Amyloid beta precursor protein (APP) and prion protein (PrP) are cell membrane elements implicated in neurodegenerative diseases. Both proteins undergo endoproteolysis. Evidence is adduced from the literature hinting that the process in the two proteins could be related, their functions may overlap and their distributions coincide. It is proposed that PrP catalyses its own cleavage, the C-terminal fragment functions as an α secretase and the N-terminal segment chaperones the active site; the α secretase releases anticoagulant and neurotrophic ectodomains from APP. (...) The proposals explain some features of spongiform encephalopathies. BioEssays 23:456–462, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Mutational robustness facilitates evolutionary innovations. Gene duplications are unique kinds of mutations, in that they generally increase such robustness. The frequent association of gene duplications in regulatory networks with evolutionary innovation is thus a special case of a general mechanism linking innovation to robustness. The potential power of this mechanism to promote evolutionary innovations on large time scales is illustrated here with several examples. These include the role of gene duplications in the vertebrate radiation, flowering plant evolution and heart development, (...) which encompass some of the most striking innovations in the evolution of life. BioEssays 30:367–373, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Evolutionary genetics is concerned with natural selection and neutral drift, to the virtual exclusion of almost everything else. In its current focus on DNA variation, it reduces phenotypes to symbols. Varying phenotypes, however, are the units of evolution, and, if we want a comprehensive theory of evolution, we need to consider both the internal and external evolutionary forces that shape the development of phenotypes. Genetic systems are redundant, modular and subject to a variety of genomic mechanisms of “turnover” (transposition, gene (...) conversion, unequal crossingover, slippage and so on). As such the construction and spread of novel combinations of modules by turnover, in particular within gene promoters, contributes significantly to the evolution of phenotypes. Furthermore, redundancy, turnover and modularity lead to ever more complex networks of genetic interactions and ever more functions for a given module. The significant interaction between genomic turnover and natural selection leads to a molecular coevolution between interacting modules and hence facilitates the establishment of biological novelties. BioEssays 22:1153–1159, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

The origin of novel traits is what draws many to evolutionary biology, yet our understanding of the mechanisms that underlie the genesis of novelty remains limited. Here I review definitions of novelty including its relationship to homology. I then discuss how ontogenetic perspectives may allow us to move beyond current roadblocks in our understanding of the mechanics of innovation. Specifically, I explore the roles of canalization, plasticity and threshold responses during development in generating a reservoir of cryptic genetic variation free (...) to drift and accumulate in natural populations. Environmental or genetic perturbations that exceed the buffering capacity of development can then release this variation, and, through evolution by genetic accommodation, result in rapid diversification, recurrence of lost phenotypes as well as the origins of novel features. I conclude that, in our quest to understand the nature of innovation, the nature of development deserves to take center stage. BioEssays 30:432–447, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Conrad Hal Waddington integrated genetics with embryology and evolution by formulating and providing experimental evidence for the mechanisms of canalization and genetic assimilation in the context of stabilizing selection, and by fostering an epigenetic rather than the prevailing gene-centered view of embryonic development and of evolutionary change in development and adult form. Waddington saw phenotypes as processes, not static structures and behaviors. Trained in geology at Cambridge, Waddington turned to experimental studies on the chemical nature of the primary organizer and (...) developed the concepts of evocation and individuation as separable components of embryonic induction. A move after WW II to Edinburgh provided Waddington with his professional home for the rest of his career, during which he integrated genetics and development into an evolutionarily relevant discipline. Our conception of embryonic development as a highly integrated series of canalized pathways owes much to Waddington’s development of the concepts of canalization, chreods, epigenetics, and the epigenotype. The integrated, heritable, epigenetic organization of embryonic development is Waddington’s lasting legacy to development. He demonstrated organismal response to environmental change and hidden genetic variation, integrated environmental responsiveness into heritable change in response to selection, and coupled development, environment, and evolution. (shrink)

Organic selection (the Baldwin Effect) by which an environmentally elicitedphenotypic adaptation comes under genotypic control following selectionwas proposed independently in 1896 by the psychologists James Baldwinand Conwy Lloyd Morgan and by the paleontologist Henry Fairfield Osborn.Modified forms of organic selection were proposed as autonomization bySchmalhausen in 1938, as genetic assimilation by Waddington in 1942, andas an explanation for evolution in changing environments or for speciationby Matsuda and West-Eberhard in the 1980s. Organic selection as amechanism mediating proximate environmental effects on the (...) evolution ofmorphology and behaviour is the topic of this essay. Discussion includesthe context in which organic selection was proposed, Lamarckian or neo-Lamarckian implications of organic selection, Waddingtons experimentalstudies demonstrating the existence and efficacy of genetic assimilation,stabilizing selection and norms of reaction favoured by Schmalhausen, andMatsudas search for a mechanism of organic selection in endocrine changesand in heterochrony. (shrink)

The environmentally responsive molecular chaperone Hsp90 assists the maturation of many key regulatory proteins. An unexpected consequence of this essential biochemical function is that genetic variation can accumulate in genomes and can remain phenotypically silent until Hsp90 function is challenged. Notably, this variation can be revealed by modest environmental change, establishing an environmentally responsive exposure mechanism. The existence of diverse cryptic polymorphisms with a plausible exposure mechanism in evolutionarily distant lineages has implications for the pace and nature of evolutionary change. (...) Chaperone‐mediated storage and release of genetic variation is undoubtedly rooted in protein‐folding phenomena. As we discuss, proper protein folding crucially affects the trajectory from genotype to phenotype. Indeed, the impact of protein quality‐control mechanisms and other fundamental cellular processes on evolution has heretofore been overlooked. A true understanding of evolutionary processes will require an integration of current evolutionary paradigms with the many new insights accruing in protein science. BioEssays 26:348–362, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The vast majority (> 95%) of single-gene mutations in yeast affect not only the expression of the mutant gene, but also the expression of many other genes. These data suggest the presence of a previously uncharacterized ‘gene expression network’—a set of interactions between genes which dictate gene expression in the native cell environment. Here, we quantitatively analyze the gene expression network revealed by microarray expression data from 273 different yeast gene deletion mutants.(1) We find that gene expression interactions form a (...) robust, error-tolerant ‘scale-free’ network, similar to metabolic pathways(2) and artificial networks such as power grids and the internet.(3-5) Because the connectivity between genes in the gene expression network is unevenly distributed, a scale-free organization helps make organisms resistant to the deleterious effects of mutation, and is thus highly adaptive. The existence of a gene expression network poses practical considerations for the study of gene function, since most mutant phenotypes are the result of changes in the expression of many genes. Using principles of scale-free network topology, we propose that fragmenting the gene expression network via ‘genome-engineering’ may be a viable and practical approach to isolating gene function. BioEssays 24:267–274, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10054. (shrink)

C.H. Waddington is today remembered chiefly as a Drosophila developmental geneticist who developed the concepts of “canalization” and “the epigenetic landscape.” In his lifetime, however, he was widely perceived primarily as a critic of Neo-Darwinian evolutionary theory. His criticisms of Neo-Darwinian evolutionary theory were focused on what he saw as unrealistic, “atomistic” models of both gene selection and trait evolution. In particular, he felt that the Neo-Darwinians badly neglected the phenomenon of extensive gene interactions and that the “randomness” of mutational (...) effects, posited in the theory, was a false postulate. This last criticism dealt with the phenomenon known today as “developmental constraints.” Although population genetics itself has evolved considerably from its form at mid-20th century, much of Waddington’s critique, it is argued here, retains cogency. Yet, he did not attempt to develop a full-fledged alternative theory himself. Perhaps most surprisingly, in retrospect, is that he did not try to marry his work on gene interactions in development with his evolutionary interests, to create a theory of “genetic networks” and their evolution. Whether evolutionary genetics today will incorporate “network thinking” as a central element or whether there will be a general retreat to the more atomistic approach offered by genomics, remains an open question. (shrink)

The early gene knockout studies with a neurobiological focus were directed at fairly obvious target genes and added very little to our knowledge of behavioural neuroscience. On the contrary, since the behavioural consequences were often predictable, this helped confirm that the technology was working. However, a substantial number of knockouts of genes expressed in the brain have been without obvious behavioural consequences, supporting the concept of genetic canalisation and redundancy. Others have produced a behavioural deficit for which there is no (...) obvious explanation. Many cells of different tissue types have a capacity for memory, and in the brain, cells of the hippocampus are important for spatial learning and memory. Deleting genes that are expressed in the happpocampus has received considerable attention in this behavioural context. Although the initial studies experienced problems of interpretation, considerable advances have since been made. Knockout mice are now subject to tests of different forms of learning, multicellular hippocampal recordings, and restricted gene deletion specific to cells of component regions. This multi‐level approach is proving more informative. Nevertheless, there is still a need to recognise that behavioural expression is several steps removed from gene expression, and that the relationship between genes and behaviour can be reciprocal. (shrink)