Concept Of Canalization Research Articles

A theoretical perspective on Waddington's genetic assimilation experiments.

Genetic assimilation is the process by which a phenotype that is initially induced by an environmental stimulus becomes stably inherited in the absence of the stimulus after a few generations of selection. While the concept has attracted much debate after being introduced by C. H. Waddington 70 y ago, there have been few experiments to quantitatively characterize the phenomenon. Here, we revisit and organize the results of Waddington's original experiments and follow-up studies that attempted to replicate his results. We then present a theoretical model to illustrate the process of genetic assimilation and highlight several aspects that we think require further quantitative studies, including the gradual increase of penetrance, the statistics of delay in assimilation, and the frequency of unviability during selection. Our model captures Waddington's picture of developmental paths in a canalized landscape using a stochastic dynamical system with alternative trajectories that can be controlled by either external signals or internal variables. It also reconciles two descriptions of the phenomenon-Waddington's, expressed in terms of an individual organism's developmental paths, and that of Bateman in terms of the population distribution crossing a hypothetical threshold. Our results provide theoretical insight into the concepts of canalization, phenotypic plasticity, and genetic assimilation.

Mapping the Multi‐Modal Distribution of Craniofacial Phenotypes in NOSIP Mutants

Nitric Oxide Synthase Interacting Protein (NOSIP) is an E3 mono-ubiquitin ligase that regulates the activity of protein phosphatase 2A. Deletion of NOSIP leads to severe and variable malformations of the craniofacial complex. Our goal was to use NOSIP mutant mice to understand genetic and cellular mechanisms of phenotypic variation similar to human disease. The phenotype of an individual embryo is the result of the developmental trajectory that it previously traversed. We propose that this concept of canalization is essential for understanding the etiology of complex phenotypic outcomes. We tested this by creating a 3D morphospace of NOSIP heterozygous and homozygous mutants to determine if embryos occupy unique morphospace regions based on affected craniofacial structures. Embryos between embryonic day 10.5 (E10.5) to E17 were collected, fixed in PaxGene, and imaged (mCT). Anatomical features were reconstructed using Avizo. RNAscope was used to assess Nosip expression, and RNA was the extracted from the head of embryos and prepared for sequencing. While some heterozygous embryos appear completely unaffected, both homozygous null and heterozygous embryos presented with a mild to severe spectrum of phenotypic malformations, with no homozygous null embryos appearing unaffected. Embryos on the more severe side of the spectrum has a single telencephalic lobe with severe facial malformations, including loss of maxillary processes, micrognathia and obstructed airway. Embryos on the milder spectrum had normal telencephalic vesicle separation and had less severe facial phenotypes, including mild left-right asymmetry and clefting. NOSIP expression between E10.5 and E12.5 appears to fairly ubiquitously, with high expression in the neuroepithelium, lower jaw mesenchyme, nasal tissue. Expression was markedly reduced in normal NOSIP heterozygotes. Mutant transcriptomes at E10.5 cluster based on genotype, but by E12.5, transcriptomes cluster based on phenotype severity, suggesting that transcriptional profiles cannot be solely predicted based on genotype alone. Pathways most affected include protein function, SHH and canonical WNT signaling. Six3 and Shh appear to be negatively affected in NOSIP mutants, and correlates with more severe brain defects. Overall, it appears that Nosip-KO creates a multi-modal distribution of craniofacial phenotypes along the developmental timeline by affecting early brain development, suggesting that understanding canalization may provide insight into the complexity of genotype-phenotype map. Future work will focus on identifying specific dysregulations in protein function of mutants and normalizing early signaling pathways to rescue more normal phenotypes.

Quantifying the total effect of edge interventions in discrete multistate networks

Developing efficient computational methods to assess the impact of external interventions on the dynamics of a network model is an important problem in systems biology. This paper focuses on quantifying the global changes that result from the application of an intervention to produce a desired effect, which we define as the total effect of the intervention. The type of mathematical models that we will consider are discrete dynamical systems which include the widely used Boolean networks and their generalizations. The potential interventions can be represented by a set of nodes and edges that can be manipulated to produce a desired effect on the system. We use a class of regulatory rules called nested canalizing functions that frequently appear in published models and were inspired by the concept of canalization in evolutionary biology. In this paper, we provide a polynomial normal form based on the canalizing properties of regulatory functions. Using this polynomial normal form, we give a set of formulas for counting the maximum number of transitions that will change in the state space upon an edge deletion in the wiring diagram. These formulas rely on the canalizing structure of the target function since the number of changed transitions depends on the canalizing layer that includes the input to be deleted. We also present computations on random networks to compare the exact number of changes with the upper bounds provided by our formulas. Finally, we provide statistics on the sharpness of these upper bounds in random networks.

КОНЦЕПЦИИ КАНАЛИЗИРОВАННОСТИ И ГЕНЕТИЧЕСКОЙ АССИМИЛЯЦИИ В БИОЛОГИИ РАЗВИТИЯ. СОВРЕМЕННЫЕ ПОДХОДЫ И ИССЛЕДОВАНИЯ

The two related parts of the Conrad Waddington’s proposal, the concepts of canalization and genetic assimilation, formalized yet in the 1940s continue to arouse great interest among professionals, representing one of the most impressive examples of the transdisciplinary development of ideas. Individual development of any organism proceeds in the context of permanent and unavoidable changes in the factors of the external environment and internal perturbations of molecular and physiological processes. Considering that in any population organisms differ genetically, the implementation of the genetic program must therefore be relatively resistant to genetic variability. According to Waddington, individual development is canalized, i.e. occurs within a certain canal of environmental conditions that limits the variability in the developmental trajectory. However, strong environmental changes and considerable internal perturbations are able to “throw” some trajectories outside the walls of this canal. As a result, aberrant phenotypes may emerge, with some of them being able to get involved in subsequent selection. If the conditions that systematically lead to such an aberrant development persist, the features of these phenotypes can be fixed genetically by selection after a few generations. In other words, selection leads to the emergence of phenotype variants, most genetically suitable to the current circumstances, in which developmental trajectories are altered appropriately. Populations of organisms with altered trajectories and different genotypes continue to exist even when the impact of perturbing factors ceases. Waddington called the mechanism underlying the “same phenotype but different genotypes” evolutionary scenario genetic assimilation. Recent outcomes of evolutionary systems biology have provided a quantitative basis for Waddington’s classical concepts on the robustness of individual development and genetic assimilation. It has become possible to further develop these concepts in the light of new experimental results and theoretical ideas. Particular progress has been achieved in analyzing the molecular machinery of canalization. This paper aims to discuss the results obtained in this area of systems biology by computer modeling in comparison with experimental data.

Concepts of Canalization and Genetic Assimilation in Developmental Biology: Current Approaches and Studies

Concepts of Canalization and Genetic Assimilation in Developmental Biology: Current Approaches and Studies

Mapping the Multi‐Modal Distribution of Craniofacial Phenotypes in NOSIP Mutants

Nitric Oxide Synthase Interacting Protein (NOSIP) is a E3 mono‐ubiquitin ligase that regulates the activity of protein phosphatase 2A. Deletion of NOSIP leads to severe and variable malformations of the craniofacial complex. Our goal was to use NOSIP mutant mice to understand of mechanisms of phenotypic variation. The phenotype of an individual embryo is the product of the developmental trajectory that it previously traversed. We propose that this concept of canalization is essential for understanding the etiology of complex phenotypic outcomes. We have previously shown that the brain patterns the face, so sequential perturbations affecting the brain and face may create unique developmental trajectories that each embryo transits. We tested this by creating a 3D morphospace of NOSIP heterozygous and homozygous mutants to determine if embryos occupy unique morphospace regions based on affected craniofacial structures. Embryos between embryonic day 10.5 (E10.5) to E17.5 were collected, fixed, and imaged (mCT). Anatomical features were reconstructed using Avizo. NOISP expression appears to be restricted to the neuroepithelium, lower jaw mesenchyme, and mesenchyme and epithelium in tissue adjacent to the frontonasal ectodermal zone between stage E10.5‐11.5. Embryos with a single telencephalic lobe had more severe facial malformations, including micrognathia and obstructed airway without significant changes in early cell apoptosis (via TUNEL staining). Embryos with normal telencephalic vesicle separation had less severe facial phenotypes, including left‐right mild asymmetry and clefting. Overall, it appears that NOSIP‐KO creates a multi‐modal distribution of craniofacial phenotypes along the developmental timeline by affecting early brain development, suggesting that understanding canalization may provide insight into the complexity of genotype‐phenotype map (Fig. 1).Support or Funding InformationFunding was provided by NIH F32DE08476 and R01DE019638 grants.Schematic of the changing phenotypic landscape describing the multi‐modal distribution of craniofacial phenotypes within NOSIP+/− and NOSIP−/− embryos compared to wildtype (light blue).Figure 1

Boolean nested canalizing functions: A comprehensive analysis

Boolean network models of molecular regulatory networks have been used successfully in computational systems biology. The Boolean functions that appear in published models tend to have special properties, in particular the property of being nested canalizing, a concept inspired by the concept of canalization in evolutionary biology. It has been shown that networks comprised of nested canalizing functions have dynamic properties that make them suitable for modeling molecular regulatory networks, namely a small number of (large) attractors, as well as relatively short limit cycles.This paper contains a detailed analysis of this class of functions, based on a novel normal form as polynomial functions over the Boolean field. The concept of layer is introduced that stratifies variables into different classes depending on their level of dominance. Using this layer concept a closed form formula is derived for the number of nested canalizing functions with a given number of variables. Additional metrics considered include Hamming weight, the activity number of any variable, and the average sensitivity of the function. It is also shown that the average sensitivity of any nested canalizing function is between 0 and 2. This provides a rationale for why nested canalizing functions are stable, since a random Boolean function in n variables has average sensitivity n2. The paper also contains experimental evidence that the layer number is an important factor in network stability.

Innateness, canalization, and the modality-independence of language: A reply to Griffiths and Machery

Griffiths and Machery (2008) argue that innateness is a “folk biological” notion, which, as such, has no useful reconstruction in contemporary biology. If this is so, not only is it wrong to identify the vernacular notion with the precise theoretical concept of canalization, but worse, it would appear that many of the putative scientific claims for particular competences and capacities being innate are simply misplaced. The present paper challenges the core substantive claim of Griffiths and Machery's position, namely, that innateness understood on canalization lines as environment-independent development (somehow and to some degree) is a confused, outmoded notion. It will be contended that the modality-independence of language offers a prima facie case against Griffiths and Machery's general position.

Conrad H. Waddington: Towards a Theoretical Biology

A founding member of the Theoretical Biology Club, Conrad Hal Waddington was a pioneering theoretical biologist who was, in his own words, inspired by the philosophy espoused by the philosopher and metaphysician Alfred North Whitehead: “Thus my particular slant on evolution—a most unfashionable emphasis on the importance of the developing phenotype—is a fairly direct derivative from Whiteheadian-type metaphysics” (cited in Robertson 1977: 597). As a consequence, the phenotype was, for Waddington, a process—a concept that has more recently, with the advent of the present-day version of evolutionary developmental biology, gathered much attention. Waddington’s interest in theoretical biology, first fostered in the Theoretical Biology Club—whose members included embryologist Joseph Needham and his wife the biochemist Dorothy Needham, the biologist turned philosopher Joseph Woodger, the physicist (and some say “father of molecular biology”) John D. Bernal, the cell biologist E. Neville Willmer (long-time editor of Biological Reviews and author of the first book to comprehensively discuss the evolution of cells [Willmer 1970]), and the future Nobel Laureate Peter B. Medawar—found its most pronounced manifestation in his editorship of a four-volume series entitled Towards a Theoretical Biology (1968–1972, hereinafter, TTB). These volumes were the proceedings of four International Union of Biological Sciences (IUBS) meetings Waddington organized in the late 1960s and early 1970s at the Villa Serbelloni in Bellagio, Italy. Chance attendance at the IUBS general assembly in Amsterdam in July 1961 had resulted in Waddington being asked by the internationally renowned developmental biologist Paul Weiss to stand for President of the Union, an office that Waddington put to good use in advancing an in-depth and wide-ranging discussion on the theoretical and conceptual foundations of biology. We use this introduction to place into a conceptual context four of Waddington’s papers from TTB. The four papers, along with commentary on one of them (from TTB, Vol. 4) are reproduced in this issue. In addition, we also briefly discuss two papers published by Waddington in the journal Nature in 1941 and 1942. These are not reproduced here, but are readily available online in the digital archive of Nature or in Waddington’s collection of essays, The Evolution of an Evolutionist (Waddington 1975). These two papers together with Waddington’s seminal book Organisers and Genes (Waddington 1940) mark the beginning of Waddington’s theoretical and conceptual work on a causal theory of both development and evolution focused on the organism as, to use a current concept, a complex dynamical system. One of these papers lays out his thoughts on how developmental systems evolve, a topic that has come into considerable prominence and importance over the past decade. The second is a short but seminal paper on Waddington’s concept of canalization. The four papers reproduced here represent the core themes of TTB that are most connected to current conceptual discussions in evolutionary developmental biology. Our intention in making these papers available to a wider audience of theoretical biologists and by juxtaposing them with papers discussed at the Altenberg workshop is to stimulate discussions that take full advantage from the encounter of current problems with historical antecedents.

Innateness, Canalization, and ‘Biologicizing the Mind’

This article examines and rejects the claim that ‘innateness is canalization’. Waddington's concept of canalization is distinguished from the narrower concept of environmental canalization with which it is often confused. Evidence is presented that the concept of environmental canalization is not an accurate analysis of the existing concept of innateness. The strategy of ‘biologicizing the mind’ by treating psychological or behavioral traits as if they were environmentally canalized physiological traits is criticized using data from developmental psychobiology. It is concluded that identifying innateness with environmental canalization can only result in adding unhelpful associations from ‘folkbiology’ to the relatively precise idea of canalization.

On the origins of morphological variation, canalization, robustness, and evolvability

Canalization is a concept, introduced by Waddington that describes the reduced sensitivity of a phenotype to genetic and environmental perturbations. Some research in canalization assumes that lack of variation in a trait in one genotype with respect to another genotype in a population, is due to the existence of buffering mechanisms against environmental and/or genetic variation. This article criticizes this assumption and out points out other possible problems with the concepts of canalization, robustness, and evolvability. These involve: the neglect of alternative explanations for the lack of variation in a trait, the incompatibility with current understanding of development, the way the mutivariate nature of morphological variation is considered. In addition, this article tries to explain that these concepts implicitly assume, although not generally acknowledged, that without buffering any genetic or environmental variation should give rise to a distinct phenotypic outcome. This can be avoided by restricting the use of canalization to cases in which, as in hsp90, there is direct evidence of buffering. For the other cases it would be clearer to talk about variational properties or simply type of variation. The concept of evolvability is also biased towards univariate comparisons and is dependent on selective pressures. It is suggested that this can be replaced by "type of phenotypic variation" from a genotype or variational properties. Overall, this article proposes that the concepts of canalization and evolvability involve some assumptions that, in most situations, unnecessarily complicate the study of evolution and development.

Innateness and Canalization

Cognitive scientists often employ the notion of innateness without defining it. The issue is, how is innateness defined in biology? Some critics contend that innateness is not a legitimate concept in biology. In this paper I will argue that it is. However, neither the concept of high heritability nor the concept of flat norm of reaction (two popular accounts in the biology literature) define innateness. An adequate account is found in developmental biology. I propose that innateness is best defined in terms of C. H. Waddington's concept of canalization.

Canalization: Genetic and Developmental Aspects

The concept of canalization was used by Waddington (66) in the context of developmental biology. He emphasized two important points in the develop­ ment of higher organisms. First, the end products of development, i.e. the adult tissues, are of sharply distinct types without intergradation. Second, the normal course of development is in his view a preferred path. Deviations of this path due to disturbances in the internal or external environment are corrected by regulatory processes. This occurs not only in the development of distinct types of tissue, but also on the organismic level in the realization of morphological patterns, in size and shape of organs and in matters of growth and determination of size of whole organisms. He depicted these phenomena in what he called the epigenetic landscape. Development starts in the egg. From there numerous developmental pathways branch out, leading to a great variety of distinct end results. These pathways are represented as a system of branching valleys in a descending slope. The developmental process is visual­ ized as balls rolling through the valleys to their end point. The steeper the valley and the larger the ridges separating the valleys, the stronger the tendency of the ball, when it is pushed from its course along the valley bottom by internal or external disturbances, to go back to its original course. This

Experiential canalization of behavioral development: Theory.

Waddington's (1942) notion of canalization has been widely invoked in developmental psychology to conceptualize species-typical regularities in behavioral development as genetically determined. In contrast, a developmental systems view, such as the one described in the present article, sees the genes as only one component in a hierarchy of influences, all of which contribute to canalize behavioral development. A key issue is that genetic activity does not by itself produce finished traits; differentiation occurs as a consequence of events above as well as below the cellular level, necessarily involving factors in addition to genetic influences to canalize behavioral development. In exploring the possible experiential canalization of development, it was found that the mallard duck embryo's contact call plays a canalizing role in species-speci fic perceptual development {Gottlieb, 1991). Thus, normally occurring experience, in concert with genetic and other activities, can canalize behavioral development. The concept of canalization has been utilized in several different ways in the psychological literature. Canalization was originally put forward by Holt (1931) to call attention to prenatal conditioning as a factor in narrowing down the initially diffuse or random nature of motor activity in the embryo or fetus. Holt saw the motor activity of the fetus and the infant as becoming organized through spatial and temporal contiguity learning that narrowed down originally diffuse neural pathways to a definite neural reflex arc. Thus, for Holt, canalization referred to the development of specific sensorimotor pathways out of an original multiplicity of such pathways; it was a label to capture the developmental-behavioral phenomenon of progression from diffuse to ordered or organized motor activity, with contiguity conditioning as the experiential mechanism whereby organized motor activity was achieved. Although Holt's concept of neural reflex circles to account for the development of grasping in the fetus and infant was an ingenious example of his point of view, it has remained an entirely speculative theoretical solution of primarily historical interest. Subsequent empirical studies in behavioral embryology have kept open the possibility that motor movements in the embryo and fetus of some species are patterned from the start, whereas in other species they appear to be random (see reviews in Gottlieb, 1970; Hamburger, 1973; Oppenheim, 1974).