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Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which may lead to the development of rhesus disease models. Through phenotyping of macaques carrying a pathogenic OPA1:p.A8S variant, we identify a genetic model of autosomal dominant optic atrophy. Finally, we present a public website housing variant and genotype data from over two thousand rhesus macaques.
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Modelos Animales de Enfermedad , Variación Genética , Macaca mulatta , Animales , Macaca mulatta/genética , Humanos , Frecuencia de los Genes , Atrofia Óptica Autosómica Dominante/genética , Polimorfismo de Nucleótido Simple , Fenotipo , Aprendizaje Automático , Genotipo , Mutación MissenseRESUMEN
The marmoset is a fundamental nonhuman primate model for the study of aging, neurobiology, and many other topics. Genetic management of captive marmoset colonies is complicated by frequent chimerism in the blood and other tissues, a lack of tools to enable cost-effective, genome-wide interrogation of variation, and historic mergers and migrations of animals between colonies. We implemented genotype-by-sequencing (GBS) of hair follicle derived DNA (a minimally chimeric DNA source) of 82 marmosets housed at the Southwest National Primate Research Center (SNPRC). Our primary goals were the genetic characterization of our marmoset population for pedigree verification and colony management and to inform the scientific community of the functional genetic makeup of this valuable resource. We used the GBS data to reconstruct the genetic legacy of recent mergers between colonies, to identify genetically related animals whose relationships were previously unknown due to incomplete pedigree information, and to show that animals in the SNPRC colony appear to exhibit low levels of inbreeding. Of the >99,000 single-nucleotide variants (SNVs) that we characterized, >9800 are located within gene regions known to harbor pathogenic variants of clinical significance in humans. Overall, we show the combination of low-resolution (sparse) genotyping using hair follicle DNA is a powerful strategy for the genetic management of captive marmoset colonies and for identifying potential SNVs for the development of biomedical research models.
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Callithrix , Genotipo , Linaje , Animales , Callithrix/genética , Masculino , Femenino , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Endogamia , Folículo Piloso , Técnicas de Genotipaje/métodos , Técnicas de Genotipaje/veterinariaRESUMEN
Demand for nonhuman primates in research has increased over the past several years, while nonhuman primate supply remains a challenge in the United States. Global nonhuman primate supply issues make it increasingly important to maximize domestic colony production. To explore how housing conditions across primate breeding colonies impact infant survival and animal production more broadly, we collected medical records from 7959 rhesus macaques (Macaca mulatta) and 492 pigtail macaques (Macaca nemestrina) across seven breeding facilities and used generalized mixed-effect modeling to determine prenatal and infant survival odds by housing type and group size. Infant survival odds for each housing type and group size varied for prenatal, neonatal, early infant, and late infant age groups. Odds of prenatal survival were lowest in paired indoor housing and small and medium outdoor groups. No housing type performed better than large outdoor groups for neonatal survival. Odds of early infant survival was greatest in indoor and mixed indoor/outdoor housing compared to large outdoor enclosures. Large outdoor housing was associated with higher survival odds for late infant survival compared to small and medium outdoor housing. These results may influence housing choices at macaque breeding facilities hoping to maximize infant success, although there are relative care costs, the promotion of species-typical behaviors, and infrastructure factors to also consider. Our study used an interinstitutional collaboration that allowed for the analysis of more infant macaque medical records than ever before and used the broad variations across the seven national primate research centers to make the results applicable to many other facilities housing macaques.
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Cruzamiento , Vivienda para Animales , Humanos , Embarazo , Femenino , Animales , Macaca mulatta , Macaca nemestrinaRESUMEN
Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes. Nonhuman primates share physiological, anatomical, and behavioral similarities with humans resulting from close evolutionary relationships and high genetic homology. As the post-genomic era develops and next generation sequencing allows for the resequencing and screening of large populations of research animals, naturally occurring genetic variation in nonhuman primates with clinically relevant phenotypes is regularly emerging. Here we review nonhuman primate models of multiple rare genetic diseases with a focus on the similarities and differences in manifestation and etiologies across species. We discuss how these models are being developed and how they can offer new tools and opportunities for researchers interested in exploring novel therapeutics for these and other genetic diseases. Modeling human genetic diseases in translationally relevant nonhuman primates presents new prospects for development of therapeutics and a better understanding of rare diseases. The post-genomic era offers the opportunity for the discovery and further development of more models like those discussed here.
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Modelos Genéticos , Enfermedades Raras , Animales , Humanos , Enfermedades Raras/genética , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Primates/genéticaRESUMEN
Non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (COVID-19) to clinical trials. Here, we compare acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old rhesus macaques, baboons and old marmosets. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage was increased in old versus young baboons. Using techniques including computed tomography imaging, immunophenotyping, and alveolar/peripheral cytokine response and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent type-I interferon response. Macaques developed T-cell memory phenotypes/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young macaques. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.
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COVID-19/veterinaria , Callithrix/inmunología , Pulmón/inmunología , Macaca mulatta/inmunología , Enfermedades de los Monos/virología , Papio/inmunología , SARS-CoV-2/inmunología , Inmunidad Adaptativa , Animales , Anticuerpos Antivirales/inmunología , Lavado Broncoalveolar , Líquido del Lavado Bronquioalveolar , COVID-19/diagnóstico por imagen , COVID-19/inmunología , COVID-19/patología , Femenino , Humanos , Inmunidad Celular/inmunología , Inmunoglobulina G/inmunología , Inflamación/patología , Pulmón/virología , Masculino , Enfermedades de los Monos/inmunología , Células Mieloides/inmunología , Carga Viral , Esparcimiento de VirusRESUMEN
A large number of studies have shown that the baboon is one of the most commonly used non-human primate (NHP) research model for the study of immunometabolic complex traits such as type 2 diabetes (T2D), insulin resistance (IR), adipose tissue dysfunction (ATD), dyslipidemia, obesity (OB) and cardiovascular disease (CVD). This paper reports on innovative technologies and advanced research strategies for energetics and translational medicine with this NHP model. This includes the following: measuring resting energy expenditure (REE) with the mobile indirect calorimeter Breezing®; monitoring daily body temperature using subcutaneously implanted data loggers; quantifying metabolic heat with veterinary infrared thermography (IRT) imaging, and non-viral non-invasive, tissue-specific ultrasound-targeted microbubble destruction (UTMD) gene-based therapy. These methods are of broad utility; for example, they may facilitate the engineering of ectopic overexpression of brown adipose tissue (BAT) mUCP-1 via UTMD-gene therapy into baboon SKM to achieve weight loss, hypophagia and immunometabolic improvement. These methods will be valuable to basic and translational research, and human clinical trials, in the areas of metabolism, cardiovascular health, and immunometabolic and infectious diseases.
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Temperatura Corporal , Metabolismo Energético , Terapia Genética/veterinaria , Monitoreo Fisiológico/veterinaria , Papio/fisiología , Proyectos de Investigación , Animales , Modelos Animales de Enfermedad , Terapia Genética/métodos , Monitoreo Fisiológico/instrumentación , Monitoreo Fisiológico/métodos , Termografía/veterinariaRESUMEN
Sensitivity to variance, or risk, has been considered elementary to economic decision making, featured prominently in discussions of primate species-typical behaviors and phylogeny, and heralded as a challenge to deterministic foraging theory. Most risk sensitivity studies involve dichotomous choices and small spatial scales, providing only limited bases for predicting how variance information might be used across contexts. We examined foraging risk-sensitivity in four chimpanzees (Pan troglodytes) which were presented containers associated with particular mean food rewards/variances. Preferences were measured via indoor dichotomous choice tests. Subsequent tasks, designed to assess how well these preferences held up across situations, involved a differing food type, rank-ordering arrays of containers, and/or recovering them in a large outdoor testing area. In addition, some variations involved memory for containers previously observed being hidden. Risk preferences varied by subject, experimental context, reward type, and mean reward quantity. In rank-ordering experiments, under the reward contingencies utilized, mean food quantity was a better predictor of selection order than variance. These results bring into question arguments that species-typical primate risk traits-in the sense of enduring, generalized dispositional features of organisms-have been firmly identified, and suggest that many popular experimental strategies are alone inadequate for reconstructing risk-related traits in primate/human evolution. Models from classical foraging theory, which do not address variance, have likely been successful because they include crucial variables with robust predictive value. Determining the importance of variance to naturalistic decision-making, on the other hand, will require further testing in a wide range of experimental and observational contexts.
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Primate Cognition is the study of cognitive processes, which represent internal mental processes involved in discriminations, decisions, and behaviors of humans and other primate species. Cognitive control involves executive and regulatory processes that allocate attention, manipulate and evaluate available information (and, when necessary, seek additional information), remember past experiences to plan future behaviors, and deal with distraction and impulsivity when they are threats to goal achievement. Areas of research that relate to cognitive control as it is assessed across species include executive attention, episodic memory, prospective memory, metacognition, and self-control. Executive attention refers to the ability to control what sensory stimuli one attends to and how one regulates responses to those stimuli, especially in cases of conflict. Episodic memory refers to memory for personally experienced, autobiographical events. Prospective memory refers to the formation and implementation of future-intended actions, such as remembering what needs to be done later. Metacognition consists of control and monitoring processes that allow individuals to assess what information they have and what information they still need, and then if necessary to seek information. Self-control is a regulatory process whereby individuals forego more immediate or easier to obtain rewards for more delayed or harder to obtain rewards that are objectively more valuable. The behavioral complexity shown by nonhuman primates when given tests to assess these capacities indicates psychological continuities with human cognitive control capacities. However, more research is needed to clarify the proper interpretation of these behaviors with regard to possible cognitive constructs that may underlie such behaviors. WIREs Cogn Sci 2016, 7:294-316. doi: 10.1002/wcs.1397 For further resources related to this article, please visit the WIREs website.
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Atención , Cognición , Memoria Episódica , Metacognición , Primates/psicología , Autocontrol , Animales , Conducta Animal , HumanosRESUMEN
A recent report suggested that chimpanzees demonstrate the cognitive capacities necessary to understand cooking (Warneken & Rosati, 2015). We offered alternative explanations and mechanisms that could account for the behavioral responses of those chimpanzees, and questioned the manner in which the data were used to examine human evolution (Beran, Hopper, de Waal, Sayers, & Brosnan, 2015). Two commentaries suggested either that we were overly critical of the original report's claims and methodology (Rosati & Warneken, 2016), or that, contrary to our statements, early biological thinkers contributed little to questions concerning the evolutionary importance of cooking (Wrangham, 2016). In addition, both commentaries took issue with our treatment of chimpanzee referential models in human evolutionary studies. Our response offers points of continued disagreement as well as points of conciliation. We view Warneken and Rosati's general conclusions as a case of affirming the consequent-a logical conundrum in which, in this case, a demonstration of a partial list of the underlying abilities required for a cognitive trait/suite (understanding of cooking) are suggested as evidence for that ability. And although we strongly concur with both Warneken and Rosati (2015) and Wrangham (2016) that chimpanzee research is invaluable and essential to understanding humanness, it can only achieve its potential via the holistic inclusion of all available evidence-including that from other animals, evolutionary theory, and the fossil and archaeological records.
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Culinaria , Pan troglodytes , Psicología Comparada , AnimalesRESUMEN
A recent report suggested that chimpanzees demonstrate the cognitive capacities necessary to understand cooking (Warneken & Rosati, 2015). We offer alternate explanations and mechanisms that could account for the behavioral responses of those chimpanzees, without invoking the understanding of cooking as a process. We discuss broader issues surrounding the use of chimpanzees in modeling hominid behavior and understanding aspects of human evolution.
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Culinaria , Preferencias Alimentarias , Pan troglodytes , Animales , Condicionamiento ClásicoRESUMEN
Metacognition, the monitoring of one's own mental states, is a fundamental aspect of human intellect. Despite tests in nonhuman animals suggestive of uncertainty monitoring, some authors interpret these results solely in terms of primitive psychological mechanisms and reinforcement regimes, where "reinforcement" is invariably considered to be the delivery and consumption of earned food rewards. Surprisingly, few studies have detailed the trial-by-trial behaviour of animals engaged in such tasks. Here we report ethology-based observations on a rhesus monkey completing sparse-dense discrimination problems, and given the option of escaping trials (i.e., responding "uncertain") at its own choosing. Uncertainty responses were generally made on trials of high objective difficulty, and were characterized by long latencies before beginning visible trials, long times taken for response, and, even after controlling for difficulty, high degrees of wavering during response. Incorrect responses were also common in trials of high objective difficulty, but were characterized by low degrees of wavering. This speaks to the likely adaptive nature of "hesitation," and is inconsistent with models which argue or predict implicit, inflexible information-seeking or "alternative option" behaviours whenever challenging problems present themselves, Confounding models which suggest that nonhuman behaviour in metacognition tasks is driven solely by food delivery/consumption, the monkey was also observed allowing pellets to accumulate and consuming them during and after trials of all response/outcome categories (i.e., whether correct, incorrect, or escaped). This study thus bolsters previous findings that rhesus monkey behaviour in metacognition tasks is in some respects disassociated from mere food delivery/consumption, or even the avoidance of punishment. These and other observations fit well with the evolutionary status and natural proclivities of rhesus monkeys, but weaken arguments that responses in such tests are solely associated with associative mechanisms, and instead suggest more derived and controlled cognitive processing. The latter interpretation appears particularly parsimonious given the neurological adaptations of primates, as well as their highly flexible social and ecological behaviour.
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Beginning with Darwin, some have argued that predation on other vertebrates dates to the earliest stages of hominid evolution, and can explain many uniquely human anatomical and behavioral characters. Other recent workers have focused instead on scavenging, or particular plant foods. Foraging theory suggests that inclusion of any food is influenced by its profitability and distribution within the consumer's habitat. The morphology and likely cognitive abilities of Ardipithecus, Australopithecus, and early Homo suggest that while hunting and scavenging occurred, their profitability generally would have been considerably lower than in extant primates and/or modern human hunter-gatherers. On the other hand, early hominid diet modelers should not focus solely on plant foods, as this overlooks standard functional interpretations of the early hominid dentition, their remarkable demographic success, and the wide range of available food types within their likely day ranges. Any dietary model focusing too narrowly on any one food type or foraging strategy must be viewed with caution. We argue that early hominid diet can best be elucidated by consideration of their entire habitat-specific resource base, and by quantifying the potential profitability and abundance of likely available foods.
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Evolución Biológica , Dieta Paleolítica , Ecología , Hominidae , Raíces de Plantas , Conducta Predatoria , Animales , Ecosistema , Humanos , PrimatesRESUMEN
Considerations of primate behavioral evolution often proceed by assuming the ecological and competitive milieus of particular taxa via their relative exploitation of gross food types, such as fruits versus leaves. Although this "fruit/leaf dichotomy" has been repeatedly criticized, it continues to be implicitly invoked in discussions of primate socioecology and female social relationships and is explicitly invoked in models of brain evolution. An expanding literature suggests that such views have severely limited our knowledge of the social and ecological complexities of primate folivory. This paper examines the behavior of primate folivore-frugivores, with particular emphasis on gray langurs (traditionally, Semnopithecus entellus) within the broader context of evolutionary ecology. Although possessing morphological characteristics that have been associated with folivory and constrained activity patterns, gray langurs are known for remarkable plasticity in ecology and behavior. Their diets are generally quite broad and can be discussed in relation to Liem's Paradox, the odd coupling of anatomical feeding specializations with a generalist foraging strategy. Gray langurs, not coincidentally, inhabit arguably the widest range of habitats for a nonhuman primate, including high elevations in the Himalayas. They provide an excellent focal point for examining the assumptions and predictions of behavioral, socioecological, and cognitive evolutionary models. Contrary to the classical descriptions of the primate folivore, Himalayan and other gray langurs-and, in actuality, many leaf-eating primates-range widely, engage in resource competition (both of which have previously been noted for primate folivores), and solve ecological problems rivaling those of more frugivorous primates (which has rarely been argued for primate folivores). It is maintained that questions of primate folivore adaptation, temperate primate adaptation, and primate evolution more generally cannot be answered by the frequent approach of broad characterizations, categorization models, crude variables, weakly correlative evidence, and subjective definitions. As a corollary, many current avenues of study are inadequate for explaining primate adaptation. A true understanding of primate ecology can only be achieved through the use of mainstream evolutionary ecology and thorough linkage of both proximate and ultimate mechanisms.
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Evolución Biológica , Conducta Competitiva , Dieta , Herbivoria , Inteligencia , Primates/fisiología , Adaptación Fisiológica , Animales , Colobinae/fisiología , Frutas/crecimiento & desarrollo , Hojas de la Planta/crecimiento & desarrolloRESUMEN
Many models from foraging theory and movement ecology assume that resources are encountered randomly. If food locations, types and values are retained in memory, however, search time could be significantly reduced, with concurrent effects on biological fitness. Despite this, little is known about what specific characteristics of foods, particularly those relevant to profitability, nonhuman animals can remember. Building upon previous observations, we hypothesized that chimpanzees (Pan troglodytes), after observing foods being hidden in a large wooded test area they could not enter, and after long delays, would direct (through gesture and vocalization) experimentally naïve humans to the reward locations in an order that could be predicted beforehand by the spatial and physical characteristics of those items. In the main experiment, various quantities of almonds, both in and out of shells and sealed in transparent bags, were hidden in the test area. The chimpanzees later directed searchers to those items in a nonrandom order related to quantity, shell presence/absence, and the distance they were hidden from the subject. The recovery sequences were closely related to the actual e/h profitability of the foods. Predicted recovery orders, based on the energetic value of almonds and independently-measured, individual-specific expected pursuit and processing times, were closely related to observed recovery orders. We argue that the information nonhuman animals possess regarding their environment can be extensive, and that further comparative study is vital for incorporating realistic cognitive variables into models of foraging and movement.
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Optimal foraging theory has only been sporadically applied to nonhuman primates. The classical prey model, modified for patch choice, predicts a sliding "profitability threshold" for dropping patch types from the diet, preference for profitable foods, dietary niche breadth reduction as encounter rates increase, and that exploitation of a patch type is unrelated to its own abundance. We present results from a 1-year study testing these predictions with Himalayan langurs (Semnopithecus entellus) at Langtang National Park, Nepal. Behavioral data included continuous recording of feeding bouts and between-patch travel times. Encounter rates were estimated for 55 food types, which were analyzed for crude protein, lipid, free simple sugar, and fibers. Patch types were entered into the prey model algorithm for eight seasonal time periods and differing age-sex classes and nutritional currencies. Although the model consistently underestimated diet breadth, the majority of nonpredicted patch types represented rare foods. Profitability was positively related to annual/seasonal dietary contribution by organic matter estimates, whereas time estimates provided weaker relationships. Patch types utilized did not decrease with increasing encounter rates involving profitable foods, although low-ranking foods available year-round were taken predominantly when high-ranking foods were scarce. High-ranking foods were taken in close relation to encounter rates, while low-ranking foods were not. The utilization of an energetic currency generally resulted in closest conformation to model predictions, and it performed best when assumptions were most closely approximated. These results suggest that even simple models from foraging theory can provide a useful framework for the study of primate feeding behavior.
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Cercopithecidae/fisiología , Conducta Alimentaria , Conducta Predatoria , Altitud , Alimentación Animal , Animales , Animales de Zoológico , Cercopithecidae/psicología , Ambiente , Preferencias Alimentarias , Nepal , Evaluación Nutricional , Estaciones del AñoRESUMEN
Data on mating and birth seasonality were recorded in wild black-and-white snub-nosed monkeys (Rhinopithecus bieti) at Xiaochangdu in the Honglaxueshan National Nature Reserve, Tibet. This represents one of the harshest habitats utilized by any nonhuman primate. Variation in food availability, temperature, and photoperiod were examined to identify ecological influences on the timing of reproductive events. Mating was observed to occur mostly between July and October and to coincide with peak food availability and temperature, while births occurred between February and mid-March, the end of the period of lowest food availability. This pattern may be an adjustment to the extreme environmental conditions characteristic of this field site.