1. Analogy between protein domains and local neural architecture
A protein domain is a chain of typically 20 to 70 amino acids, which folds consistently into a specific compact shape (under normal cellular conditions). Early in protein evolution, a set of useful folds emerged; these domains are essential components of almost all known proteins (Caetano-Anolles et al. Reference Caetano-Anolles, Wang, Caetano-Anolles and Mittenthal2009a, Finn et al. Reference Finn, Mistry, Tate, Coggill, Heger, Pollington, Gavin, Gunasekaran, Ceric, Forslund, Holm, Sonnhammer, Eddy and Bateman2010). Most proteins contain several domains, many contain dozens, and some large proteins contain hundreds of domains. These domains typically perform similar physical functions, such as binding specific protein partners or catalyzing specific reactions, in most of the proteins in which the domains occur. However, the role of each of these domains in the overall economy of the cell has diverged over evolutionary time. Thus domains are prime examples of molecular reuse, reflecting the general evolutionary principle that it is hard to invent something new.
We may think of specific types of neural circuitry as analogous to protein domains. For example, the six-layer local circuit is broadly similar across the cortex, and yet this relatively narrow range of circuit architectures has become involved with almost every aspect of behavior. The typical striatal circuit with inhibitory output cells has also been reused in regions such as the central nucleus of the amygdala (Ehrlich et al. Reference Ehrlich, Humeau, Grenier, Ciocchi, Herry and Luthi2009). As the phylogeny of neurodevelopment is uncovered, we might expect to find more examples of newer brain regions borrowing (and mixing) developmental programs from older brain regions.
2. Analogy between metabolic networks and functional circuits
A metabolic network is a set of metabolites, each of which may be readily inter-converted with one of several neighboring metabolites (by gain or loss of some atoms) through the catalytic action of a specific enzyme. The principal metabolic reactions have evolved with the enzymes that catalyze them. Early enzymes catalyzed a set of analogous chemical reactions inefficiently on a wide variety of chemically similar substrates. During the course of early evolution, these enzymes were duplicated by DNA copying errors, and each of the descendant enzymes came to act much more effectively on a narrower range of substrates (Caetano-Anolles et al. Reference Caetano-Anolles, Yafremava, Gee, Caetano-Anolles, Kim and Mittenthal2009b, Yamada & Bork Reference Yamada and Bork2009).
There was for some years a controversy over how novel metabolic pathways are assembled, which is analogous to the controversy in cognitive science between dedicated modules and ad hoc neural reuse. An early theory suggested that when genes for enzymes duplicated, they acted on the same kinds of substrates, but catalyzed novel reactions. The major alternative theory, now widely accepted, is that novel metabolic pathways are assembled by duplication of genes for enzymes that perform relevant biochemistry with different substrates; these enzymes then adapt to the substrates of the novel pathway (Caetano-Anolles et al. Reference Caetano-Anolles, Yafremava, Gee, Caetano-Anolles, Kim and Mittenthal2009b; Yamada & Bork Reference Yamada and Bork2009). The enzymes that structure novel metabolic functions or pathways are therefore a “patchwork” of adapted pieces from previously existing functions.
Thus, many important pathways of recent vintage are constructed mostly of unrelated proteins. Some of these pathways are crucial to most current forms of life. For example, many of the proteins of the Krebs cycle are distant cousins of proteins that catalyze amino acid metabolism, which evolved earlier in the history of life (Gest Reference Gest1987; Melendez-Hevia et al. Reference Melendez-Hevia, Waddell and Cascante1996). This “patchwork” model is analogous to Anderson's prediction that more recently evolved pathways invoke more distal brain regions.
These themes in metabolic evolution suggest by analogy that during development many brain regions both become more specialized – dealing with a subset of functions performed previously – and also paradoxically acquire novel functions in the expanding repertoire of behavior. Although a particular behavior may elicit broad brain activity in early life, the same behavior would recruit only a subset of those early regions in later life. However, each individual region active in the original behavior would later become active in many related behavioral functions, in which the region was not originally active. This kind of idea could be tested using chronic implants in animals or using fMRI at several points during child development.
3. Analogy comparing neural reuse to proteins that acquire novel functions very different from their earlier functions
A well-known example concerns cell adhesion molecules (CAMs), whose sticky domains were crucial in forming multi-cellular bodies early in animal life. These same sticky domains have been reused in a variety of other contexts, notably as immunoglobulins in the adaptive immune system, a key to the evolutionary success of vertebrates (Edelman Reference Edelman1987). By analogy, we would expect that during development some brain regions would become important in functions unrelated to those for which they had been used. This idea could be tested as described in the previous paragraph.
4. Analogy between neural circuits and signaling proteins
The majority of proteins in mammals are not enzymes catalyzing reactions, nor even structural components of our diverse tissues, but rather regulators and organizers of small molecules or other proteins. Some of these proteins sequester or transport small molecules, while others modify other proteins (often by adding a small molecular group such as phosphate or methyl), or regulate access to DNA. These “classical” signaling pathways are well-studied because they are reused in many situations. For example, the Wnt signaling pathway is widely reused throughout animal development (Croce & McClay Reference Croce and McClay2008). (Wnt is an example of a protein with three unrelated mechanisms of action, which seem to have been acquired independently.) The fibroblast growth factor (FGF) family of proteins plays a crucial role in the emergence of limb buds, and individual members of the family are reused at several points in mammalian development (Popovici et al. Reference Popovici, Roubin, Coulier and Birnbaum2005). In all these cases, the specific protein interactions have been preserved while being adapted to a novel function. By analogy then, we might expect different brain regions to preserve the dynamics of their interactions as these regions become co-opted to new functions. This idea might be tested by identifying pairs of brain regions with multiple behavioral functions and recording from these regions simultaneously during several types of behavior in which both regions are active.
Several families of DNA-binding proteins regulate transcription of genes by attracting or blocking the transcription machinery (RNA polymerase complex) at the locations on DNA where they bind. Reuse of these proteins is at the core of some of the most exciting current work in molecular biology: evolutionary developmental biology (“evo-devo”) (Carroll et al. Reference Carroll, Grenier and Weatherbee2005). The homeobox genes are famous for their role in early patterning of the front-to-back axis of the embryos of vertebrates and many invertebrates, and these functions are believed to date to the original bilaterian ancestor. However, most of these proteins have lesser-known roles in patterning limbs or digits or epithelia of organs, using the same mechanisms but responding to different signals. By analogy, we might expect that brain regions involved in early aspects of planning actions may also play a role in the fine-tuning of a subset of actions. This suggestion might be tested by recording from “executive” regions of the prefrontal cortex (PFC) during a variety of tasks.
Molecular evolution provides many specific examples of reuse, of which I have only scratched the surface. By analogy, these may provide some concrete inspiration for further research in the evolution and development of mental function.
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Reuse is a settled issue in molecular evolution: most functions in modern cells reuse proteins, or parts of proteins, which previously evolved under different selective pressures. This commentary on Anderson's target article draws analogies between specific aspects of molecular evolution and the ideas he presents about neural reuse, and suggests how the better understood field of molecular evolution may illuminate aspects of and inform hypotheses about neural reuse.
1. Analogy between protein domains and local neural architecture
A protein domain is a chain of typically 20 to 70 amino acids, which folds consistently into a specific compact shape (under normal cellular conditions). Early in protein evolution, a set of useful folds emerged; these domains are essential components of almost all known proteins (Caetano-Anolles et al. Reference Caetano-Anolles, Wang, Caetano-Anolles and Mittenthal2009a, Finn et al. Reference Finn, Mistry, Tate, Coggill, Heger, Pollington, Gavin, Gunasekaran, Ceric, Forslund, Holm, Sonnhammer, Eddy and Bateman2010). Most proteins contain several domains, many contain dozens, and some large proteins contain hundreds of domains. These domains typically perform similar physical functions, such as binding specific protein partners or catalyzing specific reactions, in most of the proteins in which the domains occur. However, the role of each of these domains in the overall economy of the cell has diverged over evolutionary time. Thus domains are prime examples of molecular reuse, reflecting the general evolutionary principle that it is hard to invent something new.
We may think of specific types of neural circuitry as analogous to protein domains. For example, the six-layer local circuit is broadly similar across the cortex, and yet this relatively narrow range of circuit architectures has become involved with almost every aspect of behavior. The typical striatal circuit with inhibitory output cells has also been reused in regions such as the central nucleus of the amygdala (Ehrlich et al. Reference Ehrlich, Humeau, Grenier, Ciocchi, Herry and Luthi2009). As the phylogeny of neurodevelopment is uncovered, we might expect to find more examples of newer brain regions borrowing (and mixing) developmental programs from older brain regions.
2. Analogy between metabolic networks and functional circuits
A metabolic network is a set of metabolites, each of which may be readily inter-converted with one of several neighboring metabolites (by gain or loss of some atoms) through the catalytic action of a specific enzyme. The principal metabolic reactions have evolved with the enzymes that catalyze them. Early enzymes catalyzed a set of analogous chemical reactions inefficiently on a wide variety of chemically similar substrates. During the course of early evolution, these enzymes were duplicated by DNA copying errors, and each of the descendant enzymes came to act much more effectively on a narrower range of substrates (Caetano-Anolles et al. Reference Caetano-Anolles, Yafremava, Gee, Caetano-Anolles, Kim and Mittenthal2009b, Yamada & Bork Reference Yamada and Bork2009).
There was for some years a controversy over how novel metabolic pathways are assembled, which is analogous to the controversy in cognitive science between dedicated modules and ad hoc neural reuse. An early theory suggested that when genes for enzymes duplicated, they acted on the same kinds of substrates, but catalyzed novel reactions. The major alternative theory, now widely accepted, is that novel metabolic pathways are assembled by duplication of genes for enzymes that perform relevant biochemistry with different substrates; these enzymes then adapt to the substrates of the novel pathway (Caetano-Anolles et al. Reference Caetano-Anolles, Yafremava, Gee, Caetano-Anolles, Kim and Mittenthal2009b; Yamada & Bork Reference Yamada and Bork2009). The enzymes that structure novel metabolic functions or pathways are therefore a “patchwork” of adapted pieces from previously existing functions.
Thus, many important pathways of recent vintage are constructed mostly of unrelated proteins. Some of these pathways are crucial to most current forms of life. For example, many of the proteins of the Krebs cycle are distant cousins of proteins that catalyze amino acid metabolism, which evolved earlier in the history of life (Gest Reference Gest1987; Melendez-Hevia et al. Reference Melendez-Hevia, Waddell and Cascante1996). This “patchwork” model is analogous to Anderson's prediction that more recently evolved pathways invoke more distal brain regions.
These themes in metabolic evolution suggest by analogy that during development many brain regions both become more specialized – dealing with a subset of functions performed previously – and also paradoxically acquire novel functions in the expanding repertoire of behavior. Although a particular behavior may elicit broad brain activity in early life, the same behavior would recruit only a subset of those early regions in later life. However, each individual region active in the original behavior would later become active in many related behavioral functions, in which the region was not originally active. This kind of idea could be tested using chronic implants in animals or using fMRI at several points during child development.
3. Analogy comparing neural reuse to proteins that acquire novel functions very different from their earlier functions
A well-known example concerns cell adhesion molecules (CAMs), whose sticky domains were crucial in forming multi-cellular bodies early in animal life. These same sticky domains have been reused in a variety of other contexts, notably as immunoglobulins in the adaptive immune system, a key to the evolutionary success of vertebrates (Edelman Reference Edelman1987). By analogy, we would expect that during development some brain regions would become important in functions unrelated to those for which they had been used. This idea could be tested as described in the previous paragraph.
4. Analogy between neural circuits and signaling proteins
The majority of proteins in mammals are not enzymes catalyzing reactions, nor even structural components of our diverse tissues, but rather regulators and organizers of small molecules or other proteins. Some of these proteins sequester or transport small molecules, while others modify other proteins (often by adding a small molecular group such as phosphate or methyl), or regulate access to DNA. These “classical” signaling pathways are well-studied because they are reused in many situations. For example, the Wnt signaling pathway is widely reused throughout animal development (Croce & McClay Reference Croce and McClay2008). (Wnt is an example of a protein with three unrelated mechanisms of action, which seem to have been acquired independently.) The fibroblast growth factor (FGF) family of proteins plays a crucial role in the emergence of limb buds, and individual members of the family are reused at several points in mammalian development (Popovici et al. Reference Popovici, Roubin, Coulier and Birnbaum2005). In all these cases, the specific protein interactions have been preserved while being adapted to a novel function. By analogy then, we might expect different brain regions to preserve the dynamics of their interactions as these regions become co-opted to new functions. This idea might be tested by identifying pairs of brain regions with multiple behavioral functions and recording from these regions simultaneously during several types of behavior in which both regions are active.
Several families of DNA-binding proteins regulate transcription of genes by attracting or blocking the transcription machinery (RNA polymerase complex) at the locations on DNA where they bind. Reuse of these proteins is at the core of some of the most exciting current work in molecular biology: evolutionary developmental biology (“evo-devo”) (Carroll et al. Reference Carroll, Grenier and Weatherbee2005). The homeobox genes are famous for their role in early patterning of the front-to-back axis of the embryos of vertebrates and many invertebrates, and these functions are believed to date to the original bilaterian ancestor. However, most of these proteins have lesser-known roles in patterning limbs or digits or epithelia of organs, using the same mechanisms but responding to different signals. By analogy, we might expect that brain regions involved in early aspects of planning actions may also play a role in the fine-tuning of a subset of actions. This suggestion might be tested by recording from “executive” regions of the prefrontal cortex (PFC) during a variety of tasks.
Molecular evolution provides many specific examples of reuse, of which I have only scratched the surface. By analogy, these may provide some concrete inspiration for further research in the evolution and development of mental function.