Comp. Biochem. Physiol.. Vol. 62R pp. I 5. © Pergamon Press Ltd 1979. Printed in Great Britain

0305-0491/79/0115-0001502.(g)/0

MINIREVIEW

EVOLUTION OF HOMOLOGOUS PHYSIOLOGICAL MECHANISMS BASED O N P R O T E I N SEQUENCE DATA W. C. B~a~KER and M. O. DAYHOFF National Biomedical Research Foundation, Georgetown University Medical Center, Washington, D.C. 20007, U.S.A. (Received 3 May 1978) Abstraet--l. Genetic duplications can give rise to homologous physiological mechanisms that include

structurally related protein components. There are many such examples of related proteins within the human body. 2. Evolutionary histories showing the origins and subsequent divergences of these distantly related proteins can be derived from the protein sequences and correlated with the functional characteristics of these proteins. 3. The hormones related to glucagon provide an example of homology of physiological mechanisms and emergence of new functions subsequent to gene duplications. 4. The proteins related to troponin C illustrate the participation of distantly related proteins in the same mechanism (muscle contraction), the relationship of proteins characteristic of a specialized tissue to proteins found in all eukaryote ceils, and the correlation of genetic duplications with the evolutionary appearance of different types of muscle.

HOMOLOGOUS

PHYSIOLOGICAL

MECHANISMS

Gene duplications in ancestral species have led to the presence of distantly related proteins in present-day organisms. These duplications provided the potential for major evolutionary advances including the emergence of new physiological mechanisms homologous (evolutionarily related) to existing mechanisms. A duplication may involve the entire genome, an individual chromosome, part of a chromosome, a single gene, or part of a gene (Ohno, 1970). Thereafter, the independently accumulating genetic changes will produce gradual modifications in the originally redundant mechanisms. Eventually, the two mechanisms will evolve sufficiently different functions so that both will be essential to the normal development of the organism. These homologous physiological mechanisms will have component parts (e.g. hormones, enzymes, cell types) that are structurally related, and these respective parts will follow a similar developmental sequence and will function similarly and in the same order with respect to each other. Sometimes a protein component will be missing in one of the mechanisms through loss or inactivation of the gene coding for that protein; occasionally a component will have been added. Also, the control of expression of the mechanism or its parts may be modified. There may be extensive correspondence between the genetic programming that controls the differentiation of homologous mechanisms and the physiological programming that controls their normal operation. The genes that code for the protein components of a physiological mechanism are organized in the

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genome in ways that are to a considerable extent essential for the orderly differentiation and proper functioning of the mechanism. This genetic organization is also a result, of an evolutionary history that includes different types of duplications, point mutations and crossover events. Entire mechanisms duplicate when a genome duplicates and perhaps also when a chromosome duplicates. Duplication of single genes produces related genes tandemly arranged on the same chromosome. These genes may evolve to produce proteins that appear serially during development, as do the epsilon, gamma, delta and beta chains of hemoglobin (Kitchen & Boyer, 1974). Duplication of part of the gene often produces a protein with multiple functional sites (e.g. skeletal muscle troponin C with four calcium-binding sites). Such proteins seem to be particularly important for the development of complex physiological functions including muscle contraction, lipid transport and immunological defense (Barker et al., 1978; Barker & Dayhoff, 1977). PROTEIN SUPERFAMILIES

Dayhoff et al. (1975) and Zuckerkandl (1975) have independently estimated that all proteins could be grouped on the basis of evolutionary relationship into about 1000 groups, which we have called superfamilies. If 50,000 proteins are coded by the human genome, we would expect to find an average of 50 genes coding for the related proteins in each superfamily. Recently duplicated genes may code for identical proteins, as is the case for two genes that code for human hemoglobin alpha chains (Kitchen & Boyer, 1974). The more than 1000 proteins t h a t have been sequenced fall into about 180 superfamilies,

W. C. BARKER and M. O. DAYHOFF

G I P inhibits secretion of gastric juice. Because of the evolutionary relationships of these hormones, we would expect them to have similar mechanisms of action and, although their normal physiological actions are distinctive, they might have overlapping effects at higher doses or in certain assay procedures. Glucagon, secretin and VIP bind to specific receptor proteins in target-cell membranes, causing the activation of adenyl cyclase and an increase in intracellular cyclic AMP. The actions of G I P have not been as extensively investigated. EVOLUTIONARY TREES FROM The overlapping activities that have been demonPROTEIN SEQUENCES strated with these hormones have been reviewed elseEvolutionary trees can be derived from the where in more detail (Barrington & Dockray, 1976). sequences of related proteins. Each point on such a In adipose cells, secretin and VIP were bound by one tree represents a definite time, a particular species, set of membrane receptors and glucagon and G I P and a predominant protein structure within the indi- by another. GIP, however, did not activate adenyl viduals of this species. There is a "point of earliest cyclase and therefore acted as an inhibitor of glucatime" on any such tree. Time increases on all gon-stimulated lipolysis (Dupre et al., 1976). In the branches radiating from this point. Protein sequences rat colon, secretin and VIP, but not glucagon and from living organisms lie at the ends of branches. The GIP, were shown to bind to the same receptor, actiseries of branchings in the tree then indicates the rela- vate adenyl cyclase, and stimulate secretion (Waldtive order in which the protein sequences became dis- man et al., 1977). In liver cells the adenyl cyclase systinct from one another. The location of the point of tem activated by secretin and VIP is distinct from earliest time, that is, the connection of the trunk to that activated by glucagon. Pancreatic acinar cells of the branching structure, usually cannot be inferred guinea pig have two classes of membrane receptors: directly from the sequences but must be estimated one binds VIP strongly and secretin weakly, with VIP from other considerations. Several methods of con- but not secretin activating adenyl cyclase; the other structing such trees from protein sequence data have binds secretin strongly and VIP weakly, with both been described by us and others (Dayhoff et al., 1972; hormones activating adenyl cyclase (Robberecht et al., Fitch & Margoliash, 1967; Fitch & Farris, 1974; 1976). These examples illustrate that each of these horGoodman & Pech~re, 1977). Evolutionary trees have been derived from protein sequence data in order to mones is part of a physiological mechanism whose study such problems as the phylogeny of particular protein components include the hormone, the targetgroups of organisms, the development of eukaryotes cell membrane receptor that recognizes the hormone, from prokaryotes and the origins of mitochondria, and an adenyl cyclase in the target cell. The memchloroplasts and other intracellular organelles brane receptors of the target cells must evolve with (Schwartz & Dayhoff, 1978), or the characteristics of the hormones. We predict that the protein comthe mutation process (for additional references, see ponents of the membrane receptors will be related. Wilson et al., 1977; for examples, see Dayhoff, 1972, There may be a series of related adenyl cyclases, each 1976, 1978). A few such studies have aimed at eluci- found in a particular target cell. On the other hand, dating the development and differentiation of impor- it is possible that all or some of these hormones actitant physiological mechanisms. For instance, the vate the same intracellular adenyl cyclase. If this were the case, a change (mutation) in the gene for this analysis of the sequences of V regions of immunoglobulins has been pursued largely with the aim of adenyl cyclase would have profound effects on the uncovering the evolutionary and developmental ori- organism. Thus, there could be selection pressure in favor of duplicating entire mechanisms rather than gins of antibody diversity (Hood et al., 1975), Furthermore, the immune system may serve as a model for preserving related mechanisms with some essential other differentiation processes in higher organisms common components. If so, the components of functionally important related mechanisms may even(Hood & Prahl, 1972). tually become separate, even if the genetic duplications must occur in a stepwise fashion. EMERGENCE OF NEW HORMONAL The topology shown in Fig. 1 represents the most MECHANISMS probable evolutionary history of the glucagon-related The protein hormones provide the clearest hormones. The rate of change of glucagon since the examples of homology of physiological mechanisms. divergence of birds and mammals is only about 1.2% One superfamily includes the hormones glucagon, se- per 100 million years, and VIP is changing about creted from the pancreas, and secretin, vasoactive in- twice as fast. Sequences of G I P and secretin are availtestinal polypeptide (VIP), and gastric inhibitory able only from pig. Both glucagon and secretin are polypeptide (GIP), all secreted from the intestinal found in bony fishes (Barrington & Dockray, 1976), which diverged from land vertebrates over 400 million mucosa. VIP has also been found in brain and other nervous tissues and is now believed to be an impor- years ago. It is probable that homologs of both proteins exist in invertebrates. The duplications eventant neurotransmitter (Bryant et al., 1976). The major effects of these hormones are that glucagon raises tually giving rise to genes for VIP and G I P may even blood sugar, VIP lowers blood pressure, secretin have occurred in an ancestor of vertebrates and certain invertebrates. If so, they may not have changed stimulates secretion of pancreatic juice and bile, and nearly half of which include some mammalian proteins (Dayhoff, 1978). About one-third of these contain sequences of two or more distantly related mammalian proteins. Two examples have been known from the earliest days of protein sequencing. By 1965, sequences of myoglobin and of the alpha, beta and gamma chains of hemoglobin were known to be homologous, as were the sequences of the digestive enzymes trypsin and chymotrypsin.

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Evolution of homologous physiological mechanisms based on protein sequence data.

Comp. Biochem. Physiol.. Vol. 62R pp. I 5. © Pergamon Press Ltd 1979. Printed in Great Britain 0305-0491/79/0115-0001502.(g)/0 MINIREVIEW EVOLUTION...
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