Why primate models matter

Phillips, Kimberley A.; Bales, Karen L.; Capitanio, John P.; Conley, Alan J; Czoty, Paul W.; Hart, Bert A. ’t; Hopkins, William D.; Hu, Shiu Lok; Miller, Lisa; Nader, Michael A.; Nathanielsz, Peter W.; Rogers, Jeffrey; Shively, Carol A.; Voytko, Mary Lou

doi:10.1002/ajp.22281

Cited by 469 publications

(352 citation statements)

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“…Although rhesus macaques have been valuable models for human disease research for many years (Phillips et al 2014), the putative functional variants identified in this study can greatly increase their value as models for human genetics. Direct in vivo experimental analyses of the cellular and physiological consequences of both protein-coding and noncoding variation in primate models that closely mimic human biology are now feasible, including analyses that test specific hypotheses concerning genotype-phenotype relationships that develop out of human association studies.…”

Section: Discussionmentioning

confidence: 99%

“…These codon-specific mutations are particularly valuable in rhesus macaques because this species models human retinal disease more closely than rodent models (Lillo et al 2003;Coleman et al 2004;Francis et al 2008;Colella et al 2013). Across a variety of physiological systems, human genetic mechanisms can be modeled more effectively in primates than in other species (Barr et al 2004;Loffredo et al 2007;Vallender et al 2010;Rogers et al 2013;Phillips et al 2014); thus, functional variants in macaque genes orthologous to human disease genes (eye diseases or others) will provide significant and unique opportunities to model genetic mechanisms or test therapies for those disorders.…”

Section: Functional Annotation Of Rhesus Snvsmentioning

confidence: 99%

“…Only the apes (like humans, members of Superfamily Hominoidea) are more closely related to humans than are Old World monkeys. In part because of their adaptability and overall genetic and physiological similarity to humans, rhesus macaques are widely used as an animal model for biomedical studies related to human health and disease (Phillips et al 2014). These macaques are the premier models for investigations related to several human infectious diseases, are critical to research in neurobiology and psychobiology, and play a central role in studies of reproductive endocrinology, metabolism, and other basic aspects of biology and medicine.…”

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confidence: 99%

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The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences

et al. 2016

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Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species. A detailed understanding of extant genomic variation among rhesus macaques has implications for the use of this species as a model for studies of human health and disease, as well as for evolutionary population genomics. Whole-genome sequencing analysis of 133 rhesus macaques revealed more than 43.7 million single-nucleotide variants, including thousands predicted to alter protein sequences, transcript splicing, and transcription factor binding sites. Rhesus macaques exhibit 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans. This functional variation in macaques provides opportunities for analyses of coding and noncoding variation, and its cellular consequences. Despite modestly higher levels of nonsynonymous variation in the macaques, the estimated distribution of fitness effects and the ratio of nonsynonymous to synonymous variants suggest that purifying selection has had stronger effects in rhesus macaques than in humans. Demographic reconstructions indicate this species has experienced a consistently large but fluctuating population size. Overall, the results presented here provide new insights into the population genomics of nonhuman primates and expand genomic information directly relevant to primate models of human disease.

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Section: Discussionmentioning

confidence: 99%

Section: Functional Annotation Of Rhesus Snvsmentioning

confidence: 99%

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confidence: 99%

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The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences

et al. 2016

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“…In the present study, cynomolgus monkeys were used as a primate model because of their evolutionary closeness to humans and similarities with our reproductive system [23,24]. Approval for this study was obtained from the Animal Ethics Review Board of the Catholic University of Louvain (2011/UCL/MD/012).…”

Section: Animalsmentioning

confidence: 99%

Impact of the cryopreservation technique and vascular bed on ovarian tissue transplantation in cynomolgus monkeys

Dolmans

Binda

Jacobs

et al. 2015

J Assist Reprod Genet

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Purpose The aim of this study was to determine the best combination in terms of cryopreservation techniques and vascular bed preparation before grafting in order to obtain functional ovarian tissue after transplantation. Methods Five cynomolgus monkeys were used. Strips from 10 ovaries were cryopreserved, 5 by vitrification (V), and 5 by slow-freezing (SF). Pieces of fresh ovarian tissue were used for controls. After 1 month, the strips were autografted to two different vascular beds, healed (HB) or freshly decorticated (FDB), constituting four study groups: SF-HB, SF-FDB, V-HB, and V-FDB. These were compared to fresh tissue. After 6 months, the ovaries were removed and several parameters analyzed: follicle quality, stage, density, proliferation, apoptosis, functionality, vascularization, and fibrosis. Mixed effect linear regression models were built to assess the impact of cryopreservation and vascular bed preparation on ovarian tissue viability and functionality. p values were adjusted for multiple testing using the Benjamini-Hochberg method, and q values<0.20 were considered significant in order to achieve a 20 % false discovery rate. Results Compared to fresh tissue, no difference was observed in the percentage of morphologically normal follicles, while a significant increase was noted in the follicle proliferation rate (41 %, q=0.19), percentage of antral follicles (12 %, q=0.14), and number of vessels per area (3.3 times, q=0.07) in the V-FDB group. Conclusions Vitrification associated with FDB vascular bed preparation is the best combination to obtain functional autografted ovarian tissue. Further studies are nevertheless required, with confirmed pregnancies and live births before introducing the procedure into clinical practice.Capsule Vitrification associated with freshly decorticated vascular bed preparation appears to be the best combination to obtain functional autografted ovarian tissue. M. M. Dolmans and M. M. Binda contributed equally to this work.Electronic supplementary material The online version of this article

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“…This is especially so in the area of infectious disease research concerning pathogens such as human immunodeficiency virus type 1 and tuberculosis (Legrand et al, 2009;Holder et al, 2014;Phillips et al, 2014;Scanga and Flynn, 2014), as the host-pathogen interactions involved in these pathologies are most accurately reproduced in a NHP model. In these diseases as well as others, NHP models are often used to test the efficacy of therapeutic agents that are metabolized by the P450 pathway (Nishimuta et al, 2011;Uno et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Methamphetamine Metabolism in Rhesus Macaque as Compared with Human: An Analysis Using a Novel Method of Liquid Chromatography with Tandem Mass Spectrometry, Kinetic Study, and Substrate Docking

Earla

Kumar²,

Wang

et al. 2014

Drug Metab Dispos

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Methamphetamine (MA), which remains one of the widely used drugs of abuse, is metabolized by the cytochrome P450 (P450) family of enzymes in humans. However, metabolism of methamphetamine in macaques is poorly understood. Therefore, we first developed and validated a very sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using solid phase extraction of rhesus plasma with a lower limit of quantitation at 1.09 ng/ml for MA and its metabolites, 4-hydroxy methamphetamine (4-OH MA), amphetamine (AM), 4-OH amphetamine (4-OH AM), and norephedrine. We then analyzed plasma samples of MA-treated rhesus, which showed >10-fold higher concentrations of AM (∼29 ng/ml) and 4-OH AM (∼28 ng/ml) than MA (∼2 ng/ml). Because the plasma levels of MA metabolites in rhesus were much higher than in human samples, we examined MA metabolism in human and rhesus microsomes. Interestingly, the results showed that AM and 4-OH AM were formed more rapidly and that the catalytic efficiency (V max /K m ) for the formation of AM was ∼8-fold higher in rhesus than in human microsomes. We further examined the differences in these kinetic characteristics using three selective inhibitors of each human CYP2D6 and CYP3A4 enzymes. The results showed that each of these inhibitors inhibited both D-and L-MA metabolism by 20%-60% in human microsomes but not in rhesus microsomes. The differences between human and rhesus CYP2D6 and CYP3A4 enzymes were further assessed by docking studies for both d and l-MA. In conclusion, our results demonstrated an enhanced MA metabolism in rhesus compared with humans, which is likely to be caused by differences in MA-metabolizing P450 enzymes between these species.

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Why primate models matter

Cited by 469 publications

References 345 publications

The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences

The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences

Impact of the cryopreservation technique and vascular bed on ovarian tissue transplantation in cynomolgus monkeys

Enhanced Methamphetamine Metabolism in Rhesus Macaque as Compared with Human: An Analysis Using a Novel Method of Liquid Chromatography with Tandem Mass Spectrometry, Kinetic Study, and Substrate Docking

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