Generation of transgenic monkeys with human inherited genetic disease

Modeling human diseases using nonhuman primates including chimpanzee, rhesus, cynomolgus, marmoset and squirrel monkeys has been reported in the past decades. Due to the high similarity between nonhuman primates and humans, including genome constitution, cognitive behavioral functions, anatomical structure, metabolic, reproductive, and brain functions; nonhuman primates have played an important role in understanding physiological functions of the human body, clarifying the underlying mechanism of human diseases, and the development of novel treatments for human diseases. However, nonhuman primate research has been restricted to cognitive, behavioral, biochemical and pharmacological approaches of human diseases due to the limitation of gene transfer technology in nonhuman primates. The recent advancement in transgenic technology that has led to the generation of the first transgenic monkey in 2001 and a transgenic monkey model of Huntington’s disease (HD) in 2008 has changed that focus. The creation of transgenic HD monkeys that replicate key pathological features of human HD patients further suggests the crucial role of nonhuman primates in the future development of biomedicine. These successes have opened the door to genetic manipulation in nonhuman primates and a new era in modeling human inherited genetic disorders. We focused on the procedures in creating transgenic Huntington’s disease monkeys, but our work can be applied to transgenesis in other nonhuman primate species.     

On the origin and evolution of the human immunodeficiency virus (HIV)

The human AIDS viruses--HIV-1 and HIV-2--impose major burdens on the health and economic status of many developing countries. Surveys of other animal species have revealed that related viruses--the SIVs are widespread in a large number of African simian primates where they do not appear to cause disease. Phylogenetic analyses indicate that these SIVs are the reservoirs for the human viruses, with SIVsm from the sooty mangabey monkey the most likely source of HIV-2, and SIVcpz from the common chimpanzee the progenitor population for HIV-1. Although it is clear that AIDS has a zoonotic origin, it is less certain when HIV-1 and HIV-2 first entered human populations and whether cross-species viral transmission is common among primates. Within infected individuals the process of HIV evolution takes the form of an arms race, with the virus continually fixing mutations by natural selection which allow it to escape from host immune responses. The arms race is less intense in SIV-infected monkeys, where a weaker immune response generates less selective pressure on the virus. Such a difference in virus-host interaction, along with a broadening of co-receptor usage such that HIV strains are able to infect cells with both CCR5 and CXCR4 chemokine receptors, may explain the increased virulence of HIV in humans compared to SIV in other primates.     

Intellectual activity during formation of quantitative concepts in the lower and higher monkeys

Results of study of formation of quantitative concepts in the lower and higher monkey are presented. Various authors used different methods of study of this issue. It has been established that not only the higher primates, such as chimpanzees and orangutans, but also the lower ones—macaques, capuchins, squirrel monkeys—have the “mathematical capabilities.” The detailed study of formation of quantitative concepts in primates of different levels of phylogenesis allows disclosing mechanisms of formation of this function in human.     

Multidirectional chromosome painting reveals a remarkable syntenic homology between the greater galagos and the slow loris

We report on the first reciprocal chromosome painting of lorisoids and humans. The chromosome painting showed a remarkable syntenic homology between Otolemur and Nycticebus. Eight derived syntenic associations of human segments are common to both Otolemur and Nycticebus, indicative of a considerable period of common evolution between the greater galago and the slow loris. Five additional Robertsonian translocations form the slow loris karyotype, while the remaining chromosomes are syntenically equivalent, although some differ in terms of centromere position and heterochromatin additions. Strikingly, the breakpoints of the human chromosomes found fragmented in these two species are apparently identical. Only fissions of homologs to human chromosomes 1 and 15 provide significant evidence of a cytogenetic link between Lemuriformes and Lorisiformes. The association of human chromosomes 7/16 in both lorisoids strongly suggests that this chromosome was present in the ancestral primate genome.     

The second-agent effect: communicative gestures increase the likelihood of perceiving a second agent

Background

Beyond providing cues about an agent''s intention, communicative actions convey information about the presence of a second agent towards whom the action is directed (second-agent information). In two psychophysical studies we investigated whether the perceptual system makes use of this information to infer the presence of a second agent when dealing with impoverished and/or noisy sensory input.

Methodology/Principal Findings

Participants observed point-light displays of two agents (A and B) performing separate actions. In the Communicative condition, agent B''s action was performed in response to a communicative gesture by agent A. In the Individual condition, agent A''s communicative action was replaced with a non-communicative action. Participants performed a simultaneous masking yes-no task, in which they were asked to detect the presence of agent B. In Experiment 1, we investigated whether criterion c was lowered in the Communicative condition compared to the Individual condition, thus reflecting a variation in perceptual expectations. In Experiment 2, we manipulated the congruence between A''s communicative gesture and B''s response, to ascertain whether the lowering of c in the Communicative condition reflected a truly perceptual effect. Results demonstrate that information extracted from communicative gestures influences the concurrent processing of biological motion by prompting perception of a second agent (second-agent effect).

Conclusions/Significance

We propose that this finding is best explained within a Bayesian framework, which gives a powerful rationale for the pervasive role of prior expectations in visual perception.     

Comparative morphometrics of the primate apical tuft

The relationship between the structure and function of the primate apical tuft is poorly understood. This study addresses several hypotheses about apical tuft morphology using a large modern primate comparative sample. Two indices of tuft size are employed: expansion and robusticity. First, comparisons of relative apical tuft size were drawn among extant nonhuman primate groups in terms of locomotion and phylogenetic category. Both of these factors appear to play a role in apical tuft size among nonhuman primates. Suspensory primates and all platyrrhines had the smallest apical tufts, while terrestrial quadrupeds and all strepsirrhines (regardless of locomotor category) had the largest tufts. Similarly, hypotheses regarding the apical tufts of hominins, especially the large tufts of Neandertals were addressed using a comparison of modern warm- and cold-adapted humans. The results showed that cold-adapted populations possessed smaller apical tufts than did warm-adapted groups. Therefore, the cold-adaptation hypothesis for Neandertal distal phalangeal morphology is not supported. Also, early modern and Early Upper Paleolithic humans had apical tufts that were significantly less expanded and less robust than those of Neandertals. The hypothesis that a large apical tuft serves as support for an expanded digital pulp is supported by radiographic analysis of modern humans in that a significant correlation was discovered between the width of the apical tuft and the width of the pulp. The implications of these findings for hypotheses about the association of apical tuft size and tool making in the hominin fossil record are discussed.     

Effects of habitat fragmentation and disturbance on howler monkeys: a review

We examined the literature on the effects of habitat fragmentation and disturbance on howler monkeys (genus Alouatta) to (1) identify different threats that may affect howlers in fragmented landscapes; (2) review specific predictions developed in fragmentation theory and (3) identify the empirical evidence supporting these predictions. Although howlers are known for their ability to persist in both conserved and disturbed conditions, we found evidence that they are negatively affected by high levels of habitat loss, fragmentation and degradation. Patch size appears to be the main factor constraining populations in fragmented habitats, probably because patch size is positively related to food availability, and negatively related to anthropogenic pressures, physiological stress and parasite loads. Patch isolation is not a strong predictor of either patch occupancy or population size in howlers, a result that may be related to the ability of howlers to move among forest patches. Thus, we propose that it is probable that habitat loss has larger consistent negative effects on howler populations than habitat fragmentation per se. In general, food availability decreases with patch size, not only due to habitat loss, but also because the density of big trees, plant species richness and howlers' home range size are lower in smaller patches, where howlers' population densities are commonly higher. However, it is unclear which vegetation attributes have the biggest influence on howler populations. Similarly, our knowledge is still limited concerning the effects of postfragmentation threats (e.g. hunting and logging) on howlers living in forest patches, and how several endogenous threats (e.g. genetic diversity, physiological stress, and parasitism) affect the distribution, population structure and persistence of howlers. More long‐term studies with comparable methods are necessary to quantify some of the patterns discussed in this review, and determine through meta‐analyses whether there are significant inter‐specific differences in species' responses to habitat loss and fragmentation. Am. J. Primatol. 72:1–16, 2010. © 2009 Wiley‐Liss, Inc.     

New adapiform primate fossils from the late Eocene of Egypt

Abstract

Caenopithecine adapiform primates are currently represented by two genera from the late Eocene of Egypt (Afradapis and Aframonius) and one from the middle Eocene of Switzerland (Caenopithecus). All are somewhat anthropoid-like in several aspects of their dental and gnathic morphology, and are inferred to have been highly folivorous. Here we describe a new caenopithecine genus and species, Masradapis tahai, from the ~37 million-year-old Locality BQ-2 in Egypt, that is represented by mandibular and maxillary fragments and isolated teeth. Masradapis is approximately the same size as Aframonius but differs in having a more dramatic distal increase in molar size, more complex upper molar shearing crests, and an exceptionally deep mandibular corpus. We also describe additional mandibles and part of the orbit and rostrum of Aframonius which suggest that it was probably diurnal. Phylogenetic analyses place Masradapis either as the sister taxon of Aframonius (parsimony), or as the sister taxon of Afradapis and Caenopithecus (Bayesian methods). Bayesian tip-dating analysis, when combined with Bayesian biogeographic analysis, suggests that a common ancestor of known caenopithecines dispersed to Afro-Arabia from Europe between 49.4 and 47.4 Ma, and that a trans-Tethyan back-dispersal explains Caenopithecus’ later presence in Europe.

For Masradapis: https://www.zoobank.org/urn:lsid:zoobank.org:act:41BC8459-7CCE-487F-BC59-1C34257D5C4E

For Masradapis tahai: https://www.zoobank.org/urn:lsid:zoobank.org:act:C0A620AD-6FCA-4649-A980-FCA237AFE39D     

Complex behavior forms in the lower monkeys in the process of identification of quantitative signs of visual stimuli

Complex behavior forms and the ability of monkeys to recognize and to compare by identity the two-dimensional images and three-dimensional objects of various colors in the amount from 5 to 9 were studied. The study was carried out on two species of the lower monkeys of different levels of phylogenetic development: on rhesus monkeys (Macaca mulatta) and on brown capuchins (Cebus apella). It has been established that the representatives of the studied monkey species are able to differentiate large counted multitudes of two-dimensional (images of squares) and three-dimensional (objects of round shape) stimuli of red, yellow, and green colors in different quantitative ratios—from 5 to 9 at solving modifications of task of the type “choice by the sample.” In the course of learning, species-related differences of the monkeys’ behavior are revealed. The brown capuchins managed solving all tasks and their combinations better than rhesus monkeys. The obtained data indicate the capability for recognition of counted multitudes (from 5 to 9) regardless of color of the stimuli and the existence of quantitative notions of the idea of “quantity” in the lower monkeys.     

Flexibility in the use of requesting gestures in squirrel monkeys (Saimiri sciureus)

Three squirrel monkeys, trained to make a requesting gesture, were tested in the presence of a human assistant whose visual attention varied across trials. When food was available in one dish and an empty dish was nearby, the monkeys pointed overwhelmingly toward the former, regardless of where the assistant was looking. Looking at the assistant while pointing (“monitoring”) peaked when she looked at them and when she attempted to engage them in joint attention. When only one dish was present, the monkeys refrained from gesturing if it was empty and if no assistant was present. They gestured more when the assistant made eye contact with them. Furthermore, when the assistant's focus of attention switched from the dish or the ceiling to the monkeys, the latter resumed pointing and increased their monitoring of the assistant. This is the first demonstration of such flexible use of an intentionally communicative requesting gesture in New World monkeys. Am. J. Primatol. 72:707–714, 2010. © 2010 Wiley‐Liss, Inc.     

Clinical outcome of a protocol to produce immunosuppression in rhesus monkeys (Macaca mulatta): application to infectious disease and gene therapy studies

Induced immunosuppression is required for a number of studies using rhesus monkeys (Macaca mulatta). This report describes the clinical outcome and safety of a dose-finding experiment that determined doses of cyclophosphamide and prednisone that could be used to induce a state of immunosuppression in rhesus monkeys. After determining the optimum dose of immunosuppressive agents, the protocol was then used on animals participating in infectious disease and gene therapy studies. Splenectomy was performed in some animals to increase the severity of immunosuppression. The onset, duration, and severity of lymphopenia and leukopenia were consistent in all animals. In most animals, physical examination findings and clinical serum chemistry profiles demonstrated only transient abnormalities. With proper clinical monitoring, combination treatment with cyclophosphamide and prednisone is an effective and safe method for inducing immunosuppression in rhesus monkeys.     

Locomotor activity differences between sympatric patas monkeys (Erythrocebus patas) and vervet monkeys (Cercopithecus aethiops): Implications for the evolution of long hindlimb length in Homo

Homo erectus is notable for its taller stature and longer lower limbs relative to earlier hominids, but the selective pressures favoring such long limbs are unclear. Among anthropoid primates, patas monkeys (Erythrocebus patas) and extant hominids share several extreme characteristics involved with foraging and movement, including the relatively longest lower limb proportions, longest daily travel distances and largest home ranges for their body or group size, occupancy of some of the driest habitats, and very efficient thermoregulatory systems. We suggest that patas monkeys are an appropriate behavioral model with which to speculate on the selective pressures that might have operated on H. erectus to increase lower limb length. Here, in a comparison of the locomotor activities of patas monkeys and sympatric, closely related vervet monkeys (Cercopithecus aethiops), we provide evidence for the hypothesis that patas use their long stride more to increase foraging efficiency while walking than to run, either from predators or otherwise. Am J Phys Anthropol 105:199–207, 1998. © 1998 Wiley-Liss, Inc.     

Evaluation of the cardiovascular function of older adult Rhesus monkeys by ultrasonography

OBJECTIVE: To evaluate the cardiovascular structure and function of older adult Rhesus monkey by utrasonography. METHODS: Sixteen monkeys aged from 17 to 20 years and weighing from 8.2 to 15.3 kg, six adults aged 7-8 years and weighing from 8.1 to 9.2 kg. All monkeys were determined to be free from hypertension, hyperglycaemia and cardiac disease. The normal values of index related to heart and blood vessels including structure, haemodynamics and systolic or diastolic function were detected by 2D, M-mode, pulsed Doppler and tissue Doppler echocardiography respectively under ketamine hydrochloride sedation. Meanwhile, blood pressures were also measured by electronic sphygmomanometer. Each monkey underwent repeated detections in 2 weeks and all data were analysed with statistical methods. RESULTS: Compared with young adult monkeys, the older's heart rate (HR), the left ventricular diastolic function and the compliance of big artery including right and left common carotid artery, bulbus caroticus, internal carotid artery and abdominal aorta were decreased and the associated indexes changed significantly (P < 0.05 or P < 0.01). Meanwhile, older monkeys exhibited significant increase in the aorta diameter (AO), amplitude of aortic wall (AAO), left atrial diameter (LAD), end diastolic volume of left ventricle (EDV), stroke volume (SV), left ventricular mass (LVM) (P < 0.05 vs. young adult monkeys); however, cardiac output (CO) only slightly increased but the difference did not reach the statistical significance (P = 0.418, P = 0.644 respectively). CONCLUSIONS: The present results demonstrated the profiles of cardiovascular function and structure in the older Rhesus monkeys. Older monkey is accompanied by diminished left ventricular diastolic function and big artery compliance. Ultrasonography provides a means to non-invasively evaluate the anatomy and function of the heart and blood vessel, and plays an increasingly important role in the drug evaluation against cardiovascular dysfunction.     

Social enrichment of the environment with infants for singly caged adult rhesus monkeys

The practicability of social enrichment for singly caged adult rhesus monkeys was examined. Twenty-nine weaned rhesus monkey infants were removed from breeding troops to avoid overcrowding and were placed with unfamiliar singly caged adults. An adult-infant pair was considered compatible when (1) the two animals started huddling with each other within the first 5 days after pair formation and (2) the infant showed no signs of depression and took its share from a limited amount of favored food. Adult-infant pairs were compatible in 90% (26/29) of cases. Compatibility depended neither on the sex, age, and origin of the adult nor on the sex of the infant. There was no evidence that partners lost interest in each other during 7–11 months of follow-up observations. Three adults exhibiting stereotypical behavior abandoned their peculiar habits after they had lived with their young companions for 4 months. It was concluded that the often-heard notion that rhesus monkeys are highly aggressive should not prevent simple attempts to provide singly caged animals with a companion.     

Evaluating the genetic status of a closed colony of titi monkeys (Callicebus cupreus) using multigenerational pedigrees

Pedigree metrics are essential for investigating colony genetic structure. The genetic structure of a closed Callicebus cupreus colony was examined using multigenerational pedigrees. Inbreeding was low, but genetic drift caused the loss of founder genome representation. Pedigrees can be used to detect founder representation and prevent bottlenecks and allele loss.     

Radiation and speciation of spider monkeys,genus Ateles,from the cytogenetic viewpoint

The chromosomes of 22 animals of four subspecies of the genus Ateles (A. paniscus paniscus, A. p. chamek, A. belzebuth hybridus, and A. b. marginatus) were compared using G/C banding and NOR (nucleolar organizer region) staining methods. The cytogenetic data of Ateles in the literature were also used to clarify the phylogenetic relationships of the species and subspecies and to infer the routes of radiation and speciation of these taxa. Chromosomes 6 and 7 that showed more informative geographic variation and the apomorphic form 4/12, exclusively in A. p. paniscus, are the keys for understanding the evolution, radiation, and specification of the Ateles taxa. The ancestral populations of the genus originated in the southwestern Amazon Basin (the occurrence area of A. paniscus chamek) and spread in the Amazon Basin and westward, crossing the Andes and colonizing Central America and northwesternmost regions of South America. The evolutionary history of the northern South American taxa is interpreted using the model of biogeographical evolution postulated by Haffer [Science 185:131–137, 1969]. Ateles paniscus paniscus is the genetically most differentiated form and probably derives from A. belzebuth hybridus. Based on the karyotype differences, the populations of Ateles can be divided into four different group. These findings indicate the necessity of a more coherent taxonomic arrangement for the taxa of Ateles. Am. J. Primatol. 42:167–178, 1997. © 1997 Wiley-Liss, Inc.     

Plasma and red blood cell total phospholipid fatty acid status of nonpregnant female Vervet monkeys (Cercopithecus aethiops) on a high carbohydrate maintenance diet

Nonhuman primates are of interest as models of human physiology to study the effect of multiple pregnancies on birth weight. Reference plasma and red blood cell (RBC) total phospholipids fatty acids were established in nonpregnant breeding female Vervet monkeys. Twenty-three clinically healthy nonpregnant Vervet monkeys (Cercopithecus aethiops), contained in a controlled closed environment and consuming a high carbohydrate diet (68 E%) that contained 20 E% fat and 12 E% protein were sampled for blood during a cross-sectional study. A low intake of ω3 fatty acids was reflected by a high ω6/ω3 ratio (66:1) of the diet. Inverse relations were seen between plasma and RBC total phospholipid fatty acids, 18:2ω6, 20:3ω6, and 20:4ω6, which suggested selective incorporation in membranes. Low levels of 20:5ω3 and 22:6ω3 of plasma and RBC total phospholipids render Vervet monkeys as ideal subjects to study the effect of ω3 fatty acid supplementation on pregnancy outcomes. Tichelaar HY, van Jaarsveld PJ, Smuts CM, Marais M, Mdhluli MC, Kruger M, Benadé AJS. Plasma and red blood cell total phospholipid fatty acid status of nonpregnant female Vervet monkeys (Cercopithecus aethiops) on a high carbohydrate maintenance diet. J Med Primatol 1998; 27:240–243. © Munksgaard, Copenhagen     

Germline repertoire of the immunoglobulin V H 3 family in rhesus monkeys

 To facilitate molecular studies of antibody responses in rhesus monkeys (Macaca mulatta), we cloned and sequenced germline segments from its largest and most diverse immunoglobulin heavy-chain gene family, V _H 3. Using a PCR-based approach, we characterized 29 sequences, 20 with open reading frames (ORFs) and 9 pseudogenes. The leader sequences, introns, exons, and recombination signal sequences of M. mulatta V _H 3 gene segments are not strictly identical to those of humans, but the mature coding regions demonstrate, on average, greater than 90% sequence similarity. Although the framework regions are more highly conserved, the complementarity-determining regions (CDRs) also show strong similarities, and their predicted three-dimensional structures resemble those of their human homologues. In one instance, homologous macaque and human CDR1 sequences were 100% identical at the nucleotide level, and some CDR2s shared nucleotide identity as high as 96.5%. However, some rhesus V _H 3 ORFs have unusual structural features, including atypical CDR lengths and uncommon amino acids at structurally crucial positions. The similarity of rhesus and human V _H 3 homologues reinforces the notion that humoral immunity in this nonhuman primate species is an appropriate system for modeling human antibody responses. Received: 10 August 1999 / Revised: 30 December 1999     

The genetic structure of a primate species: Rhesus macaques and other Cercopithecine monkeys

Among rhesus macaques (Macaca mulatta)and other cercopithecine monkeys, social groups occupying adjacent home ranges (i.e., members of the same local population) exchange individuals and genes and thus exhibit marked genetic similarities. To assess the degree to which this pattern extends beyond the local population, the genetic structure of M. mulattaand six other primate species was determined using Nei’s (1973) gene-diversity analysis. The genetic similarities seen among social groups in the Dunga Gali population of M. mulatta (Melnick et al.,1984a) can be seen over the entire species range. Comparison of these results with the structures of other similarly organized primate species indicates that (1) the average social group contains most of its local population’s genetic diversity, (2) the average local population contains the majority of the genetic diversity found in the region to which it belongs, and (3) the proportion of species gene diversity found in the average regional population varies substantially between species. Genetic homogeneity within local and regional populations is probably the product of gene flow. The application of a number of analytical models of selection and gene flow strongly suggests that gene flow, genetic drift, and zoogeography offer a more parsimonious and plausible explanation for interspecific variation in regional differentiation than does stabilizing selection.