The evolutionary dynamics of evolvability in a gene network model.

Evolvability, the ability of populations to adapt, has recently emerged as a major unifying concept in biology. Although the study of evolvability offers new insights into many important biological questions, the conceptual bases of evolvability, and the mechanisms of its evolution, remain controversial. We used simulated evolution of a model of gene network dynamics to test the contentious hypothesis that natural selection can favour high evolvability, in particular in sexual populations. Our results conclusively demonstrate that fluctuating natural selection can increase the capacity of model gene networks to adapt to new environments. Detailed studies of the evolutionary dynamics of these networks establish a broad range of validity for this result and quantify the evolutionary forces responsible for changes in evolvability. Analysis of the genotype-phenotype map of these networks also reveals mechanisms connecting evolvability, genetic architecture and robustness. Our results suggest that the evolution of evolvability can have a pervasive influence on many aspects of organisms.

Multivariate mutation-selection balance with constrained pleiotropic effects.

A multivariate quantitative genetic model is analyzed that is based on the assumption that the genetic variation at a locus j primarily influences an underlying physiological variable yj, while influence on the genotypic values is determined by a kind of "developmental function" which is not changed by mutations at this locus. Assuming additivity among loci the developmental function becomes a linear transformation of the underlying variables y onto the genotypic values x, x = By. In this way the pleiotropic effects become constrained by the structure of the B-matrix. The equilibrium variance under mutation-stabilizing selection balance in infinite and finite populations is derived by using the house of cards approximation. The results are compared to the predictions given by M. Turelli in 1985 for pleiotropic two-character models. It is shown that the B-matrix model gives the same results as Turelli's five-allele model, suggesting that the crucial factor determining the equilibrium variance in multivariate models with pleiotropy is the assumption about constraints on the pleiotropic effects, and not the number of alleles as proposed by Turelli. Finally it is shown that under Gaussian stabilizing selection the structure of the B-matrix has effectively no influence on the mean equilibrium fitness of an infinite population. Hence the B-matrix and consequently to some extent also the structure of the genetic correlation matrix is an almost neutral character. The consequences for the evolution of genetic covariance matrices are discussed.

Epistasis and the mutation load: a measurement-theoretical approach.

An approximate solution for the mean fitness in mutation-selection balance with arbitrary order of epistatic interaction is derived. The solution is based on the assumptions of coupling equilibrium and that the interaction effects are multilinear. We find that the effect of m-order epistatic interactions (i.e., interactions among groups of m loci) on the load is dependent on the total genomic mutation rate, U, to the mth power. Thus, higher-order gene interactions are potentially important if U is large and the interaction density among loci is not too low. The solution suggests that synergistic epistasis will decrease the mutation load and that variation in epistatic effects will elevate the load. Both of these results, however, are strictly true only if they refer to epistatic interaction strengths measured in the optimal genotype. If gene interactions are measured at mutation-selection equilibrium, only synergistic interactions among even numbers of genes will reduce the load. Odd-ordered synergistic interactions will then elevate the load. There is no systematic relationship between variation in epistasis and load at equilibrium. We argue that empirical estimates of gene interaction must pay attention to the genetic background in which the effects are measured and that it may be advantageous to refer to average interaction intensities as measured in mutation-selection equilibrium. We derive a simple criterion for the strength of epistasis that is necessary to overcome the twofold disadvantage of sex.

Epistasis can facilitate the evolution of reproductive isolation by peak shifts: a two-locus two-allele model.

The influence of epistasis on the evolution of reproductive isolation by peak shifts is studied in a two-locus two-allele model of a quantitative genetic character under stabilizing selection. Epistasis is introduced by a simple multiplicative term in the function that maps gene effects onto genotypic values. In the model with only additive effects on the trait, the probability of a peak shift and the amount of reproductive isolation are always inversely related, i.e., the higher the peak shift rate, the lower the amount of reproductive isolation caused by the peak shift. With epistatic characters there is no consistent relationship between these two values. Interestingly, there are cases where both transition rates as well as the amount of reproductive isolation are increased relative to the additive model. This effect has two main causes: a shift in the location of the transition point, and the hybrids between the two alternative optimal genotypes have lower average fitness in the epistatic case. A review of the empirical literature shows that the fitness relations resulting in higher peak shift rates and more reproductive isolation are qualitatively the same as those observed for genes causing hybrid inferiority.

Is the genotype-phenotype map modular? A statistical approach using mouse quantitative trait loci data.

Various theories about the evolution of complex characters make predictions about the statistical distribution of genetic effects on phenotypic characters, also called the genotype-phenotype map. With the advent of QTL technology, data about these distributions are becoming available. In this article, we propose simple tests for the prediction that functionally integrated characters have a modular genotype-phenotype map. The test is applied to QTL data on the mouse mandible. The results provide statistical support for the notion that the ascending ramus region of the mandible is modularized. A data set comprising the effects of QTL on a more extensive portion of the phenotype is required to determine if the alveolar region of the mandible is also modularized.

Evolution and multi-functionality of the chitin system.

Chitin, that is, the beta-1, 4 linked polysaccharide of N-acetylglucosamine, is best known as a cell wall component of fungi and as skeletal material of invertebrates. In recent years this simple picture has changed dramatically. Three developments have taken place: the discovery of chitinous tissues in vertebrates, the molecular analysis of the chitin-synthase genes, and the discovery that chitin derivatives play a crucial role in the interaction between higher plants and symbiotic bacteria. In this paper the methods for chitin detection and the current data on the evolution of chitin synthesis are reviewed. In addition, data is summarized which suggest that chitin synthesis may serve roles other than the production of skeletal material. In particular, anecdotal evidence suggests that chitin derivatives may play a role as signals in plant as well as animal development. Two major unresolved questions are identified: 1) Is there historical continuity of all the chitin synthesizing systems in protists, animals and, in particular, the deuterostome animals. 2) Are chitin derivatives actually involved in the development of plants and animals?

A research programme for testing the biological homology concept.

The classical homology concept has served as a heuristic principle for organizing the enormous wealth of information on comparative anatomical patterns across a wide range of organisms. However, the classical homology concept reaches its limit as knowledge of the evolutionary, genetic and developmental processes that underlie these anatomical patterns increases. The biological homology concept places the known anatomical patterns into a mechanistic context and asserts that character identity is based on common variational properties in this chapter a research programme for testing the biological homology concept that involves the following steps is outlined: (1) identifying of two or more putative homologues is a clade; (2) determining the phylogenetic distribution of the putative homologues; (3) describing the intra- and interspecific variation patterns of each putative homologue; (4) describing the development of each putative homologue, and determining if modes of development and distribution of homologues are phylogenetically congruent; and (5) providing and testing a model of how differences in modes of development between putative homologues effect differences in variational tendencies. The goal is to demonstrate a link between developmental and variational differences of two homologues.

Evolution of chordate hox gene clusters.

In this article, we consider the role of the Hox genes in chordate and vertebrate evolution from the viewpoints of molecular and developmental evolution. Models of Hox cluster duplication are considered with emphasis on a threefold duplication model. We also show that cluster duplication is consistent with a semiconservative model of duplication, where following duplication, one daughter cluster remains unmodified, while the other diverges and assumes a new architecture and presumably new functions. Evidence is reviewed, suggesting that Hox gene enhancers have played an important role in body plan evolution. Finally, we contrast the invertebrates and vertebrates in terms of genome and Hox cluster duplication which are present in the latter, but not the former. We question whether gene duplication has been important in vertebrates for the introduction of novel features such as limbs, a urogenital system, and specialized neuromuscular interactions.

Entorhinal lesions result in shrinkage of the outer molecular layer of rat dentate gyrus leading subsequently to an apparent increase of glutamate decarboxylase and cytochrome oxidase activities.

In intact dentate gyrus, glutamate decarboxylase immunoreactivity (GAD) and cytochrome oxidase activity (CyO) showed different distributions patterns. Entorhinal lesions caused increases of GAD and CyO in the outer molecular layer (OML) of the ipsilateral side. Submicroscopical localization of these enzymes did not change, except for CyO labeling more astrocytic mitochondria. The increase in numerical density of GAD puncta correlated quantitatively with shrinkage of OML, whereas in the whole molecular layer the number of GAD puncta remained unchanged. Hence, the localized increase of enzyme activities and lysosomes is apparently related to shrinkage of OML, but does not indicate plasticity of GABAergic neurons.

Regeneration in Salaria pavo (Blenniidae, Teleostei). Histogenesis of the regenerating pectoral fin suggests different mechanisms for morphogenesis and structural maintenance.

The pectoral fin of blennies is differentiated into a dorsal field and a ventral hook field. A histogenetic analysis of the regenerating pectoral fin was related to two questions. First, are histological specializations of the hook field responsible for the impairment of the regenerative capacity of pectoral fins of blennies? Second, can analysis of the temporal sequence of histogenetic events be used to make testable predictions about the tissue interactions required to re-establish the adult pattern? Regeneration of pectoral fins was examined in Salaria pavo (Blenniidae, Teleostei). Approximately 80% of the length of the fin rays was amputated. Fin ray stumps were evaluated 7, 14, 24, 48 and 72 h after amputation, regenerates 4, 5, and 6 days after amputation and at length of about 30%, 50% and 60% regeneration of the original fin length. The regeneration process is subdivided into four stages: wound healing, blastema formation, fin ray formation and distal outgrowth and differentiation of hook characters. Analysis of the early events of regeneration, wound healing, blastema formation and distal outgrowth, yielded no profound differences from those of conventional fins in general. Impairment of regenerative capacity becomes manifested before histological differentiation of hook characters, and it is thus unlikely that their presence is the proximate cause of heteromorphic regeneration. The sequence in which the anatomical specializations characteristic of fin hooks (lepidotrichal cord, cuticle, fin web regression) appear was variable. Detailed analysis of older regenerates revealed a more regular pattern. In the first phase the characters appear to be largely independently organized, while they become locally correlated later. It is concluded that the anatomical differentiation passes through two stages, initiation of anatomical differentiation, and then mutual adjustment of character expression leading to spatially correlated expression of the lepidotrichal cord, the cuticle and the fin web regression.

Coevolution of functionally constrained characters: prerequisites for adaptive versatility.

One of the major problems of organismic evolution theory is to explain how complex organisms were able to evolve by random mutations in spite of the severe functional constraints that canalize their route of change. The problem is discussed on the basis of a quantitative genetic model. How the degree of genetic variation influences the adaptation speed of functionally coupled but genetically uncorrelated characters is examined. It was found, that if more than three independent characters contribute to the variation of a functionally constrained system, optimal degrees of genetic variation exist. Higher degrees of variation lead to decreasing adaptation rates. Conversely, functional constraints do not limit the degree of adaptely reasonable genetic variability as long as the number of independent characters is not higher than three. The conclusion is drawn that there is no need to develop a genetic correlation between functionally coupled characters as long as not many more than three characters are integrated into a functional system. This explains the fact that there is no genetic coupling between the inherited signal sender and receiver mechanisms in orthopterians, even though there is a strong functional coupling between them.

THE ORIGIN OF MORPHOLOGICAL CHARACTERS AND THE BIOLOGICAL BASIS OF HOMOLOGY.

A homolog is a part of the phenotype that is homologous to equivalent parts in other species. A biological homology concept is expected to explain three properties of homologs: 1) the conservation of those features that are used to define a homolog, 2) the individualization of the homolog with regard to the rest of the body, and 3) the uniqueness of homologs, i.e., their specificity for monophyletic groups. The main obstacle to describing a mechanistic basis for homology is the variability of the developmental pathways of undoubtedly homologous characters. However, not all aspects of the developmental pathway are of equal importance. The only organizational features of the developmental system that matter are those that have been historically acquired and cause developmental constraints on the further evolutionary modification of the characters. Two main factors contribute to historically acquired developmental constraints: generative rules of pattern formation and ontogenetic networks. In particular, hierarchical and cyclical inductive networks have the required properties to explain homology. How common such networks are is an open empirical question. The development and variation of pectoral fin hooks in blenniid fishes is presented as a model for the study of a simple ontogenetic network.

Small lesions in the primary visual cortex of rats cause a specific reorganization of associational connections.

Neuroplastic changes in associational connections were investigated 3 weeks after the intrinsic organization of the visual cortex of rats had been partially damaged by small cylindrical lesions (type I). These lesions caused the degeneration of short intracortical connections and associational connections that form patches in the primary and secondary visual areas. The resulting terminal degeneration disappeared within 20 days p.o. after which only some fiber degeneration was evident in the infragranular layers. Patches of terminal degeneration reappeared in the vicinity of the stab wounds, when the associational connections between the retrosplenial and the primary visual cortex had been secondarily interrupted by elongated lesions (type II), which penetrated the paramedian cortex and subcortical white matter. When type-II lesions were made in the intact cortex, patches of degeneration were absent, although in both cases some terminal degeneration was diffusely distributed in the primary visual cortex. Horseradish peroxidase (HRP) was applied to sites similar to those where type-I lesions were applied. In the intact cortex, HRP caused a granular labeling of numerous neurons in various positions including the retrosplenial cortex and patches of the postero-median visual cortex. HRP was also applied to type-I lesions that had been made 3 weeks earlier. In these cases, apparently HRP labeled the same subpopulations of neurons as it did in the intact cortex. However, a fraction of the labeled neurons showed a Golgi-like staining (e.g., 27% of the labeled neurons in the retrosplenial cortex) only when HRP was applied to stab wounds.(ABSTRACT TRUNCATED AT 250 WORDS)

On the evolution of dominance modifiers II: a non-equilibrium approach to the evolution of genetic systems.

The evolution of dominance is both the simplest and best investigated example of the evolution of genetic systems. Nevertheless, there exists striking empirical material, e.g. industrial melanism, for which no satisfactory explanation could so far be provided. In this paper we take an approach to this classical problem based on a global analysis together with computer simulations. It reveals that during the evolution of dominance one has to distinguish a "nonequilibrium phase" and a "Fisherian phase". The non-equilibrium phase appears to be characterized by the fact that in general the selection intensity at the primary locus does not affect the degree of modifier selection but only the time necessary for passing through this phase. A further essential conclusion is that modifier evolution only obtains a reasonable amount of efficiency if the population reaches the Fisherian phase already with a high modifier frequency. Using these results, predictions on the population genetic prerequisites for the evolution of dominance are derived. From these we conclude that even in populations in which dominance evolution has occurred it cannot be expected that back-crosses into relics of the ancestral population lead to a breakdown of dominance within a few generations. These predictions are in accordance with empirical data on Biston betularia and Odontopera bidentata.

Evolutionary modification of regenerative capability in vertebrates: a comparative study on teleost pectoral fin regeneration.

The regenerative ability of the pectoral fins of 14 species from 6 euteleostean families was tested. Blastema formation and distal outgrowth was observed in all species, indicating the initiation of regeneration in all species tested. Interspecific variation exists with respect to the frequency of malformations and the patterns produced by heteromorphic regeneration. Taking into account published reports on pectoral fin regeneration, the systematic distribution of homo- and heteromorphic regeneration leads to the following conclusions: 1) regenerative ability of pectoral fins is a property inherited from the common ancestor of euteleosteans. Whether it is also the ancestral condition for the whole teleostean group cannot be determined, because reports on more primitive teleosteans like the herring and the osteoglossimorphs are missing. 2) A propensity to produce high frequencies of heteromorphic regenerates originated independently at least three times in Cypriniformes, Scorpaeniformes, and Perciformes. 3) Impaired regeneration is most commonly found in bottom fishes, although not all ground fish groups show heteromorphic regeneration. This suggests that impaired regeneration is not directly related to bottom dwelling, but most probably originated as a side effect of other adaptive changes. Hence, neither the presence nor the loss of faithful regeneration can be associated with particular adaptive scenarios in this group, since regeneration seems to be ancestral to all major euteleost groups and its loss has no clear adaptive significance. Whether there are adaptive reasons to maintain regenerative capability or whether there are cases of reestablishment of regeneration after it was lost cannot be decided on the basis of recent evidence. More observations on phylogenetically closely related species with variable regenerative capability are necessary to assess adaptive explanations of regeneration.

Modeling genetic architecture: a multilinear theory of gene interaction.

The map from genotype to phenotype is an exceedingly complex function of central importance in biology. In this work we derive and analyze a mathematically tractable model of the genotype-phenotype map that allows for any order of gene interaction. By assuming that the alterations of the effect of a gene substitution due to changes in the genetic background can be described as a linear transformation, we show that the genotype-phenotype map is a sum of linear and multilinear terms of operationally defined "reference" effects at each locus. The "multilinear" model is used to study the effect of epistasis on quantitative genetic variation, on the response to selection, and on genetic canalization. It is shown how the model can be used to estimate the strength of "functional" epistasis from a variety of genetic experiments.

Evidence for four Hox clusters in the killifish Fundulus heteroclitus (teleostei).

We analyzed the HOM/Hox cluster composition of the teleost Fundulus heteroclitus (Killifish) using a PCR survey. We found a total number of 30 unique homeobox sequences which could be assigned to specific cognate groups of the Hox clusters by sequence comparisons. One sequence was of the msh group. Ten homeobox fragments could be identified as orthologs with specific mammalian Hox genes of cluster A-D. The number of representatives in cognate groups 1, 4, 5, 6, 7, 8 and 9 differed from those of human and mouse. For groups 1 and 9 we found four representatives, which provides the first evidence for possible four Hox clusters in a diploid teleost, a lower vertebrate. Furthermore, it demonstrates significant differences of the Fundulus clusters compared to those of mouse and humans. The implications of our data for the interpretation of the evolution of Hox clusters are discussed.