© 2000 by The Society for Integrative and Comparative Biology
Insulin Through the Ages: Phylogeny of a Growth Promoting and Metabolic Regulatory Hormone1
1 Howard Hughes Medical Institute, University of Chicago, 5841 S. Maryland Avenue, MC 1028, Chicago, Illinois 60637
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Insulin was discovered in 1922 as the causative factor for a human metabolic disorder (diabetes mellitus), but it was recognized early that the hormone had a broad phylogenetic distribution. By the mid 1970s, insulin had been isolated and sequenced from all classes of vertebrates, including Agnatha. Also it was discovered that the insulin gene family in vertebrates included two closely related hormones named insulin-like growth factor (IGF)-I and -II. More recently, the application of recombinant DNA techniques have identified insulin-like peptide genes in invertebrates, including insects, molluscs and nematode and these findings clearly establish that insulin is an evolutionarily ancient hormone which is present in all metazoa. Here we briefly review the structure and function of the insulin/IGF gene family in vertebrates and invertebrates. Although these studies are ongoing, it appears that in invertebrates the insulin-like peptides function predominately as mitogenic growth factors that act to promote tissue growth and development. However, in vertebrates the mitogenic growth function has been subsumed by IGF-I and -II while insulin has acquired the function of being primarily a metabolic regulatory hormone. The gene duplication and divergence events necessary for this development probably occurred early during vertebrate evolution in the transition from protochordates, represented by extant amphioxus, to primitive jawless vertebrates, represented by extant lamprey and hagfish.
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INTRODUCTION |
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The discovery of insulin by Banting and Best in 1922
represented a milestone in clinical medicine but it has also contributed substantially to progress in the fields of molecular and comparative endocrinology. The importance of insulin used in the treatment of diabetes elicited great interest in this hormone and consequently resources became available for studies to characterize its structure and function. As a result, insulin was the first protein whose primary amino acid sequence was determined (Ryle et al., 1955); the radioimmunoassay technique was developed using insulin as the model (Yalow and Berson, 1970); insulin was the first hormone for which the 3-dimensional crystal structure was solved (Adams et al., 1969); proinsulin was the first hormone precursor discovered (Steiner et al., 1967); and the insulin cDNA and gene were among the first to be cloned by recombinant DNA techniques (Ullrich et al., 1977). Together with these impressive "firsts" in molecular endocrinology, there has also been considerable interest to determine the phylogenetic and evolutionary origin of insulin. Shortly after the discovery of insulin, some researchers thought that it was a unique hormone present only in mammals and birds. However, as early as 1923 Collip reported finding insulin-like activity in a bivalve mollusc, Mya arenaria. Assisted by advances in a number of biochemical techniques, including the development of an efficient method for isolating pure insulin from the pancreas, improved immunological and immunohistochemical assays for insulin, and importantly development of the Edman degradation method for amino acid sequence analysis, scientists by 1975 had isolated and sequenced insulin molecules from representative species in all classes vertebrates including hagfish (Fig. 1). The hagfish, together with lampreys, are living representatives of the jawless vertebrates (class Agnatha) and are considered to be the most evolutionarily ancient vertebrates.
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In contrast to the success achieved in vertebrates, early attempts to isolate and characterize an insulin-like molecule from an invertebrate species were unsuccessful. However, in 1986 Nagasawa and coworkers in a herculean effort successfully purified and sequenced a 4 kilodalton peptide from the silkworm Bombyx mori which they originally called 4K-prothoracicotropic hormone-II and later renamed bombyxin A2 (Nagasawa et al., 1986
). The amino acid sequence of bombyxin A2 clearly showed that it was an insulin-like molecule, i.e., it consisted of two peptide chains (A and B) crosslinked by highly conserved insulin type disulfide bonds. The overall sequence identity between bombyxin A2 and human insulin was 40%.
More recently, recombinant DNA techniques have been used to clone insulin-like peptide genes in a variety of invertebrate species, including mollusc, insects and the nematode Caenorhabditis elegans (Smit et al., 1988; Lagueux et al., 1990; Duret et al., 1998; Gregoire et al., 1998). An insulin receptor-like tyrosine kinase cDNA has also been cloned from a colenterate, hydra (Steele et al., 1996) and from C. elegans (Kimura et al., 1997). Although a previous report claimed that sponges contain an insulin mRNA (Robitzki et al., 1989), this has been retracted (Duret et al., 1998). Recently, the yeast genome was completely sequenced and no insulin-like genes were found (Chervitz et al., 1998). These results suggest that insulin-like genes have coevolved with the appearance of the metazoa (multicellular animals with differentiated tissues).
In the present review our goals are to briefly summarize the structure and function of insulin and insulin-like growth factors (IGFs) in vertebrates and compare these with the insulin-like peptides found in invertebrates. Based on the available data we propose that the ancestral insulin-like molecule functioned primarily as a mitogenic growth factor but in vertebrates the insulin gene has evolved to become a predominantly metabolic regulatory hormone.
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THE INSULIN GENE SUPERFAMILY |
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In mammals, the insulin gene superfamily includes not only insulin, IGF-I and IGF-II but also relaxin and the recently discovered Leydig insulin-like peptide (Ley I-L) (Adham et al., 1993
). These genes have been placed into a single superfamily based on the finding that they contain 6 highly conserved cysteine residues and molecular modelling studies showed that all the proteins fold to form a similar insulin-type tertiary structure (Fig. 2). However, this similarity in tertiary structure could be the result of either divergent evolution (descent from a common ancestral form) or convergent evolution (descent from unrelated ancestral forms). In the case of insulin, IGF-I and IGF-II, there is strong evidence that these three genes were derived during evolution from a common ancestor. In primary sequence, human insulin, IGF-I and -II share 50% amino acid identity in the A and B domains (Rinderknecht and Humbel, 1978). The biological actions of insulin, IGF-I and IGF-II are remarkably similar at the cellular level and the insulin receptor (IR) and type I IGF receptor (IGF-IR), which mediate the signal transduction of these hormones, are structurally homologous (Ebina et al., 1985; Ulrich et al., 1986).
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In contrast, much less is known about the relaxin and Ley I-L hormones. In mammals relaxin has a decidedly different biological action than insulin or IGF, which is to relax muscles in the pubic symphysis during parturition (Sherwood, 1988
). Relaxin molecules have been found in nonmammalian vertebrates but their biological function is unknown (Bullesbach et al., 1986). The relaxin receptor has not yet been characterized and the primary sequence of porcine relaxin is only 24% identical to insulin. Similarly, little is known about the function of Ley I-L except that it is expressed at high levels in testicular cells (Adham et al., 1993). A nonmammalian Ley I-L gene has not been reported and the predicted amino acid sequence of porcine Ley I-L, deduced from the cloned cDNA, is 29% identical to insulin. Due to the paucity of information currently available on relaxin and Ley I-L it is not possible to evaluate a possible evolutionary relationship between these hormones and the insulin/IGF family. |
STRUCTURE AND FUNCTION OF INSULIN AND IGF IN VERTEBRATES |
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In all vertebrates insulin is produced by clusters of pancreatic endocrine cells, beta cells in the islets of Langerhans, which are formed by outpouching of the endodermal gut during embryonic development (Pictet and Rutter, 1972
). The primary structure of insulin consists of two polypeptide chains, 30 amino acid B-chain and 21 amino acid A-chain, crosslinked by one intra- and 2 inter-chain disulfide bonds. Insulin is synthesized as a precursor, preproinsulin, and after removal of the signal peptide, proinsulin folds to form the correct tertiary structure (Steiner et al., 1993). The single chain proinsulin is then proteolytically cleaved in the secretion granule to release insulin and the connecting C-peptide.
In mammals, the anabolic action of insulin is well established (Cheatham and Kahn, 1995). Insulin secretion from beta cells is increased after a meal in response to secretagoues, principally a rise in blood glucose level, and it acts to stimulate postprandial uptake of glucose by liver and muscle and glucose and fatty acid uptake and lipogenesis by adipose tissue. Insulin also increases amino acid uptake and protein synthesis in liver and muscle. An important net effect of these anabolic actions is that insulin acts dynamically to maintain a constant blood glucose concentration which is essential for normal central nervous system activity.
The action of insulin in nonmammalian vertebrates is less well characterized but there is good evidence that it also acts primarily as a metabolic regulatory hormone. When the islet cells were excised from the teleost Gillichthys mirabilis, severe hyperglycemia and other classical symptoms of insulin deficient diabetes developed within 16 days (Kelley, 1993). Similarly, complete isletectomy performed on Southern lamprey Geotria australis by Epple, A and coworkers (Epple et al., 1992) resulted in a marked increase in blood glucose level. In general, the hypoglycemic action of insulin in ectotherms develop more slowly and can require days instead of hours to achieve a full effect.
Structurally, the insulin protein has been highly conserved throughout vertebrate evolution. Figure 3 shows the alignment of human and hagfish insulin. Though the evolutionary divergence time between humans and hagfish is about 400 million years, their insulin sequences share 61% amino acid identity and the key residues which are thought to be important for receptor binding have been maintained. The crystal structure of hagfish insulin has also been determined and it is virtually superimposable with porcine insulin (Cutfield et al., 1979). Consistent with these findings, hagfish insulin has full biological activity, albeit with lowered affinity, when added to mammalian cells and vice versa.
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Using recombinant DNA techniques, insulin genes have been cloned from species representing each class of vertebrates and the results show that the gene organization has also been highly conserved (Steiner et al., 1985
). The vertebrate insulin gene (except mouse and rat insulin I) contains 3 exons and 2 introns: exon1 contains 5' untranslated sequence; exon2 contains the coding sequence for the signal peptide, B-chain and the amino terminal 5–7 amino acids of C-peptide; exon3 contains the coding sequence for the remaining C-peptide, A-chain and 3' untranslated region (Fig. 4). With a few exceptions, notably mice and rats and a few teleost species, insulin is present as a single copy gene per haploid genome.
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In addition to insulin, most vertebrates contain two peptide hormones, IGF-I and IGF-II, which are related to insulin in structure but have a different physiological function, to regulate cell and tissue growth during development. Structurally, IGF-I and IGF-II are single chain molecules which are homologous to proinsulin except that the C domain is truncated and the IGFs contain a short carboxyl peptide, D domain, attached to the end of the A domain. The precursor forms (preproIGFs) contain an amino terminal signal peptide and also an extended carboxyl peptide sequence, the E domain. The primary sequences of human IGF-I and -II are 62% identical to each other and they share 50% identity with insulin. The IGF-I and -II genes contain 5–9 exons but they share a similarity to the insulin gene in that the critical B, C, A domains are encoded in two exons (Fig. 4).
The identification of IGF-I and -II as mitogenic growth factors was established when it was discovered that IGF-I was identical to a blood borne factor, first characterized by Salmon and Daughaday (1957), that mediated the effect of growth hormone in stimulating cartilage growth in mice. Subsequent experiments have shown that IGF-I and -II can stimulate mitogenesis and cell growth in a variety of cell types when added in vitro and in vivo. However, definitive evidence that the IGFs function as essential growth factors have come from recent gene knockout studies in mice (DeChiara et al., 1990; Baker et al., 1993). In these studies, transgenic mice with null mutations in the IGF-I or IGF-II gene exhibited a retardation in the embryonic and postembryonic growth rates, resulting in the production of dwarf mice.
In addition to similarities in protein and gene structure, molecular cloning and functional studies have shown that the ligand receptors for insulin and IGF are also homologous (Ebina et al., 1985: Ulrich et al., 1986). Specifically, IR and IGF-IR are both heterotetrameric membrane bound receptors and both receptors contain an integral tyrosine kinase activity. The receptors share 50% identity in primary sequence and the receptors and ligands can cross react with each other. Taken together, these findings strongly suggested that the vertebrate insulin, IGF-I and -II genes have evolved from a common ancestral gene through the process of gene duplication and divergence.
In particular, the close similarity between IGF-I and -II suggested a recent gene duplication event that might have occurred during vertebrate phylogeny. In order to address the latter question, our laboratory has undertaken to characterize the IGF genes in species representing different vertebrate classes. Our results indicate that all jawed vertebrates (gnathostomes), including Chondrichthyes, contain distinct IGF-I and IGF-II genes (Duguay et al., 1995). However, in the agnathan hagfish we were able to clone only a single IGF cDNA and sequence comparisons show that hagfish IGF was equally related to IGF-I and IGF-II (Nagamatsu et al., 1991). These results suggest that the ancestral IGF gene was duplicated during the transition from agnathans to gnathosomes. However, because hagfish contains a distinct insulin and IGF gene, the divergence of these genes must predate the appearance of the vertebrates. In any attempt to reconstruct the latter phylogeny, it is thus necessary to examine the insulin-like genes in invertebrate species and in key prevertebrates species such as amphioxus.
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INVERTEBRATE INSULIN-LIKE PEPTIDE GENES |
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Several early attempts to isolate and characterize insulin-like molecules from invertebrates were made based on the known properties of vertebrate insulin. In these studies extracts were prepared from gut tissue and assayed for insulin immunoactivity or insulin specific bioactivity, such as increased glucose uptake. However, the studies were not successful and none of the invertebrate insulin-like peptides that have been characterized to date fit the above criteria.
BombyxinA2 was the first invertebrate insulin-like peptide to be purified and sequenced (Nagasawa et al., 1986). BombyxinA2 was isolated from silkworm brain and was originally called a prothoracicotropic hormone based on its ability to stimulate ecdyson release from the prothoracic gland in a related species. This activity is an artefact since purified bombyxinA2 had no prothoracicotropic activity when it was injected into the same species and the function of the hormone remains unknown. However, the sequence of bombyxinA2 proved that it was definitely an insulin-like peptide. It contained the A and B peptide chains crosslinked by invariant disulfide bonds found in all insulin-like molecules and exhibited 30% sequence identity to human insulin. Adachi and coworkers (1989) subsequently cloned bombyxinA2 cDNA and showed that the deduced sequence for probombyxinA2, like proinsulin, contained a 19 residue C-peptide.
In addition to bombyxinA2, insulin-like peptides have now been identified primarily by recombinant DNA methods in a variety of invertebrate species including mollusc (Smit et al., 1988), Locust (Lagueux et al., 1990), and the nematode C. elegans (Duret et al., 1998). Figure 5 shows an alignment of human insulin with the invertebrate insulin-like peptide sequences. The amino acid residues necessary to form the insulin type hydrophobic core and tertiary structure have been conserved but otherwise the peptide sequences are highly divergent. Many of the amino acid differences are located on the hormone surface and this suggests that the ligand-receptor binding contacts may be different between vertebrate insulin and invertebrate insulin-like peptides. However, all the insulin-like peptides contain a two chain structure which is homologous to vertebrate insulin. To date no invertebrate molecule with a single chain IGF-like structure has been found.
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Interestingly, the invertebrate insulin-like peptides are not single copy genes but instead form large member gene families. Cloning studies show that the silkworm contains at least 25 bombyxinA2-related genes (Kondo et al., 1996
), Lymnaea stygnalis contains 7 molluscan insulin-like peptide (MIP) genes (Smit et al., 1998) and 10 insulin-like peptides have been identified in the C. elegans genome (Gregoire et al., 1998). The reason for such a high gene number is unknown. The invertebrate insulin-like peptides are neuroendocrine hormones. Locusta insulin-related peptide (LIRP) was isolated from neurohaemal lobes located in the corpora cardiaca. In Lymnaea it has been shown that all the MIP genes are coexpressed in giant neuron cells. Similarly, in situ hybridization assays have established that multiple bombyxin genes are expressed in neuronal cells in the silkworm brain.
Functionally, the invertebrate insulin-like peptides appear to act as growth factors. In Lymnae, cauterization of the neurons which produce MIP resulted in a strong retardation of the snail's growth (Geraerts, 1976). However, growth was restored when healthy neurons were transplanted back into the snail. More recently, insulin-like peptide receptor genes have been characterized in fruit flies and C. elegans and in these organisms, mutations in the receptors caused defects in growth and development (Chen et al., 1996; Kimura et al., 1997).
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INSULIN-LIKE PEPTIDE GENE IN AMPHIOXUS |
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An analysis of the invertebrate insulin-like peptides strongly suggested that the ancestral hormone contained a two chain insulin structure but failed to provide any clues as to the phylogenetic origin of vertebrate IGF. To search for a possible transition form which may be related to insulin and IGF, we therefore analyzed the structure and expression of an insulin-like peptide (ILP) gene from an amphioxus species, Branchiostoma californiensis. Amphioxus occupies a key position in phylogeny because it is believed to be an extant representative of the ancestral invertebrate species that gave rise to the vertebrates. Technically an invertebrate, amphioxus is classified in subphylum Protochordata, phylum Chordata.
Using a RT-PCR approach, a cDNA containing the full-length coding sequence for ILP was cloned from whole amphioxus RNA (Chan et al., 1990). The deduced sequence showed that proILP contained the B chain, C-peptide, and A chain expected for a proinsulin molecule. However, proILP also contained a carboxyl peptide extension which could be divided into D and E domains similar to that found in proIGF-I and -II (Fig. 6).
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Amino acid sequence comparison showed that amphioxus ILP was equally similar to vertebrate insulin and IGF. To determine whether the ILP structure was unique to B. californiensis, we have also cloned ILP cDNAs from European (B. lanceolatus) and Florida (B. floridae) species. Several amino acid changes were found in the C, D and E domains, but the A and B chains were identical and the overall proILP structure was conserved (Chan, unpublished results).
Southern blot analysis established that ILP is a single copy gene. We performed extensive RT-PCR assays using degenerate oligonucleotide primers to search for additional insulin or IGF-like sequences in amphioxus but none were found. Thus amphioxus is the only chordate species in which distinct insulin and IGF genes have not been found.
Based on the above results, we proposed that amphioxus ILP may be an extant representative of the ancestral gene from which vertebrate insulin and IGF genes were derived. In particular, the structure of proILP also suggested a pathway by which an ancestral insulin-like gene could have mutated to express a single chain IGF molecule. First, a point mutation in the termination codon would extend the A chain to form the D and E domains as is found in proILP. Subsequently, mutations in the basic residue(s) flanking the C-peptide would inhibit proteolytic processing to yield a single chain hormone.
Recently, the ILP receptor (ILPR) cDNA was cloned from amphioxus and the receptor sequence revealed a consistent phylogenetic relationship. Amphioxus ILPR is a membrane-bound receptor tyrosine kinase and it is 48.6% identical to human IR and 47.3% identical to type I IGFR (Pashmforoush et al., 1996). When ILPR was transiently expressed in cultured fibroblast cells, it was equally activated by mammalian insulin and IGF-I although the ligand binding affinity was low.
The physiological function of ILP in amphioxus is unknown. In preliminary studies we have found that the ILP mRNA is expressed at high levels both in adults and during larval development. This suggests that ILP has active function throughout the amphioxus life cycle.
Recently, McRory and Sherwood (1997) reported characterizing distinct insulin and IGF cDNAs cloned from the tunicate Chelyosoma productum, which is also a nonvertebrate chordate species. However, the predicted amino acid sequences for the tunicate insulin and IGF peptides shared a remarkably high sequence identity; in fact, their percent identity with each other was greater than that with any of the vertebrate insulin and IGF sequences compared. Also remarkable was the authors finding that there was a high sequence identity between tunicate insulin and IGF in the evolutionarily highly variable C domain (a high sequence identity was also obtained when the tunicate sequences were compared with amphioxus ILP C domain). These results are discordant with their proposal that the tunicate genes are true orthologues of the vertebrate insulin and IGF genes. It is more likely that the tunicate sequences are the product of a recent gene duplication event. However, to fully resolve this controversy, it will be necessary to perform additional structural and functional studies in a related tunicate species such as Ciona intestinalis.
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SUMMARY AND HYPOTHESIS |
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SYNOPSISINTRODUCTIONTHE INSULIN GENE SUPERFAMILYSTRUCTURE AND FUNCTION OF...INVERTEBRATE INSULIN-LIKE...INSULIN-LIKE PEPTIDE GENE IN...SUMMARY AND HYPOTHESISReferences |
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Thanks to the extensive use of recombinant DNA cloning techniques within the past decade, it is now established that the insulin gene superfamily is represented in all metazoa. Insulin-like peptide genes have been cloned from a wide variety of invertebrate species, including insects, mollusc and worm, and an insulin-like receptor cDNA has been characterized in hydra. However, when the structure and function of the invertebrate insulin-like peptides are compared with vertebrate insulin and IGF an interesting dichotomy emerges. The invertebrate insulin-like peptides all contain a two peptide chain structure which is a feature characteristic of vertebrate insulin. However, the invertebrate hormones function as mitogenic growth factors much like vertebrate IGF. To date, no invertebrate insulin-like peptide that acts predominately as a metabolic regulatory hormone has been characterized.
From our studies on amphioxus ILP, we have proposed that an ancestral insulin-like gene was duplicated early in vertebrate evolution and the two daughter genes subsequently diverged to form insulin and IGF. We now hypothesize that this ancestral insulin-like gene functioned primarily as a mitogenic growth factor but after gene duplication, the mitogenic activity was retained by the vertebrate IGF gene. This then allowed the vertebrate insulin gene to develop a new function, to regulate metabolism.
Figure 7 shows a schematic of the possible evolutionary relationship between invertebrate insulin-like peptides, amphioxus ILP, and vertebrate insulin and IGF genes. If our hypothesis is correct the vertebrate IGF genes, though structurally less conserved, are functionally homologous to the invertebrate insulin-like peptides. In contrast, the vertebrate insulin gene became a metabolic regulatory action of insulin early during vertebrate evolution since insulin regulates glucose homeostasis even in hagfishes and lampreys.
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Gene knock-out studies have clearly shown that loss of IGF-I and -II function in mammals results in growth retardation. Similarly, ablation of MIP producing neurons from Lymnaea also leads to cessation of growth. At the cellular level these phenotypic effects as well as the metabolic action of insulin are mediated by a signal transduction mechanism generated by their respective hormone receptors. The IR and IGF-IR are closely homologous in structure but there is increasing evidence that these receptors may have significant differences in cellular action (Miura et al., 1995
). To gain further insight into the evolution of the insulin family, it will be particularly interesting to express an invertebrate insulin-like peptide receptor, IGF-IR and IR in the same cell type and compare mitogenic and metabolic activities.
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ACKNOWLEDGMENTS |
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This work was supported by the Howard Hughes Medical Institute and in part by National Institutes of Health grants (DK 13914). We thank Rosie Ricks for assistance in the preparation of the manuscript.
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FOOTNOTES |
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1 From the symposium A Tribute to Erika M. Plisetskaya: New Insights on the Function and Evolution of Gastroenteropancreatic Hormones presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 6–10 January 1999, at Denver, Colorado.
2 E-mail: shuchan{at}midway.uchicago.edu
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