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Baboon and cotton-top tamarin B2m cDNA sequences and the evolution of primate beta 2-microglobulin.

Nonhuman primates represent phylogenetic intermediates for studying the divergence of human and murine beta 2Ms. We report the nucleotide sequences of B2m cDNA clones from a baboon cell line, 26CB-1 (Papio hamadryas; primates: Cercopithecoidea), and a cotton-top tamarin cell line, 1605L (Saguinus oedipus; primates: Ceboidea). The baboon and tamarin B2m sequences indicate a very slow rate of B2m evolution in primates relative to that in murid rodents. Phenotypic evolution of beta 2M has also been very conservative in primates, with only 9-14 substitutions separating baboon or tamarin beta 2Ms from those of humans or orangutans. Analyses of silent and amino-acid-altering nucleotide substitutions provide evidence that negative selection has acted to limit variability in beta strands of primate beta 2Ms, while positive selection has promoted diversity in non-beta-strand regions of murine beta 2Ms. No evidence for the action of selection upon beta 2M residues that contact the class I heavy chain was found in primates or mice. The finding that different selective forces have operated upon primate and murine beta 2Ms suggests that beta 2M may have evolved to serve distinct functions in primates and mice.

Amino Acid Sequence

Toward a molecular paleontology of primate genomes. II. The KpnI families of alphoid DNAs.

KpnI restriction of anthropoid primate DNAs, from a New World monkey to man, releases a series of segments that are remarkable among all of the alphoid DNAs in the constancy of their relative amounts in the various primate genomes, in their long-range organization, and in their internal sequence structure. These segments are labeled the KpnI A, B, C and D segments. Cross-hybridization analysis by Southern filter-transfer hybridization indicates that the KpnI segments represent separate and distinct families of alphoid DNAs. These families are termed the KpnI A, B, C and D families of alphoid sequences, of which only the KpnI A and B families were studied in detail here. - Evidence is presented suggesting that the KpnI segments do not exist as long, tandemly repeated sequences in the primate genome: rather, they may occur interspersed among other, perhaps nonalphoid sequences. From the stained gel patterns and from Southern filter-transfer hybridization experiments, the KpnI families appear to be absent from the genomes of the two prosimians studied - the galago and the black lemur. The KpnI A and B families are found among all of the anthropoid primates, including the New World capuchin monkey. The KpnI C family was detected in the genomes of the Old World anthropoid primates whereas the KpnI D family was detected only among the great apes and man. - The results are in accord with the observation (Musich et al., 1980) that with the continued evolutionary development of the primate Order, there has been a parallel trend toward an increased number and variety of alphoid DNA sequences. The properties of the KpnI families suggest that these sequences, unique among the alphoid DNAs, have been conservatively maintained throughout primate phylogeny and that they are among the most ancient of all primate DNAs.

Animals

Evolution of DNA sequences has been retarded in Malagasy primates.

It is generally accepted that there are six major groups of living primates: (1) lemurs (including all the primates of Madagascar), (2) lorises (including galago and potto), (3) tarsiers, (4) New World monkeys, (5) Old World monkeys and (6) apes (including man). Tree shrews, once considered to be primates, are now generally recognized as not significantly more closely related to the six groups than other mammals. The first surviving primate lines to diverge from the common primate ancestor are believed to have given rise to one or more of the first three groups. However, the fossil record is insufficient to determine their relative branching order. Furthermore, neither morphological considerations nor studies of protein evolution produce unanimity as to whether tarsiers are more closely related to the prosimians (the lemurs plus lorises) or the simians (the monkeys and apes). In an attempt to resolve these discrepancies, we have measured the DNA sequence difference between several primates. We report here that the evolution of DNA of primates from Madagascar is significantly less than that of all other groups of living primates. This is not expected in the simplest form of the theory of neutral selection and may be important for our understanding of evolution at the molecular level.

Animals

Plasma cortisol transport and primate evolution.

Primates have diverged into three major evolutionary groups: prosimians, Old World primates, and New World primates; the last group is distinguished by high circulating cortisol concentrations and resistance to the action of glucocorticoids. We have studied a large spectrum of primate species within these groups to characterize the phylogenetic relationships of cortisol-binding globulin (CBG) among them. The CBG in each species was found to be glycosylated, as judged from lectin interactions, and to exhibit an electrophoretic mobility similar to that of human CBG. Although the CBG affinity for cortisol differed among species, the effects of changes in temperature on the CBG affinity were similar. Strikingly, the CBG-binding capacity of plasma in the New World primates was 1/10th to 1/100th those in the Old World primates and prosimians, while the CBG-binding affinity for cortisol was lower. The reduced capacity and affinity of CBG result in a markedly higher fraction of unbound plasma cortisol in the New World primates than in the Old World primates or the prosimian species examined. This evolutionary pattern of CBG may be a compensatory mechanism for the target organ resistance to glucocorticoids that characterizes the New World monkeys.

Animals

Comparative sequence analysis of cytokine genes from human and nonhuman primates.

Two major issues severely limit the studies of human recombinant cytokines/growth factors in nonhuman primates. First, assays and reagents specific for the detection and quantitation of human cytokines do not all function when utilized to detect/quantitate the nonhuman primate cytokines. Second, although most of the human cytokines appear to induce similar, if not identical, biologic function when used with cells from nonhuman primates in vitro or in vivo, they invariably induce Ab responses in vivo, precluding their repeated and/or continued use in vivo. Our laboratory has thus initiated studies to clone, sequence, and prepare recombinant cytokines from nonhuman primates and to define assays and reagents for their detection and quantitation at the nucleic acid and protein level. The data that were derived from such studies show that the nonhuman primate cytokines IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 alpha, IL-12 beta, IL-15, IFN-alpha, IFN-gamma, and TNF-alpha share 93 to 99% homology at the nucleic acid and protein level with the human equivalents. The most prominent differences between human and nonhuman primate cytokine sequences were noted for IL-1 alpha/beta, IL-2, IL-8, IFN-alpha, IFN-gamma, and IL-12 beta. The aligned sequences of cytokines for human and several nonhuman primate species are provided herein, and a phylogenetic analysis of the published sequences of select cytokines from other species, along with those of the nonhuman primates, are described. In addition, comparative analysis of the relative bioactivity of our immunoaffinity-purified recombinant rhesus macaque IL-4, IL-15, and IFN-gamma with commercially available human recombinant cytokines is described herein.

Amino Acid Sequence

The neuroanatomical organization of pathways between the dorsal lateral geniculate nucleus and visual cortex in Old World and New World primates.

Pathways between the dorsal lateral geniculate nucleus (dLGN) and visual cortex in Old World (Macaca, Papio, Erythrocebus, Cercopithecus) and New World (Saimiri, Cebus) primates were studied after injections of horseradish peroxidase and H3 or S35 amino acids into the dLGN or visual cortex. Trans-synaptic autoradiography was also used to study these pathways after an injection of H3 proline-fucose into one eye. The subsequent autoradiographs of visual cortex showed that Old World primates have separate eye inputs (ocular dominance columns) in the striate cortex, whereas New World monkeys have overlapping or non-separated eye inputs. In both primate groups the geniculocortical input to layer IVA formed a pattern which resembled a honeycomb in tangential sections, unlike the solidly labeled layer IVC. Also common to the two primate groups was a projection from dLGN to layer VI. There was no dLGN projection to any prestriate area in any of the primates. However, after an injection limited to the prestriate cortex of Macaca, light autoradiographic labeling was seen in the interlaminar zones and the magnocellular and S laminae, demonstrating a prestriate-dLGN pathway. Our results indicate that the primate visual system differs significantly from the cat in having no dLGN projection to area 18. There are also signficant differences between primates in the level at which the possibility of binocularity (of an excitatory nature) first occurs in the striate cortex because in the species studied thus far with neuroanatomical methods, Old World primates have ocular dominance columns in layer IV but most New World monkeys lack them.

Animals

The topography of primate retina: a study of the human, bushbaby, and new- and old-world monkeys.

The distribution of ganglion cells has been studied in the retinas of four primates: the prosimian bushbaby, the New-World squirrel monkey, the Old-World crab-eating cynamolgous monkey, and the human. The sizes of ganglion cell somas were also measured at a number of retinal locations and compared with similar measurements in the cat retina to test for the presence in primates of retinal specializations such as the visual streak, and for gradients in retinal structure, such as that between temporal and nasal retina. In all four primates, ganglion cell somas in peripheral retina ranged considerably in diameter (6-16 micrometer in the bushbaby, 8-22 micrometer in the squirrel monkey, 8-23 micrometer in the cynamolgous monkey, 8-26 micrometer in the human). It seems likely that the strong physiological correlates of soma size which have been described among cat retinal ganglion cells and among the relay cells of the macaque lateral geniculate nucleus are generally present in primates. In all four primates, evidence was also obtained of a visual streak specialization; the isodensity lines in ganglion cell density maps were horizontally elongated, and small-bodied ganglion cells were relatively more common in the region of the proposed streak than in other areas of peripheral retina. However, the visual streak seems less well developed than in the cat; among the four primate species examined it was best developed in the bushbaby, at least as assessed by the shape of the isodensity lines. All four primates showed a clear foveal specialization, but this feature seemed least developed in the bushbaby. At the fovea, ganglion cells are smaller in soma size than in peripheral retina; they also seemed more uniform in size, although some distinctly larger cells persist in the human and bushbaby. Soma size measurements also provided evidence of a difference between nasal and temporal areas of peripheral retina comparable to that reported for the cat and other species. Thus the primate retinas examined show features, such as the foveal specialization, which seem unique to them among mammals. They also show features, such as nasal-temporal differences in ganglion cell size, and (though weakly developed) a visual streak, which they have in common with other mammals with widely different phylogenetic histories.

Animals

Comparison of canine and non-human primate animal models for periodontal regenerative therapy: results following a single administration of PDGF/IGF-I.

Two commonly used animal models for evaluating putative periodontal regenerative therapies are the beagle dog model with natural periodontal disease and the non-human primate with ligature-induced attachment loss. The host response, microbiology, and skeletal rates of remodeling of these two models are summarized. In addition, the results of experiments comparing the healing response to periodontal surgery with and without concurrent use of the combination of platelet-derived growth factor (PDGF) and insulin-like growth factor-I (IGF-I) in these models are presented. At 1 month, PDGF/IGF-I administration resulted in a 64.1% and 51.4% increase in new attachment formation in the non-human primate and canine, respectively, while controls (surgery plus placebo) demonstrated 34.1% and 8.6% increases in new attachment formation in the non-human primate and canine models, respectively. Further, application of PDGF/IGF-I stimulated 21.6% and 65% osseous defect fill in the non-human primate and canine, respectively, while controls demonstrated 8.5% and 14.5% osseous defect fill in the non-human primate and canine, respectively. The osseous response in the canine appears greater than that of the non-human primate, and the new attachment formation was more substantial in the non-human primate than the canine. However, in general these data demonstrate a high degree of consistency in the effects of PDGF/IGF-I in promoting periodontal regeneration. Positive results in these two models--the dog with natural periodontal disease and the non-human primate with ligature-induced attachment loss--justify human clinical trial testing of a putative regenerative therapy.

Alveolar Bone Loss

Selective myocardial cell necrosis in nonhuman primates.

A retrospective study was performed to describe the histologic stages of selective myocardial cell necrosis (SMCN) in nonhuman primates, and to compare the incidence of SMCN in two groups of nonhuman primates. Myocardial tissues taken at the time of autopsy from 50 primates at an experimental center were compared with similar tissues from 50 primates housed in a breeding colony. SMCN was confirmed in 20% of the experimental primates and 30% of the breeding primates, proportions that were not significantly different. The incidence and histologic characteristics of SMCN in nonhuman primates were similar to those described in humans, and resembled the lesion produced in experimental primates by administration of catecholamines of by hypokalemia.

Animals

Evolution of the primate cytochrome c oxidase subunit II gene.

We examined the nucleotide and amino acid sequence variation of the cytochrome c oxidase subunit II (COII) gene from 25 primates (4 hominoids, 8 Old World monkeys, 2 New World monkeys, 2 tarsiers, 7 lemuriforms, 2 lorisiforms). Marginal support was found for three phylogenetic conclusions: (1) sister-group relationship between tarsiers and a monkey/ape clade, (2) placement of the aye-aye (Daubentonia) sister to all other strepsirhine primates, and (3) rejection of a sister-group relationship of dwarf lemurs (i.e., Cheirogaleus) with lorisiform primates. Stronger support was found for a sister-group relationship between the ring-tail lemur (Lemur catta) and the gentle lemurs (Hapalemur). In congruence with previous studies on COII, we found that the monkeys and apes have undergone a nearly two-fold increase in the rate of amino acid replacement relative to other primates. Although functionally important amino acids are generally conserved among all primates, the acceleration in amino acid replacements in higher primates is associated with increased variation in the amino terminal end of the protein. Additionally, the replacement of two carboxyl-bearing residues (glutamate and aspartate) at positions 114 and 115 may provide a partial explanation for the poor enzyme kinetics in cross-reactions between the cytochromes c and cytochrome c oxidases of higher primates and other mammals.

Amino Acid Sequence

Coraco-clavicular joint: normal variant in humans. A radiographic demonstration in the human and non-human primate.

The coraco-clavicular joint is a true synovial joint that may become painful in some patients after trauma. Among the descriptions of this entity is the assertion that the coraco-clavicular joint is routinely seen in gorillas and gibbons. We undertook to assess the incidence of this variant among gorillas, gibbons, and other non-human primates. All available radiographs of large primates performed at the International Wildlife Conservation Park/Bronx Zoo (IWCP) over the past 10 years were reviewed by a musculoskeletal radiologist (human radiology). All radiographs were taken during the normal clinical care of the non-human primate population of the IWCP and are a part of each animal's clinical record. Eighty-one non-human primate radiographs were suitable for study as they contained the region of interest. The 81 radiographic examinations included 14 different species of non-human primates. The coraco-clavicular joint was seen in 4 out of 9 silver-leaf langur, 2 out of 8 lowland gorilla, and in 1 out of 6 white-handed gibbon. In all non-human primate cases where the coraco-clavicular joint occurred, it was bilateral. In 1 out of 8 mandrill, there were very wide distal clavicular ends that articulated both with the coracoid and with the acromion. The coraco-clavicular joint differs from an ossified coraco-clavicular ligament. The radiographic appearance is characteristic and is found in both humans and some non-human primate species. It may rarely become painful following trauma. When symptomatic in humans, resection of this anomalous articulation is curative.

Acromioclavicular Joint

Effects of environmental conditions on the psychological well-being of primates: a review of the literature.

Amendments made to the Animal Welfare Act in 1985 require primate researchers to provide "a physical environment adequate to promote the psychological well-being of primates". Regulations have not yet been promulgated, in part because "the psychological well-being" of primates is extremely difficult to define. Ideally, those regulations would be based upon observable changes in behavior rather than assumed psychological changes. Regardless, new primate care regulations pertaining to social environment, cage size, exercise and other forms of environmental enrichment are anticipated. A review of the literature suggests that there is little scientific data to support changing existing regulations. For instance, although it is clear that total social isolation in very young primates can be behaviorally devastating in terms of normal social behaviors, there are few, if any, demonstrable adverse effects of individual housing in adult primates. On the other hand, group housing, particularly with groups changing frequently in composition, increases aggression, trauma and disease transmission. In addition, existing research suggests there are important species differences in terms of social preferences. It is impossible to justify an increase in cage size based upon the available literature. An additional practical consideration is that any change in cage size requirements will necessitate replacement of current primate housing on a national level, an enormously expensive proposition. Regarding environmental enrichment, research suggests that providing a naturalistic environment is not as critical as arranging dynamic events that are contingent upon behavior. However, new research is necessary to specify the types of environmental enrichment that are valuable and appropriate before useless, even damaging, and expensive changes are mandated.

Animal Welfare

Evolutionary radiation of visual and olfactory brain systems in primates, bats and insectivores.

How brains have evolved in response to particular selection pressures is illuminated by ecological correlates of differences in brain structure among contemporary species. The focus of most comparative studies has been on the overall size of brains relative to body size, hence ignoring the ways in which selection operates on specific neural systems. Here we investigate evolutionary radiations in the size of visual and olfactory brain structures within three orders of mammals: primates, bats and insectivores. The comparative relationships within these three orders show both similarities and differences. After removal of the allometric effect of overall brain size, the sizes of different structures within each sensory modality are positively correlated in all three orders. Correlations between visual and olfactory structures, however, are negative in primates, negative but non-significant in insectivores, and positive in bats. In both primates and insectivores, nocturnal lineages tend to have larger olfactory structures than do diurnal or partly diurnal lineages, and among the primates diurnal lineages have larger striate visual cortexes. Hence the apparent trade-off between vision and olfaction in primates seems to be related to the divergence of nocturnal and diurnal forms. However, negative correlations between visual and olfactory structures were also found when nocturnal strepsirhines and diurnal haplorhines were analysed separately, suggesting that ecological variables in addition to activity timing may be significant. Indeed, there were also associations with diet: frugivory was associated with enlargements of the geniculostriate visual system in diurnal primates, enlargements of olfactory structures in nocturnal primates, and possibly enlargements of both in bats. Further ecological associations were found within insectivores: aquatic lineages had smaller olfactory structures than in their non-aquatic counterparts, and fossorial lineages had smaller optic nerves than in non-fossorial forms. We conclude that activity timing, diet and habitat have each played a role in the evolutionary radiation of mammalian sensory systems, but with varying effects in the different taxa. Some of the associations between ecology and sensory systems suggest alternative explanations for correlates of overall brain size, which have in the past commonly been interpreted in terms of selection on intelligence.

Adaptation, Biological

Development and regulation of growth and differentiated function in human and subhuman primate fetal gonads.

We have attempted to summarize the research on primate fetal gonadal development that has occurred over the past three decades. Many similarities exist between fetal gonadal development in human and subhuman primates; therefore, comparisons and analogies between these species can be made. Fetal gonadal development is a complex process dependent on timely maturation and differentiation of several cell types with different functions. Adequate development is important for normal sexual development and intact adult fertility potential as well as for intrauterine priming of neural centers in the central nervous system. While the fetal primate testis is active in steroidogenesis, the fetal ovary seems to be quiescent throughout most of gestation, although some ovarian steroidogenic enzymes have been demonstrated. Growth and development of both gonads are controlled during late gestation at least in part by pituitary hormones, while earlier in gestation other yet undefined regulators (placental, intragonadal) likely also are active. The main goal of this review was to demonstrate that gonadal growth and differentiation, both in males and females, is regulated by endocrine factors as well as by intragonadal, autocrine/paracrine agents. Although many parts of the puzzle are still missing it is probable that, similar to fetal development of other endocrine tissues and to events in postnatal gonads, these local regulators have important functions. Currently, primate fetal gonadal research is lacking in at least two key aspects: 1) the definition of paracrine and autocrine nonsteroidal factors that are involved in the regulation of gonadal growth and differentiation in vitro; and 2) in vivo studies in subhuman primates that might better help to clarify the biological roles of the multiple extra- and intragonadal hormones and their complex interactions. To date, the regulation of gonadal steroidogenesis has been investigated more thoroughly than the regulation of gonadal growth. Most of our knowledge stems from observations of gonadal development in anencephalics or subhuman primates after pituitary ablation. Because of the constraints of small organ size and limitation of material, studies of fetal primate gonadal development have been limited. Given such limitations, new molecular biological techniques, including polymerase chain reaction and in situ hybridization, may provide the means of addressing these questions. Further, because of these limitations, sensitive cell separation techniques need to be developed to achieve enriched primary gonadal cell cultures from individual gonads.

Animals

Cortisol levels, binding, and properties of corticosteroid-binding globulin in the serum of primates.

New World primates have exceptionally high plasma levels of cortisol and other steroid hormones when compared with humans and other primates. It has been suggested that this difference can be explained by either low affinity or concentration of cellular steroid receptors. We have assessed cortisol availability in serum from several species of New and Old World primates under physiological conditions (whole serum at 37 degrees C). Measurements were made of total and free cortisol, corticosteroid-binding globulin (CBG) binding capacity and affinity for cortisol, distribution of cortisol in serum, and its binding to albumin. In agreement with earlier reports, plasma free cortisol levels in Old World primates, prosimians, and humans range from 10-300 nM. However, very high total plasma cortisol together with low CBG binding capacity and affinity result in free cortisol concentrations of 1-4 microM in some New World primates (squirrel monkey and marmosets) but not in others such as the titi and capuchin. In squirrel monkeys, free cortisol levels are far greater than might be predicted from the affinity of the glucocorticoid receptor estimated in cultured skin fibroblasts. In addition to low affinity, CBG from squirrel monkeys and other New World primates exhibits differences in electrophoretic mobility and sedimentation behavior in sucrose density ultracentrifugation, suggestive of a molecular weight that is approximately twice that of CBG from other species. Together with other data these results indicate that the apparent glucocorticoid resistance found in New World primates is a complex phenomenon that is not easily explained by present concepts of glucocorticoid action.

Animals

The comparative anatomy of the forelimb veins of primates.

One hundred and thirteen forelimbs taken from 62 individuals belonging to 17 primate genera were dissected to reveal the entire course of the superficial venous system. The course of the deep venous system was also documented in at least one forelimb of each primate genus, and the number and location of perforating veins was recorded in 18 human and 45 non-human primate limbs. In Pan, Gorilla and in about 25% of human specimens the lateral superficial vein was confined to the forearm, while in all other primates, and in the majority of humans, this vein extended from the carpus to the clavicular region. Only Pongo and humans exhibited a second main superficial vein on the medial side of the forearm. In all primates the deep veins of the forelimb usually accompanied the arteries. Thus variation in the deep venous system reflected the different arterial patterns exhibited by these primates. The number of perforating veins in the forelimb was related to the length of the limb. Primate genera with longer forelimbs had more perforators, though not as many as would be expected if the number of perforators scaled linearly with limb length.

Animals

Genetic significance of some common primate models in biomedical research.

Nonhuman primates are excellent animal models for human diseases because of their close relationship to humans. Indeed, comparisons of the chromosomes and DNA homologies between primates and humans testify to the commonality of the genetic material between these phylogenetically related species. Not surprisingly, this close relationship at the genotypic level extends to the phenotypic level. Thus, the patho-physiological responses of humans and nonhuman primates to internal and external insults are remarkably similar. Two types of human diseases for which nonhuman primates are paramount animal models are discussed. One type includes diseases with defined, single agent etiologies and to which all members of the species are genetically susceptible. Examples of these are leprosy, AIDS, hepatitis and Parkinson's disease. A second type represents diseases that have a substantial genetic component, but are multifactorial and are greatly influenced by the environment. Examples of these are diabetes, lymphoma, atherosclerosis, alcoholic cirrhosis and anxiety disorders. Nonhuman primates are also ideally suited to the role of animal models in the new area of human gene therapy. In the future, biomedical research will focus increasingly on genetic manipulations such as the transfer of genes from one individual to another to correct genetic diseases, particularly those diseases caused by single recessive gene defects. Before gene transfers are attempted in humans, they should be done in nonhuman primates. In a real sense, nonhuman primates, as animal models, represent the "step to man."

Animals

Enteric viruses of nonhuman primates.

The phylogenetic relationship of nonhuman primates to man implies that many of these animals could serve as surrogates for studies of diseases of man. Many nonhuman primate species are susceptible not only to viruses of human origin but also to nonhuman primate viruses that are counterparts of viruses of man. All monkeys and great apes do not respond similarly to an antigenic stimulus. Some agents are highly pathogenic for one species and completely innocuous for another. For example, poliovirus causes disease and fatalities in great apes, but picornaviruses given orally cause few lesions in most nonhuman primates. Other enteroviruses (coxsackie-, echoviruses) have caused disease in nonhuman primates. It is difficult to separate viruses into distinct categories according to their anatomic affinities. Many viruses not considered to be enteric may be recovered from the intestinal tract. Adenoviruses, both human and nonhuman strains, which are not considered enteric viruses, nonetheless are recovered frequently from the intestinal tract. Adult animals show little evidence of disease, with the possible exception of diarrhea, after adenovirus infection. Newborns, however, may respond with a fatal pneumoenteritis. Adenovirus may be associated with diseases in organs other than the intestines. The reoviruses, which may be recovered from the intestinal tract, also are generally innocuous. Rotaviruses as pathogens in nonhuman primates are presently under study, and it is suspected that rotaviruses of man may produce experimental disease in nonhuman primates. Production of diabetes by several of the enteric viruses has been suggested but not demonstrated conclusively.

Adenoviruses, Simian