Perspective Evolvability

Evolvability is an organism’s capacity to generate heritable phenotypic variation. Metazoan evolution is marked by great morphological and physiological diversification, although the core genetic, cell biological, and developmental processes are largely conserved. Metazoan diversification has entailed the evolution of various regulatory processes controlling the time, place, and conditions of use of the conserved core processes. These regulatory processes, and certain of the core processes, have special properties relevant to evolutionary change. The properties of versatile protein elements, weak linkage, compartmentation, redundancy, and exploratory behavior reduce the interdependence of components and confer robustness and flexibility on processes during embryonic development and in adult physiology. They also confer evolvability on the organism by reducing constraints on change and allowing the accumulation of nonlethal variation. Evolvability may have been generally selected in the course of selection for robust, f lexible processes suitable for complex development and physiology and specifically selected in lineages undergoing repeated radiations. Darwin based his origin of species theory on heritable variation and natural selection, although he conceded that ‘‘our ignorance of the laws of variation is profound’’ (1). Although much of the mystery of heredity and genetic variation has been dispelled by Mendelian genetics and the modern synthesis, the relationship of genetic variation to selectable phenotypic variation is far from understood (2). The consequences of mutation for phenotypic change are conditioned by the properties of the cellular, developmental, and physiological processes of the organism, namely, by many aspects of the phenotype itself. We may expect that many of these processes constrain variation, making much of it maladaptive. Nevertheless, we may ask whether certain properties of these processes bias the kind and amount of phenotypic variation produced in response to random mutation, such that more favorable and nonlethal kinds of variation are available on which natural selection can act. The capacity of a lineage to evolve has been termed its evolvability, also called evolutionary adaptability. By evolvability, we mean the capacity to generate heritable, selectable phenotypic variation. This capacity may have two components: (i) to reduce the potential lethality of mutations and (ii) to reduce the number of mutations needed to produce phenotypically novel traits. We can ask whether modern metazoa of highly diversified phyla, have cellular and developmental mechanisms with characteristics of evolvability and whether this evolvability is under selection and has itself evolved. The concept of evolvability was formulated in the past by several evolutionary biologists drawing from morphological examples such as limb, jaw, or tooth diversification (3–5), and the possible evolution of evolvability has been discussed (5–7). Evolvability also was formulated in theoretical models by several authors (7–9). Though artificial, these models confirm in principle that rules for generating phenotypic variation can affect the evolvability of a system. We will address evolvability at the molecular, cellular, and developmental levels with the conviction that it is more clearly demonstrable at these levels than at the level of morphology. It is difficult to evaluate how the particular characteristics of cellular, developmental, and physiological mechanisms affect the quantity and quality of phenotypic variation after genetic change and hence affect evolvability. To understand the consequence of mutation for a protein’s activity, one needs to understand the interactions of that protein with many other cell components. A current view is that conserved core processes constrain phenotypic variation, acting as a barrier to evolution (4, 6). Many core processes are conserved throughout metazoa (e.g., many signaling pathways and genetic regulatory circuits), others throughout eukaryotes (e.g., the cytoskeleton and cdkycyclin-based cell cycle, and yet others throughout all life forms (e.g., metabolism and replication). It is natural to assume that highly conserved mechanisms are optimized after repeated selections or are ‘‘frozen accidents’’ (because natural selection works with the best available at the time, not the best possible) that are now extensively embedded in other mechanisms. By either assumption, the process would be highly constrained, and most changes would be detrimental, i.e., lethal. Much has been made of constraint in recent discussions of evolution (4, 6, 10). Constraint results from functional interactions of proteins with each other, other cell components, and environmental agents. The greater the number and exactness of a protein’s requirements for function, the fewer the possibilities for changes of its amino acid residues by mutation. For example, if residues reside in a binding site for ligands or substrates or other proteins, they would be constrained to change. However, there is no reason to assume that constraint alone ensures evolutionary retention (survival) of a process. Even constrained processes must be conserved because of repeated positive selection (11)—the view we will espouse in this essay. The exact nature of embedment and selection in the conservation of core processes will depend on the ecological history of a lineage of organisms. Metazoa have undergone rapid and diverse phenotypic change, particularly in morphology, tissue organization, development, and physiology, that has entailed an extensive elaboration of cell–cell communication. By contrast, eubacteria have undergone limited morphological change but have instead achieved extensive biochemical diversification. Bacteria are microscopic, asexual, ubiquitous, and slowly changing generalists, whereas metazoa are macroscopic, sexual, ecologically restricted, and morphologically © 1998 by The National Academy of Sciences 0027-8424y98y958420-8$2.00y0 PNAS is available online at http:yywww.pnas.org. Abbreviations: SOP, sensory organ precursor; MT, microtubule; 3-D, three dimensional; CAM, cell adhesion molecule. A commentary on this article begins on page 8417. †To whom reprint requests should be addressed. e-mail: marc@ hms.harvard.edu.