Integrative and Comparative Biology Advance Access originally published online on August 20, 2007
Integrative and Comparative Biology 2007 47(3):409-419; doi:10.1093/icb/icm081
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Evolutionary novelties: the making and breaking of pleiotropic constraints
*Institute of Biology, Leiden University, PO Box 9516, 2300 RA Leiden, The Netherlands; International Institute for Applied Systems Analysis, Evolution and Ecology Program, A-2361 Laxenburg, Austria
Correspondence: 1E-mail: f.galis{at}biology.leidenuniv.nl
 |
Synopsis |
|---|
Top
Synopsis
Integration and selection of...Body plans are remarkably well conserved, but on (very) rare occasions important novelties evolve. Such novelties involve changes at the genotypic and phenotypic level affecting both developmental and adult traits. At all levels, duplications play an important role in the evolution of novelties. Mutations for duplications, including mutations for duplications of body parts, as well as mutations for other changes in the body plan, in particular homeotic ones, occur surprisingly frequently. Hence the limitation of mutations appears to be relatively unimportant for the conservation of body plans. However, mutations for duplications of body parts and homeotic changes rarely persist in populations. We argue that the root cause of the conservation of body plans is the strong interactivity during the patterning of the embryonic axes, including the interactivity between patterning and proliferation processes. Due to this interactivity, mutations cause many negative pleiotropic effects (malformations and cancers) that dramatically lower fitness. As an example, we have shown that in humans there is extreme selection against negative pleiotropic effects of the, surprisingly frequent, mutations affecting the number of cervical vertebrae. Moreover, we argue for the relevance of relaxed selection, which temporarily allows just-arisen novelties to persist, for the effective breaking of pleiotropic constraints. We illustrate this with two empirical examples.
Evolutionary novelties involve a complex set of changes: changes at the genetic level lead to developmental changes at the phenotypic level and these developmental changes lead to changes in the adult phenotype. In addition, selection acts upon the phenotype during all stages of development and the outcome of this selective process determines whether genetic changes can persist in populations, or not. For a full understanding of the evolution of novelties one, therefore, needs to understand (1) the processes that lead to, or constrain, changes at all organizational levels and (2) the links between the levels.
The complexity of the underlying processes has slowed down progress in the understanding of evolutionary novelties. Fortunately, research over the past decades has shown that there are important similarities in the process of evolutionary change at all organizational levels. An important similarity is that duplication of units, followed by modification of one or both copies, appears singularly important as a source of evolutionary change (Serebrovsky 1938
; Ohno 1970; Lynch and Force 2000). Duplication has been observed at the level of whole genomes (e.g., tetraploidy in plants), chromosomes (trisomy), genes, parts of genes, networks of genes, developmental units, and body parts and one can even argue that it plays a role at the level of populations where it facilitates speciation. We argue here that another important similarity is that mutations that provide duplications and homeotic changes are less rare than may be naively expected, but that the incipient novelties almost always fail to persist due to strong selection against many negative pleiotropic effects that are associated with them. The inference is that periods of relaxed stabilizing selection, as occur for instance after mass extinction or on the invasion of a new territory, are important in facilitating the evolutionary incorporation of novelties.
|
Integration and selection of duplications |
|---|
There are at least two reasons that can explain why duplication, followed by modification of one or both duplicated units, is an important source for evolutionary novelties. One reason is that duplication produces new units with a ready-made and finely-tuned internal integration. For instance, a duplicated segment in an annelid will come with all the necessary elements to function as part of the organism. The second reason is that when there are two units that function in the same way, selection on the functioning of one, or both, copies may be relaxed if there is excess capacity for the original function(s) of the ancestral unit (Serebrovsky 1938
; Ohno 1970; Arthur 2002; Kondrashov et al. 2002; Taylor and Raes 2004; Kondrashov and Kondrashov 2006). For instance, if duplicated genes code for a particular visual pigment, selection on the modification of one of the genes is expected to be relaxed, because one copy will still produce that particular visual pigment. Indeed, differentiation of duplicated visual pigment genes (opsins) that code for different pigments has happened several times independently in vertebrate evolution (Dulai et al. 1999; Parry et al. 2005; Trezise and Collin 2005). More in general, stabilizing selection and its occasional relaxation are expected to play an important role in the evolution of novelties.
Initially, there may be a direct selective advantage for duplication. For instance, an extra vertebra may lead to a longer and more flexible neck that is advantageous under certain circumstances (Fig. 1) or an extra gene may lead to the advantageous production of more gene product (Kondrashov et al. 2002; Kondrashov and Kondrashov 2006). An example of the latter is the duplication of the CCL3L1 gene in humans, which provides a lower susceptibility to HIV infection (Gonzalez et al. 2005). Very often, however, there will be strong stabilizing selection against duplications. For instance, duplicated genes may lead to a suboptimal quantity of gene products. An increased gene dosage due to duplication of Sox3 genes probably causes the perturbation of pituitary and hypothalamic development that underlies X-linked hyperthyroidism in male humans (Solomon et al. 2004). In general, stabilizing selection against duplications is expected if the duplicated unit disturbs the integration of the organization at a higher level. Thus, duplications of developmental units may disrupt developmental integration and duplications of structures may disrupt functional integration. Examples of disruptions of functional integration caused by duplicated structures are duplicated veins that lead to an enhanced chance of thrombosis (Quinlan et al. 2003) and a duplicated urethra that can cause recurrent urinary tract infections (Horie et al. 1986).
|
|
Modification of duplicated units |
|---|
Duplication followed by modification of one, or both, copies appears to have been by far the most important source of novel genes (Long et al. 2003
; Taylor and Raes 2004). There is an abundance of examples among both structural and regulatory genes: crystallin genes (Wistow and Piatigorsky 1987a and b; Piatigorsky and Wistow 1991), snail and slug genes (Locascio et al. 2002), tRNA endonuclease genes in Archaea (Tocchini-Valentini et al. 2005), many plant MADS-box genes (Becker et al. 2003; Zahn et al. 2006), and the aforementioned opsin genes (Dulai et al. 1999; Parry et al. 2005; Trezise and Collin 2005), amongst others.
Duplication followed by modification seems to have been as important for the evolution of new networks of genes, i.e., the cooption of gene networks by different parts of the body. A striking example is the cooption of the developmental pathway of median fins by the lateral plate mesoderm that led to the evolution of paired fins in fishes (Freitas et al. 2006). This example shows that the duplication of gene networks can lead to duplications of developmental units and, hence, structures. Duplicated structures are also recognized as a major source of evolutionary change in body plans (Bonner 1988; Müller and Wagner 1991; Vermeij 1995; Galis 2000; Arthur 2002; Theißen 2006a and b). A beautiful example is the vertebral column. This structure with repeated (duplicated) elements has been of outstanding importance in the evolution of the large variety of body plans in vertebrates (Slijper 1946; Radinsky 1987). Arguably, even more important are the flower organs and leaves in plants (Honma and Goto 2001; Geuten et al. 2006). The earlier mentioned fins form another good example, as do the teeth (Jernval et al. 1996) and pharyngeal arches of vertebrates (Mallatt 1996, 1997), the segments and appendages of arthropods (Minelli 2003; Arthur and Chipman 2005) among many other examples.
|
Mutations for duplications are common |
|---|
Duplications of units are usually technically easy changes, even in cases where the duplication involves the building of entire structures. Cohn et al. (1995
) showed how the mere ectopic expression of fibroblast growth factor (Fgf-8 and also Fgf-4) (Ohuchi and Noji 1999) in the lateral plate mesoderm, leads to the induction of an extra limb in chickens. Mutations for the duplication of structures are very frequent in humans, which are perhaps not surprising, given the technical ease with which they can be produced. Extra digits are among the most frequent mutations in humans (0.01–0.02% in livebirths) (Castilla et al. 1996, 1998). The medical and veterinary literature shows that many other organs are occasionally duplicated, e.g., spleens, kidneys, ureters, vaginas, penises, testicles, breasts, teeth, arteries, veins, vertebrae, ribs, rudimentary ears, and even extremely rarely additional arms and legs, although additional legs are sometimes remnants of conjoined twins (Lin et al. 2000; Brown and Schwartz 2003; Uchida et al. 2006; Lilje et al. 2007). Yet, despite their relatively high frequency of occurrence, such mutations very rarely persist in populations and, thereby do not lead to evolutionary change. Newly duplicated structures are virtually always associated with negative pleiotropic effects on functions that are under strong stabilizing selection (Wright, 1935, 1969; Grüneberg 1963; Lande 1978; Horie et al. 1986; Opitz 1987; Galis et al. 2001, 2006, Biesecker 2002; Quinlan et al. 2003; Bartram et al. 2005). Selection, thus, appears to be mainly indirect and conservation is largely due to pleiotropic constraints (Galis et al. 2006; Hansen and Houle 2004). The previous considerations lead to two important questions: why are pleiotropic constraints so prevalent and how can such constraints be overcome, so that novelties emerge?
|
Duplications, homeotic changes, and early organogenesis |
|---|
Most duplications of metazoan structures have their origin during the early organogenesis stage, because this is when organ primordia make their first appearance. A duplicated structure requires a duplicated organ primordium during this stage. Similarly, homeotic changes that modify the identity of a repeated structure usually have their origin during this stage, e.g., transformation of a cervical vertebra into a thoracic vertebra with rib, or an insect antenna into a limb (Galis et al. 2002
, 2006). This stage is strongly conserved in at least mammals and insects (Sander, 1983; Raff 1996; Hall 1996; Galis and Metz, 2001; Galis et al. 2002; Sander and Schmidt-Ott 2004, but see Richardson et al. 1997 for an alternative view) and there is strong selection against mutations at this stage (Galis and Metz 2001; Galis et al. 2006; Ploeger et al., in press). We propose that duplications and homeotic changes are rare events in evolution because they usually require changes in the conserved early organogenesis stage (or phylotypic stage) and because the strong stabilizing selection against mutations for duplications and homeotic changes forms part of a more general stabilizing selection against changes of this stage. |
Conservation of early organogenesis |
|---|
Sander (1983
) and Raff (1996) proposed that high interactivity between modules is the major cause of conservation in this stage. The high interactivity causes mutations affecting traits determined in this stage to have negative pleiotropic effects; these become amplified as development proceeds. Conservation is a consequence of consistently strong stabilizing selection on those pleiotropic effects. We earlier found support for the validity of this hypothesis in an analysis of teratological studies in rodents (Fig. 2) (Galis and Metz 2001). We found that chemical and other disturbances of this stage (phenocopies of mutations) lead to a considerably higher mortality than do disturbances of earlier and later developmental stages. From the pattern of multiple induced abnormalities (i.e., pleiotropic effects), we concluded that it is the high interactivity and low effective modularity that is the root cause of the vulnerability of the stage: a particular, potentially useful, change almost always will induce lethality even before the organism is exposed to external or ecological selection. Hence, this is a good example of the importance of internal or developmental selection (Whyte 1964; Arthur 2002). The importance of internal selection for the conservation of early organogenesis in insects is also in agreement with this hypothesis (Galis et al. 2002).
|
|
Selection against homeotic transformations that change the number of cervical vertebrae |
|---|
Further, support for the hypothesis on the conservation of early organogenesis and the selection against duplications and homeotic changes comes from a recent study showing extremely strong selection against changes in the number of cervical vertebrae in humans (Galis et al. 2006
). The number of cervical vertebrae is highly conserved and virtually always seven in mammals. This number is determined during early organogenesis. Changes of this number are extremely common and mostly seen as unilateral and bilateral ribs on the seventh vertebra, which implies both a homeotic transformation of the seventh cervical vertebra into a thoracic vertebra, as well as an increase in the number of repeated (duplicated) rib structures (Fig. 3). Rudimentary or complete cervical ribs occur in at least half of deceased fetuses and infants (cf. 0.04–1.1% in adults) and, hence in 
8% of all human conceptions. The large early mortality indicates strong selection against such changes. Selection is indirect and mutations that change the number of cervical vertebrae almost always appear to be associated with multiple, major congenital abnormalities causing mortality in fetuses and infants (Fig. 4 and Table 1). The fact that more than half of all fetal and infant deaths in this study came with cervical ribs emphasizes once again the vulnerability of early organogenesis.
|
|
|
|
Low effective modularity during the early patterning of the anterior–posterior axis leads to pleiotropic constraints |
|---|
The determination of the cervico-thoracic boundary of the vertebral column is mediated by Hox genes and forms part of the early anterior–posterior patterning of the presomitic mesoderm (Gaunt 1994
; Burke et al. 1995; Cohn and Tickle 1999; Chernoff and Rogers 2004; Stern et al. 2006). The association of cervical ribs with multiple and major abnormalities in other parts of the body suggests an interaction of early anterior–posterior patterning with many other patterning and morphogenetic processes. Corroboration for this viewpoint is, firstly, provided by grafting experiments in which the anterior–posterior position of paraxial mesoderm was altered, leading to changes in (1) the anterior–posterior patterning of the adjacent neuroepithelium (Bel-Vialar et al. 2002; Grapin-Botton et al. 1997; Ensini et al. 1998), (2) the timing of the migration of neural crest cells (Sela-Donenfeld and Kalcheim 2000) and (3) the initiation and outgrowth of the limbs (Saito et al. 2006). Second, this viewpoint is corroborated by experiments in which two processes that are involved in the determination of the anterior–posterior patterning of paraxial mesoderm were manipulated: the opposing and antagonistic gradient of the morphogens Fgfs, Wnts, and Retinoic acid, the oscillatory gene expression (somatic clock) in the paraxial mesoderm. These experiments have demonstrated couplings of the anterior–posterior patterning of paraxial mesoderm with morphogenetic processes such as proliferation and axial lengthening (Dubrulle et al. 2001; Dubrulle and Pourquié 2004), somitogenesis (Dubrulle et al. 2001; Zakany et al. 2001; Cordes et al. 2004), convergent extension (Ninomiya et al. 2004; Mathis et al. 2002) and cell migration (Yang et al. 2002), as well as with patterning along other embryonic axes, i.e. left–right and midline patterning (Raya et al. 2004; Krebs et al. 2003; Latimer et al. 2002; Yamamoto et al. 2003) and dorso-ventral patterning (Diez del Corral et al. 2003). There is thus a wealth of data supporting the precise coordination of the patterning of the three embryonic axes in the three adjacent germ-layers with a central role of the mesoderm in this process (Kumar et al. 2003) and, additionally, there is strong support for a coupling between patterning and morphogenetic processes. |
Duplications of posterior vertebrae, mammae, and phalanges |
|---|
Lumbar ribs and supernumerary ribs at the first lumbar vertebra occur less frequently in humans than do cervical ribs, but selection against them is not nearly as strong, so they are more frequent in the general population (Galis et al. 2006
). The lower frequency of such shifts of the thoraco-lumbar boundary suggests that interference with the determination of this boundary occurs less often than is true of the cervico-thoracic boundary. Absent twelfth ribs also occur less often. Furthermore, we found no significant association between shifts of the thoraco-lumbar boundary and congenital abnormalities. This suggests that the later stage at which this boundary is determined may be characterized by a lower overall interactivity.
The number of thoracic vertebrae varies considerably amongst mammals (from nine in the Sowerby's beaked whale, Mesoplodon bidens to 23 in Linnaeus’ two-toed sloth, Choloepus didactylis), much more than does the number of cervical vertebrae, which varies from six in manatees (Trichechus) and two-toed sloths (Choloepus) to nine in three-toed sloths (Bradypus, Galis 1999; Narita and Kuratani 2005), and seven in all other mammals. The much weaker selection against shifts of the thoraco-lumbar boundary is, thus, in agreement with the apparently much weaker evolutionary constraint. The number of the more caudal lumbar, sacral, and coccygeal vertebrae also vary considerably among mammals and other vertebrates. The more caudal the vertebrae are, the later the number is specified. We hypothesize that duplications of structures for which the number is determined after the most vulnerable and interactive part of early organogenesis has occurred may be less evolutionarily constrained.
In mice, the period of high vulnerability resulting from global inductive interactions is from embryonic day (E) 7–11, and vulnerability sharply decreases thereafter (Fig. 2). The number of digits is determined within this vulnerable period, but the number of phalanges, carpal, and tarsal elements are determined later (Kimura and Shiota 1995; Ngo-Muller and Muneoka 2000). The number of phalanges, carpal, and tarsal elements is more variable among taxa than is the number of digits, at least as specified during organogenesis (Galis et al. 2001). Evolutionary reduction of the number of digits has happened many times and suggests high variability, but at least in amniotes evolutionary reduction proceeds by developmental arrest, usually followed by degeneration of tissue. Even horses appear to initially have five digit condensations. The strength of the apparent evolutionary constraint, thus, again appears to be in agreement with the timing of specification after the vulnerable and interactive period.
The weaker constraint on variation in the number of cervical vertebrae in birds, compared to mammals, may in part be due to the later stage at which the cervico-thoracic boundary is determined. The higher the number of cervical vertebrae, the later is the determination of the cervico-thoracic boundary, due to the rostro-caudad formation of the somites from which the vertebrae develop. In swans that have the highest number of cervical vertebrae among birds, there is even intraspecific variability of the number of cervical vertebrae and the number varies from 22 to 25 (Woolfenden 1961). Other examples of structures whose number appear to be determined at a relatively later stage are teeth and mammae. Indeed, the number of these structures is highly variable among taxa. It will be interesting to measure the selection strength against duplications of such structures.
On the other hand, the number of most structures (e.g., heart, eyes, ears, lungs, digits, cervical vertebrae, and kidneys, amongst others) is determined early during vulnerable early organogenetic stages and is highly conserved. Changes in numbers of most of these structures are particularly common among deceased fetuses and infants in humans (Galis et al. 2006; Wijnaends and Galis, unpublished data). This suggests that there is strong selection against duplications of these structures.
|
The breaking of constraints |
|---|
Taxa-specific pleiotropy associations
The difficulty for the breaking of specific constraints varies among taxa. One reason for this is that the specific pleiotropic effects that are associated with a certain trait will vary for different taxa. For instance, one of the negative pleiotropic effects associated with cervical ribs in humans is childhood cancers. As a result of this association, individuals that are born with a cervical rib and no other observable abnormalities have an estimated chance of 12% to get such a cancer (Galis 1999
). This provides a very high selective force. In birds, cancer rates are very low (minimal cancer risk) and much lower than in mammals, and most observed cancers are virally induced (Fig. 5) (Galis 1999; Galis and Metz 2003). We have hypothesized that the lower cancer rate in birds may be implicated in the weaker evolutionary constraint on the cervical vertebrae in birds, in addition to the above-mentioned lower cervico-thoracic boundary. A lower cancer rate may also play a role in fishes, amphibians, and reptiles and in those exceptional mammals that have an aberrant number of cervical ribs: manatees (six cervical vertebrae) and sloths (six to nine cervical vertebrae, Galis 1999). Manatees and sloths stand out among mammals as having an extremely low metabolic rate. The existence of a relation between metabolic rate and oxidative DNA damage and, thus, to cancer (Shigenaga and Ames 1993; Bajra 2004; Valko et al. 2007) suggests, combined with their very low metabolic rate, that their susceptibility for cancer may be low. For manatees, this low susceptibility for cancer has been confirmed (Galis and Metz 2003).
|
Relaxed selection and the emergence of novelties
Another reason why there is variation in the difficulty of breaking constraints is that there are differences in the history of selection regimes among taxa. Absence of stabilizing selection that normally acts against novelties allows such novelties to persist for some time. Such periods of persistence may lead to a reduction of the pleiotropic connections through small reorganizations of the developmental pathways, so that when stabilizing selection again increases, the chance for further persistence is increased. A good example can be found in the Semionotus fishes that invaded newly formed rift lakes in North Eastern America in the late Triassic and early Jurassic and that radiated into a species clade (McCune 1990
, 2004). McCune found that in the early history of the lake, when supposedly directional selection was strong but stabilizing selection relaxed (box 18.2, McCune 2004), many dorsal-ridge-scale anomalies occurred. Gradually, these anomalies became less prevalent, but interestingly some of the anomalies became incorporated into new body plans.
Another example that shows how the absence of stabilizing selection can lead to the persistence of characters against which there is normally strongly selection can be found in the evolution of pets. A character that is strongly evolutionarily constrained among amniotes, polydactyly, is particularly common among many dog breeds and some breeds are even required to have one or two extra toes according to the breed standard (Galis et al. 2001). Selection in dogs is relaxed due to human care and dogs with many different congenital abnormalities can breed and reproduce. Longevity is extremely reduced in many breeds, in particular in large breeds, but this does not lead to the extinction of these breeds (Galis et al. 2007). At the same time, directional selection has been very strong in dogs leading to remarkable variation in size and shape. The combination of strong directional selection (for changes in size and shape) and relaxed indirect stabilizing selection (providing food and medical care) has presumably led to the extreme variations in the body plans of dogs.
Periods of relaxed selection may be the colonization of new habitats, the disappearance of predators and the availability of new prey. Such relaxed selection may, thus, be associated with the initial phase of adaptive radiation and with the emergence of key innovations. Directional selection is also expected to be important in such circumstances, when conditions are drastically altered.
We conclude that the importance of directional selection for the evolution of novelties has been overestimated. Directional selection for novelties is important, but only in combination with relaxed selection. The latter is effectively more dominant in determining the options for the evolution of novelties, given the large availability of mutations.
Furthermore, we argue that the importance of hidden variation for the generation of evolutionary novelties has been exaggerated. Hidden variation that becomes exposed in response to severe stress can indeed lead to genetic assimilation, as Waddington has shown for the phenotype of the crossveinless and bithorax mutations in Drosophila in his classic experiments (Waddington 1953, 1956, 1961). Hidden directional selection is deemed important as it is usually invoked to explain the often observed differences between laboratory and field data in the effects of an imposed directional selection. It is plausible, however, that these differences will often be due to relaxed stabilizing selection in the laboratory in all directions orthogonal to that of the imposed directional selection, and strong overall stabilizing selection in the field. The above-mentioned strange shapes for which there has been selection in dogs, and also in other pets like pigeons and chickens, show how powerful the effects of directional selection in combination with an otherwise relaxed selection regime can be. Thus, without denying the evolutionary importance of phenotypic plasticity and genetic assimilation (Pigliucci et al. 2006; Chapman et al. 2000; West-Eberhard 2003), we think that for the generation of macro-evolutionary novelties the evidence for the impact of hidden variation is, thus far, limited (Hansen and Houle 2004).
|
Conclusions |
|---|
Duplications are an important source of novelties at all levels of organization of organisms. Despite the high frequency of mutations for duplications such mutations, nevertheless, rarely persist in populations. The persistence problems seem to stem to an important extent from a suboptimal integration of the new unit at a higher level of organization. For the duplication of developmental modules and structures, we suggest that these integration problems are probably mainly due to the interactivity of the patterning of the embryonic axes, and to the interactivity between patterning and morphogenetic processes (including proliferation). Due to this interactivity, mutations cause many negative pleiotropic effects that drastically lower fitness. We argue that this indirect stabilizing selection is the root cause of the selection against novelties and, hence, of the conservation of body plans. Furthermore, we argue that the relaxation of such indirect stabilizing selection, in combination with strong directional selection, is crucial for the evolutionary origin of novelties in body plan.
|
Acknowledgments |
|---|
We thank Jacques van Alphen and Tom van Dooren for many discussions and comments. We thank Joris van Alphen and Martin Brittijn for help with the figures.
|
Footnotes |
|---|
From the symposium "Linking Genes and Morphology in Vertebrates" presented at the annual meeting of the Society for Integrative and Comparative Biology, January 3–7, 2007, at Phoenix, Arizona.
|
References |
|---|
Arthur W. The origin of animal body plans. A study in evolutionary developmental biology. (2002) Cambridge: Cambridge University Press.
Arthur W, Chipman AD. The centipede Strigamia maritima: what it can tell us about the development and evolution of segmentation. BioEssays (2005) 27::653–60.[CrossRef][Web of Science][Medline]
Barja G. Free radicals and aging. Trends Neurosci (2004) 27::595–600.[CrossRef][Web of Science][Medline]
Bartram U, Wirbelauer J, Speer CP. Heterotaxy syndrome – asplenia and polysplenia as indicators of visceral malposition and complex congenital heart disease. Biol Neonate (2005) 88::278–90.[CrossRef][Web of Science][Medline]
Becker A, Saedler H, Theißen G. Distinct MADS-box gene expression patterns in the reproductive cones of the gymnosperm Gnetum gnemon. Dev Genes Evol (2003) 213::567–72.[CrossRef][Web of Science][Medline]
Bel-Vialar S, Itasaki N, Krumlauf R. Initiating Hox gene expression: in the early chick neural tube differential sensitivity to FGF and RA signalling subdivides the HoxB genes in two distinct groups. Development (2002) 129::5103–15.[Web of Science][Medline]
Biesecker LG. Polydactyly: how many disorders and how many genes. Am J Med Genet (2002) 112::279–83.[CrossRef][Web of Science][Medline]
Bonner JT. The evolution of complexity by means of natural selection. (1988) Princeton: Princeton University Press.
Burke AC, Nelson CE, Morgan BA, Tabin C. Hox genes and the evolution of vertebrate axial morphology. Development (1995) 121::333–46.[Abstract]
Castilla EE, Lugarinho da Fonseca R, da Graça R, Dutra M, Mermejo E, Cuevas L, Martinez-Frias ML. Epidemiological analysis of rare polydactylies. Am J Med Genet (1996) 65::295–303.[CrossRef][Web of Science][Medline]
Castilla EE, Lugarinho da Fonseca R, da Graça R, Dutra M, Salgado LJ. Associated anomalies in individuals with polydactyly. Am J Med Genet (1998) 80::459–65.[CrossRef][Web of Science][Medline]
Chapman LJ, Galis F, Shinn J. Phenotypic plasticity and the possible role of genetic assimilation: hypoxia-induced trade-offs in the morphological traits of an African cichlid. Ecol Le (2000) 3::387–93.[CrossRef]
Chernoff N, Rogers JM. Supernumerary ribs in developmental toxicity bioassays and in human populations: incidence and biological significance. J Toxicol Environ Health B Crit Rev (2004) 7::437–49.[CrossRef][Web of Science][Medline]
Cohn MJ, Izpisua Belmonte JC, Abud H, Heath JK Tickle C. Fibroblast growth-factors induce additional limb development from the flank of chick-embryos. Cell (1995) 80::739–46.[CrossRef][Web of Science][Medline]
Cohn MJ, Tickle C. Developmental basis of limblessness and axial patterning in snakes. Nature (1999) 399::474–9.[CrossRef][Medline]
Cordes R, Schuster-Gossler K, Serth K Gossler A. Specification of vertebral identity is coupled to notch signalling and the segmentation clock. Development (2004) 131::1221–33.
Diez del Corral R, Olivera-Martinez I, Goriely A, Gale E, Maden M, Storey K. Opposing FGF and retinoid pathways control ventral neural pattern, neuronal differentiation, and segmentation during body axis extension. Neuron (2003) 40::65–79.[CrossRef][Web of Science][Medline]
Dubrulle J, McGrew MJ, Pourquié O. FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell (2001) 106::219–32.[CrossRef][Web of Science][Medline]
Dubrulle J, Pourquié O. fgf8 mRNA decay establishes a gradient that couples axial elongation to patterning in the vertebrate embryo. Nature (2004) 427::419–22.[CrossRef][Medline]
Dulai KS, von Dornum M, Mollon JD, Hunt DM. The evolution of trichromatic colour vision by opsin gene duplication in new world and old world primates. Genome Res (1999) 9::629–38.
Ensini M, Tsuchida TN, Belting H-G, Jessell TM. The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm. Development (1998) 125::969–82.[Abstract]
Evans TH. Birds. In: The Cambridge natural history. (1900) 3:. Macmillan.
Fishel A. Untersuchungen über die Wirbelsäule und den Brustkorb des Menschen. Anatomische Hefte (1906) 31::462–588.[CrossRef]
Galis F. Why do almost all mammals have seven cervical vertebrae? Developmental constraints, Hox genes and cancer. J exp Zool B (Mol Dev Evol) B (1999) 285::19–26.[CrossRef]
Galis F. Key innovations and radiations. In: The character concept in evolutionary biology.—Wagner GP, ed. (2000) London: Academic Press.
Galis F, Metz JAJ. Testing the vulnerability of the phylotypic stage: on modularity and evolutionary conservation. J Exp Zool B (Mol Dev Evol) (2001) 291::195–204.[CrossRef]
Galis F, Metz JAJ. Anti-cancer selection as a source of developmental and evolutionary constraints. BioEssays (2003) 25::1035–9.[CrossRef][Web of Science][Medline]
Galis F, van Alphen JJM, Metz JAJ. Why five fingers? Evolutionary constraints on digit numbers. Trends Ecol Evol (2001) 16::637–46.[CrossRef]
Galis F, Van der Sluijs I, Van Dooren TJM, Metz JAJ, Nussbaumer M. Do large dogs die young? J Exp Zool B (Mol Dev Evol) (2007) 308::119–26.[Medline]
Galis F, Van Dooren TJM, Metz JAJ. Conservation of the segmented germband stage: robustness or pleiotropy? Trends Genet (2002) 18::504–9.[CrossRef][Web of Science][Medline]
Galis F, Van Dooren TJM, Feuth H, Ruinard S, Witkam A, Steigenga MJ, Metz JAJ, Wijnaendts LCD. Extreme selection against homeotic transformations of cervical vertebrae in humans. Evolution (2006) 60::2643–54.[Web of Science][Medline]
Gaunt SJ. Conservation in the Hox code during morphological evolution. Int J Dev Biol (1994) 38::549–52.[Web of Science][Medline]
Geuten K, Becker A, Kaufmann K, Caris P, Janssens S, Viaene T, Theißen G, Smets E. Petaloidy and petal identity MADS-box genes in the balsaminoid genera Impatiens and Marcgravia. Plant J (2006) 47::501–18.[Web of Science][Medline]
Gonzalez E, et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science (2005) 307::1434–40.
Grapin-Botton A, Bonnin M-A, LeDouarin NM. Hox gene induction in the neural tube depemds on three parameters: competence, signal supply and paralogue group. Development (1997) 124::849–59.[Abstract]
Griffet J, Bastiani-Griffet F, Jund S, Moreigne M, Zabjek KF. Duplication of the leg—renal agenesis: congenital malformation syndrome. J Pediatr Orthop B (2000) 9::306–8.[Web of Science][Medline]
Grüneberg H. The pathology of development. In: A study of inherited skeletal disorders in animals. (1963) Blackwell Scientific.
Hall BK. Baupläne, phylotypic stages, and constraint - why there are so few types of animals. Evol Biol (1996) 29::215–61.
Hall BK, Myake T. All for one and one for all: condensations and the initiation of skeletal development. Bioessays (2000) 22::138–47.[CrossRef][Web of Science][Medline]
Hansen TF, Houle D. Evolvability, stabilizing selection, and the problem of stasis. In: Phenotypic integration: studying the ecology and evolution of complex phenotypes.—Pigliucci M, Preston K, eds. (2004) Oxford: Oxford University Press. 130–50.
Honma T, Goto K. Complexes of MADS-box proteins are sufficient to convert leaves into floral organs. Nature (2001) 409::525–9.[CrossRef][Medline]
Horie M, Takahashi Y, Isogai K, Yamaha M, Nishiura T. A case of male duplicated urethra in recurrent urinary tract infection. Hinyokika Kiyo (1986) 32::1045–50.[Medline]
Kimura S, Shiota K. Sequential changes of programmed cell death in developing fetal mouse limbs and its possible roles in limb morphogenesis. J Morphol (1995) 229::337–46.[CrossRef][Web of Science]
Kondrashov FA, Kondrashov AS. Role of selection in fixation of gene duplications. J Theor Biol (2006) 239::141–51.[CrossRef][Web of Science][Medline]
Kondrashov FA, Rogozin IB, Wolf YI, Koonin EV. Selection in the evolution of gene duplications. Genome Biol (2002) 3:. Research0008.1–0008.9.
Jernvall J, Hunter JP, Fortelius M. Molar tooth diversity, disparity, and ecology in cenozoic ungulate radiations. Science (1996) 274::1489–92.
Krebs LT, Iwai N, Nonaka S, Welsh IC, Lan Y, Jiang R, Saijoy Y, O’Brien TP, Hamada H, Gridley T. Notch signalling regulates left-right asymmetry determination by inducing Nodal expression. Genes Dev (2003) 17::1207–12.
Kumar M, Jordan N, Melton D, Grapin-Botton A. Signals from lateral plate mesoderm instruct endoderm toward a pancreatic fate. Dev Biol (2003) 259::109–22.[CrossRef][Web of Science][Medline]
Lande R. Evolutionary mechanisms of limb loss in tetrapods. Evolution (1978) 32::73–92.[CrossRef][Web of Science]
Latimer AJ, Dong X, Markov Y, Appel B. Delta-Notch signaling induces hypochord development in zebrafish. Development (2002) 129::2555–63.
Lilje C, Finger LJ, AScuitto RJ. Complete unilateral leg duplication with ipsilateral renal agenesis. Acta Paediat (2007) 96::464–5.[Medline]
Lin AE, Ticho BS, Houde K, Westgate M-N, Holmes LB. Heterotaxy: associated conditions and hospital-based prevalence in newborns. Genet Med (2000) 2::157–72.[Web of Science][Medline]
Locascio A, Manzanares M, Blanco MJ, Nieto MA. Modularity and reshuffling of snail and slug expression during vertebrate evolution. Proc Natl Acad Sci (2002) 99::16841–6.
Long M, Betran E, Thornton K, Wang W. The origin of new genes: glimpses from the young and old. Nat Rev Genet (2003) 4::865–75.[Web of Science][Medline]
Lynch M, Force A. The probabililty of duplicated gene preservation by subfunctionalization. Genetics (2000) 154::459–73.
Mallatt J. Ventilation and the origin of jawed vertebrates: a new mouth. Zool J Linn Soc (1996) 117::329–404.[CrossRef]
Mallatt J. Crossing a major morphological boundary: the origin of jaws in vertebrates. Zoology (1997) 100::128–40.
Mathis L, Kulesa PM, Fraser SE. FGF receptor signalling is required to maintain neural progenitors during Hensen's node progression. Nat Cell Biol (2001) 3::559–66.[CrossRef][Web of Science][Medline]
McCune AR. Morphological anomalies in the Semionotus complex: relaxed selection during colonization of an expanding lake. Evolution (1990) 44::71–85.[CrossRef][Web of Science]
McCune AR. Diversity and speciation of semionotid fishes in mesozoic rift lakes. In: Adaptive speciation.—Dieckmann U, Doebeli M, Metz JAJ, Tautz D, eds. (2004) Cambridge University press. 362–79.
Minelli A. The development of animal form. (2003) Cambridge: Cambridge University Press.
Müller GB, Wagner GP. Novelty in evolution: restructuring the concept. Annu Rev Ecol Syst (1991) 22::229–56.[CrossRef][Web of Science]
Narita Y, Kuratani S. Evolution of the vertebral formulae in mammals: a perspective on developmental constraints. J Exp Zoolog B Mol Dev Evol (2005) 304::91–106.[Medline]
Ngo-Muller V, Muneoka K. Influence of FGF4 on digit morphogenesis during limb development in the mouse. Dev Biol (2000) 219::224–36.[CrossRef][Web of Science][Medline]
Ninomiya H, Elinson RP, Winklbauer R. Antero-posterior tissue polarity links mesoderm convergent extension to axial patterning. Nature (2004) 430::364–7.[CrossRef][Medline]
Ohno S. Evolution by gene duplication. (1970) Berlin/Heidelberg/New York: Springer.
Ohuchi H, Noji S. Fibroblast-growth-factor-induced additional limbs in the study of initiation of limb formation, limb identity, myogenesis, and innervation. Cell Tissue Res (1999) 296::45–56.[CrossRef][Web of Science][Medline]
Opitz JM, Fitzgerald JM, Reynolds JF, Lewin SO, Daniel A, Ekblom LS, Philips S. The Montana fetal genetic pathology program and a review of prenatal death in humans. Am J Med Genet (1987) 3:(Suppl):93–112.
Owen R. On the anatomy of vertebrates, Vols I, II, III. (1866) London: Longmans, Green, and Co.
Parry JWL, Carleton KL, Spady T, Carboo A, Hunt DM, Bowmaker J. Mix and match colour vision: tuning spectral sensitivity by differential opsin gene expression in Lake Malawi cichlids this issue. Curr Biol (2005) 15::1734–9.[CrossRef][Web of Science][Medline]
Piatigorsky J, Wistow G. The recruitment of crystallins: new functions precede gene duplication. Science (1991) 252::1078–9.
Pigliucci M, Murren CJ, Schlichting CD. Phenotypic plasticity and evolution by genetic assimilation. J Exp Biol (2006) 209::2362–7.
Ploeger A, van der Maas H, Raijmakers M, Galis F. Why did the savant syndrome not spread in the population? A psychiatric example of a developmental constraint. Psychiat Res. In press.
Quinlan DJ, Alikhan R, Gishen P, Sidhu PS. Variations in lower limb venous anatomy: implications for US diagnosis of deep vein thrombosis. Radiology (2003) 228::443–88.
Radinsky LB. The evolution of vertebrate design. (1987) Chicago: University of Chicago Press. 188.
Raff RA. The shape of life. (1996) University of Chicago Press.
Raya A, Kawakami Y, Rodriguez-Esteban C, Ibanes M, Rasskin-Gutman D, Rodriguez-Leon J, Buscher D, Feijo JA, Izpisua Belmonte JC. Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination. Nature (2004) 427::121–8.[CrossRef][Medline]
Richardson MK, Hanken J, Gooneratne ML, Pieau C, Raynaud A, Selwood L, Wright GM. There is no highly conserved embryonic stage in the vertebrates: implications for current theories of evolution and development. Anat Embryol (Berl) (1997) 196::91–106.[CrossRef][Medline]
Saito D, Yonei-Tamura S, Takahashi Y, Tamura K. Level-specific role of paraxial mesoderm in regulation of Tbx5/Tbx4 expression and limb initiation. Dev Biol (2006) 292::79–89.[CrossRef][Web of Science][Medline]
Sander K. The evolution of patterning mechanisms: gleanings from insect embryogenesis and spermatogenesis. In: Development and evolution.—Goodwin BC, Holder N, Wylie CC, eds. (1983) Cambridge University Press. 137–54.
Sander K, Schmidt-Ott U. Evo-devo aspects of classical and molecular data in a historical perspective. J exp Zool B (Mol Dev Evol) (2004) 302::69–91.[Medline]
Sela-Donendfeld D, Kalcheim C. Inhibition of noggin expression in the dorsal neural tube by somitogenesis: a mechanism for coordinating the timing of neural crest emigration. Development (2000) 127::4845–54.[Abstract]
Serebrovsky AS. Genes scute and achaete in Drosophila melanogaster and a hypothesis of gene divergency. C. R. Acad Sci URSS (1938) 19::77–81.
Shigenaga MK, Ames BN. Oxidants and mitogenesis as causes of mutation and cancer: the influence of diet. In: Antimutagenesis and anticarcinogenesis mechanisms III.—Bronzetti G, ed. (1993) New York: Plenum Press. 419–36.
Slijper EJ. Comparative biological-anatomical investigations on the vertebral column and spinal musculature of mammals. Verh Kon Akad Wetenschappen Amsterdam (1946) 42::1–128.
Solomon NM, et al. Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3. J Med Genet (2004) 41::669–78.
Stern CD, Charité J, Deschamps J, Duboule D, Durston AJ, Kmita M, Nicolas JF, Palmeirim I I, Smith JC, Wolpert L. Head-tail patterning of the vertebrate embryo: one, two or many unresolved problems? Int J Dev Biol (2006) 50::3–15.[CrossRef][Web of Science][Medline]
Taylor JS, Raes J. Duplication and divergence: the evolution of new genes and old ideas. Ann Rev Genet (2004) 38::615–43.[CrossRef][Web of Science][Medline]
Theißen G. The proper place of hopeful monsters in evolutionary biology. Theory Biosci (2006a) 124::349–69.[CrossRef][Medline]
Theißen G. Birth, life and death of developmental control genes: new challenges for the homology concept. Theory Biosci (2006b) 124::199–212.
Tocchini-Valentini GD, Fruscoloni P, Tocchini-Valentini GP. Structure, function, and evolution of the tRNA endonucleases of Archaea: an example of subfunctionalization. Proc Nat Acad Sci USA (2005) 102::8933–8.
Trezise AE, Collin SP. Opsins: evolution in waiting. Curr Biol (2005) 15::R794–6.[CrossRef][Web of Science][Medline]
Uchida J, Naganuma T, Machida Y, Kitamoto K, Yamazaki T, Iwai T, Nakatani T. Modified extravesical ureteroneocystostomy for completely duplicated ureters in renal transplantation. Urol Int (2006) 77::104–6.[CrossRef][Web of Science][Medline]
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and aantioxidants in normal and physiological functions and human disease. Int J Biochem Cell Biol (2007) 39::44–84.[CrossRef][Web of Science][Medline]
Vermeij GJ. Economics, volcanoes, and Phanerozoic revolutions. Paleobiology (1995) 21::125–52.[Abstract]
Waddington CH. Genetic assimilation of an acquired character. Evolution (1953) 7::118–26.[Medline]
Waddington CH. Genetic assimilation of the bithorax phenotype. Evolution (1956) 10::1–13.[Medline]
Waddington CH. Genetic assimilation. Advances Genet (1961) 10::257–90.
West-Eberhard MJ. Developmental plasticity and evolution. (2003) Oxford University Press. 817.
Wistow GJ, Piatigorsky J. Lens crystallins: the evolution and expression of proteins for a highly specialized tissue. Annu Rev Biochem (1987a) 57::479–504.[CrossRef][Web of Science]
Wistow G, Piatigorsky J. Recruitment of enzymes as lens structural proteins. Science (1987b) 236::1554–6.
Woolfenden GE. Postcranial morphology of the waterfowl. Bull Florida State Museum Biol Sci (1961) 6::1–129.
Wright S. A mutation of the guinea pig, tending to restore the pentadactyl foot when heterozygous, producing a monstrosity when homozygous. Genetics (1935) 20::84–10.
Whyte LL. Internal factors in evolution. Acta Biotheoretica (1964) 17::33–48.[CrossRef]
Wright S. Evolution and the genetics of populations. (1969) I:. Genetic and Biometric Foundation: University Chicago Press.
Yamamoto M, Mine N, Mochida K, Sakai Y, Saijoh Y, Meno C, Hamada H. Nodal signaling induces the midline barrier by activating NodalI expression in the lateral plate. Development (2003) 130::1794–804.
Yang X, Dormann D, Muensterberg AE, Weijer CJ. Cell movement patterns during gastrulation in the chick are controlled by positive and negative chemotaxis mediated by FGF4 and FGF8. Dev Cell (2002) 3::425–37.[CrossRef][Web of Science][Medline]
Zahn LM, Leebens-Mack J, Arrington JM, Hu Y, Landherr L, dePamphilis C, Becker A, Theißen G, Ma H. Conservation and divergence in the AGAMOUS subfamily of MADS-Box genes: evidence of independent sub- and neofunctionalization events. Evol Dev (2006) 8::30–45.[CrossRef][Web of Science][Medline]
Zakany J, Kmita M, Alarcon P, de la Pompa JL, Duboule D. Localized and transient transcription of Hox genes suggests a link between patterning and the segmentation clock. Cell (2001) 106::207–217.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||