grenier |first2=Jennifer K. |last3=Weatherbee |first3=Scott D. |publisher=Blackwell Publishing |year=2005 |isbn=978-1-4051-1950-4}}{{Cite journal |last=Carroll |first=Sean B. |author-link=Sean B. Carroll |year=2000 |title=Endless forms: the evolution of gene regulation and morphological diversity |journal=Cell |volume=101 |issue=6 |pages=577–80 |doi=10.1016/S0092-8674(00)80868-5 |pmid=10892643 |s2cid=12375030 |doi-access=free}}{{Cite journal |last=Moczek, Armin P. |display-authors=etal |date=2015 |title=The Significance and Scope of Evolutionary Developmental Biology: A Vision for the 21st Century |url=http://www.extavourlab.com/pdfs/papers/2015_Moczek_EvolDev.pdf |journal=Evolution & Development |volume=17 |issue=3 |pages=198–219 |doi=10.1111/ede.12125 |pmid=25963198 |s2cid=9652129 |archive-url=https://web.archive.org/web/20160417114046/http://www.extavourlab.com/pdfs/papers/2015_Moczek_EvolDev.pdf |archive-date=17 April 2016 |access-date=27 November 2015 |hdl-access=free |hdl=2027.42/111768}}

=Variations in the toolkit=

{{Multiple image

| total_width = 300px

| image1 = Heliconius erato Richard Bartz.jpg

| caption1 = Heliconius erato

| image2 = Heliconius melpomene 2b Richard Bartz.jpg

| caption2 = Heliconius melpomene

| footer = Different species of Heliconius butterfly have independently evolved similar patterns, apparently both facilitated and constrained by the available developmental-genetic toolkit genes controlling wing pattern formation.

}}

Variations in the toolkit may have produced a large part of the morphological evolution of animals. The toolkit can drive evolution in two ways. A toolkit gene can be expressed in a different pattern, as when the beak of Darwin's large ground-finch was enlarged by the BMP gene,{{Cite journal |last=Abzhanov |first=A. |last2=Protas, M. |last3=Grant, B.R. |last4=Grant, P.R. |last5=Tabin, C.J. |year=2004 |title=Bmp4 and Morphological Variation of Beaks in Darwin's Finches |journal=Science |volume=305 |issue=5689 |pages=1462–1465 |bibcode=2004Sci...305.1462A |doi=10.1126/science.1098095 |pmid=15353802 |s2cid=17226774}} or when snakes lost their legs as distal-less became under-expressed or not expressed at all in the places where other reptiles continued to form their limbs.{{Cite journal |last=Cohn, M.J. |last2=Tickle, C. |year=1999 |title=Developmental basis of limblessness and axial patterning in snakes |journal=Nature |volume=399 |issue=6735 |pages=474–479 |bibcode=1999Natur.399..474C |doi=10.1038/20944 |pmid=10365960 |s2cid=4309833}} Or, a toolkit gene can acquire a new function, as seen in the many functions of that same gene, distal-less, which controls such diverse structures as the mandible in vertebrates,{{Cite journal |last=Beverdam |first=A. |last2=Merlo, G.R. |last3=Paleari, L. |last4=Mantero, S. |last5=Genova, F. |last6=Barbieri, O. |last7=Janvier, P. |last8=Levi, G. |date=August 2002 |title=Jaw Transformation With Gain of Symmetry After DLX5/DLX6 Inactivation: Mirror of the Past? |url=https://iris.unito.it/bitstream/2318/87307/1/Beverdam_2002.pdf |journal=Genesis |volume=34 |issue=4 |pages=221–227 |doi=10.1002/gene.10156 |pmid=12434331 |s2cid=19592597 |hdl-access=free |hdl=2318/87307}}{{Cite journal |last=Depew, M.J. |last2=Lufkin, T. |last3=Rubenstein, J.L. |date=October 2002 |title=Specification of jaw subdivisions by DLX genes |journal=Science |volume=298 |issue=5592 |pages=381–385 |doi=10.1126/science.1075703 |pmid=12193642 |s2cid=10274300 |doi-access=free}} legs and antennae in the fruit fly,{{Cite journal |last=Panganiban |first=Grace |last2=Rubenstein |first2=John L. R. |date=2002 |title=Developmental functions of the Distal-less/Dlx homeobox genes |url=http://dev.biologists.org/content/129/19/4371 |journal=Development |volume=129 |issue=19 |pages=4371–4386 |doi=10.1242/dev.129.19.4371 |pmid=12223397|url-access=subscription }} and eyespot pattern in butterfly wings.{{Cite journal |last=Beldade, P. |last2=Brakefield, P.M. |last3=Long, A.D. |year=2002 |title=Contribution of Distal-less to quantitative variation in butterfly eyespots |journal=Nature |volume=415 |issue=6869 |pages=315–318 |doi=10.1038/415315a |pmid=11797007 |s2cid=4430563}} Given that small changes in toolbox genes can cause significant changes in body structures, they have often enabled the same function convergently or in parallel. distal-less generates wing patterns in the butterflies Heliconius erato and Heliconius melpomene, which are Müllerian mimics. In so-called facilitated variation,{{Cite journal |last=Gerhart |first=John |last2=Kirschner |first2=Marc |year=2007 |title=The theory of facilitated variation |journal=Proceedings of the National Academy of Sciences |volume=104 |issue=suppl1 |pages=8582–8589 |bibcode=2007PNAS..104.8582G |doi=10.1073/pnas.0701035104 |pmc=1876433 |pmid=17494755 |doi-access=free}} their wing patterns arose in different evolutionary events, but are controlled by the same genes.{{Cite journal |last=Baxter, S.W. |last2=Papa, R. |last3=Chamberlain, N. |last4=Humphray, S.J. |last5=Joron, M. |last6=Morrison, C. |last7=ffrench-Constant, R.H. |last8=McMillan, W.O. |last9=Jiggins, C.D. |year=2008 |title=Convergent Evolution in the Genetic Basis of Mullerian Mimicry in Heliconius Butterflies |journal=Genetics |volume=180 |issue=3 |pages=1567–1577 |doi=10.1534/genetics.107.082982 |pmc=2581958 |pmid=18791259}} Developmental changes can contribute directly to speciation.{{Cite journal |last=Pennisi, E. |author-link=Elizabeth Pennisi |year=2002 |title=Evolutionary Biology:Evo-Devo Enthusiasts Get Down to Details |journal=Science |volume=298 |issue=5595 |pages=953–955 |doi=10.1126/science.298.5595.953 |pmid=12411686 |s2cid=154023266}}

=Consolidation of epigenetic changes=

{{Main|Genetic assimilation|Transgenerational epigenetic inheritance}}

Evolutionary innovation may sometimes begin in Lamarckian style with epigenetic alterations of gene regulation or phenotype generation, subsequently consolidated by changes at the gene level. Epigenetic changes include modification of DNA by reversible methylation,{{Cite book |last=Jablonka |first=Eva |author-link=Eva Jablonka |title=Epigenetic Inheritance and Evolution: The Lamarckian Dimension |last2=Lamb |first2=Marion |publisher=Oxford University Press |year=1995 |isbn=978-0-19-854063-2 |location=Oxford, New York}} as well as nonprogrammed remoulding of the organism by physical and other environmental effects due to the inherent plasticity of developmental mechanisms.{{Cite book |last=West-Eberhard |first=Mary Jane |author-link=Mary Jane West-Eberhard |title=Developmental plasticity and evolution |publisher=Oxford University Press |year=2003 |isbn=978-0-19-512235-0 |location=New York}} The biologists Stuart A. Newman and Gerd B. Müller have suggested that organisms early in the history of multicellular life were more susceptible to this second category of epigenetic determination than are modern organisms, providing a basis for early macroevolutionary changes.{{Cite book |title=Origination of Organismal Form: Beyond the Gene in Developmental and Evolutionary Biology |title-link=Origination of Organismal Form |publisher=MIT Press |year=2003 |editor-last=Müller, Gerd B. |editor-link=Gerd B. Müller |editor-last2=Newman, Stuart A.}}

=Developmental bias=

File:Chilipoda- Geophilomorpha (3309242471).jpgs, all members of the Geophilomorpha are constrained by a developmental bias to have an odd number of segments, whether as few as 27 or as many as 191.]]

Development in specific lineages can be biased either positively, towards a given trajectory or phenotype,{{efn|Positive bias is sometimes called developmental drive.}} or negatively, away from producing certain types of change; either may be absolute (the change is always or never produced) or relative. Evidence for any such direction in evolution is however hard to acquire and can also result from developmental constraints that limit diversification. For example, in the gastropods, the snail-type shell is always built as a tube that grows both in length and in diameter; selection has created a wide variety of shell shapes such as flat spirals, cowries and tall turret spirals within these constraints. Among the centipedes, the Lithobiomorpha always have 15 trunk segments as adults, probably the result of a developmental bias towards an odd number of trunk segments. Another centipede order, the Geophilomorpha, the number of segments varies in different species between 27 and 191, but the number is always odd, making this an absolute constraint; almost all the odd numbers in that range are occupied by one or another species.{{Cite journal |last=Arthur |first=W. |date=July 2001 |title=Developmental drive: an important determinant of the direction of phenotypic evolution |journal=Evolution & Development |volume=3 |issue=4 |pages=271–278 |doi=10.1046/j.1525-142x.2001.003004271.x |pmid=11478524 |s2cid=41698287}}{{Cite journal |last=Arthur |first=W. |date=October 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 |doi-access=free}}{{Cite journal |last=Chipman |first=Ariel D. |last2=Arthur |first2=Wallace |last3=Akam |first3=Michael |date=July 2004 |title=A Double Segment Periodicity Underlies Segment Generation in Centipede Development |journal=Current Biology |volume=14 |issue=14 |pages=1250–1255 |doi=10.1016/j.cub.2004.07.026 |pmid=15268854 |s2cid=2371623 |doi-access=free}}

Ecological evolutionary developmental biology

Ecological evolutionary developmental biology, informally known as eco-evo-devo, integrates research from developmental biology and ecology to examine their relationship with evolutionary theory.{{Cite encyclopedia |title=Eco-Evo-Devo: The Time Has Come |encyclopedia=Ecological Genomics: Ecology and the Evolution of Genes and Genomes |date=2014 |editor-last=Landry |editor-first=C.R. |series=Advances in Experimental Medicine and Biology |volume=781 |pages=107–125 |doi=10.1007/978-94-007-7347-9_6 |isbn=978-94-007-7346-2 |pmid=24277297 |last2=Favé |first2=M.-J. |last3=Ibarrarán-Viniegra |first3=A. S. |last4=Lesoway |first4=M. P. |last5=Rafiqi |first5=A. M. |last6=Rajakumar |first6=R. |last1=Abouheif |first1=E. |editor2-first=N. |editor2-last=Aubin-Horth}} Researchers study concepts and mechanisms such as developmental plasticity, epigenetic inheritance, genetic assimilation, niche construction and symbiosis.{{Cite journal |last=Schlichting |first=C.D. |date=2009 |title=An Uneven Guide to Eco-Devo |journal=BioScience |volume=59 |issue=11 |pages=1000–1001 |doi=10.1525/bio.2009.59.11.12 |s2cid=116886911}}{{Cite journal |last=Gilbert |first=S. F. |author-link=Scott F. Gilbert |last2=Bosch |first2=T. C. G. |last3=Ledón-Rettig |first3=C. |date=2015 |title=Eco-Evo-Devo: developmental symbiosis and developmental plasticity as evolutionary agents |journal=Nature Reviews Genetics |volume=16 |issue=10 |pages=611–622 |doi=10.1038/nrg3982 |pmid=26370902 |s2cid=205486234}}

Notes

References

=Citations=

=Sources=

{{Cite book |last=Gould |first=Stephen Jay |author-link=Stephen Jay Gould |title=Ontogeny and Phylogeny |title-link=Ontogeny and Phylogeny (book) |publisher=Belknap Press of Harvard University Press |year=1977 |isbn=978-0-674-63940-9 |location=Cambridge, MA |lccn=76045765 |oclc=2508336}}
{{Cite book |last=Secord |first=James A. |author-link=James A. Secord |url=https://books.google.com/books?id=6LL9PGRhlXYC |title=Victorian sensation: the extraordinary publication, reception, and secret authorship of Vestiges of the natural history of creation |publisher=University of Chicago Press |year=2003 |isbn=978-0-226-74410-0 |location=Chicago}}
{{Cite book |last=Smocovitis |first=Vassiliki Betty |title=Unifying Biology: The Evolutionary Synthesis and Evolutionary Biology |publisher=Princeton University Press |year=1996 |isbn=978-0-691-03343-3 |location=Princeton, NJ |oclc=34411399}}
{{Cite journal |last=Richardson |last2=Keuck |year=2002 |title=Haeckel's ABC of evolution and development |journal=Biological Reviews of the Cambridge Philosophical Society |volume=77 |issue=4 |pages=495–528 |citeseerx=10.1.1.578.2749 |doi=10.1017/s1464793102005948 |pmid=12475051 |s2cid=23494485}}

External links

{{Commons-inline}}

Category:Evolutionary developmental biology

Category:Subfields of evolutionary biology

Category:Developmental biology

Category:Extended evolutionary synthesis