To establish the exact rates of chromosomal mosaicism in morphologically normal rhesus macaque embryos by determining the chromosomal complement of all blastomeres.
Retrospective rhesus monkey IVF study.
Academic laboratory and Primate Research Center.
Young fertile rhesus macaque females.
Morphologically normal, in vitro produced rhesus macaque embryos were dissociated and cytogenetically assessed using a 5-color fluorescent in situ hybridization assay developed for rhesus macaque chromosomes homologous to human chromosomes 13, 16, 18, X and Y.
Main Outcome Measure(s)
The incidence and extent of chromosomal mosaicism in rhesus macaque preimplantation embryos.
Seventy-seven preimplantation embryos, displaying normal morphology and development, from 17 young rhesus macaque females were analyzed. Overall, 39 embryos (50.6%) were normal, 14 embryos (18.2%) were completely abnormal and 24 embryos were mosaic (31.2%). Of the 226 blastomeres analyzed in the mosaic group, 110 blastomeres (48.7%) were normal.
The observed rate of mosaicism in good quality rhesus embryos resembles previously-documented frequencies in poor-quality human preimplantation embryos. A high incidence of mosaicism may limit the diagnostic accuracy of preimplantation genetic diagnosis.
Mosaicism; embryos; monkey; non-human primate; aneuploidy; FISH
To establish a relevant animal model to systematically investigate chromosomal instability in human oocytes and preimplantation embryos.
Prospective rhesus monkey IVF study.
Academic laboratory, Oregon National Primate Research Center and Caribbean Primate Research Center.
Young Rhesus macaque females.
In vitro produced (IVP) entire rhesus macaque preimplantation embryos were cytogenetically assessed using a 5-color fluorescent in situ hybridization (FISH) assay developed for rhesus macaque chromosomes homologous to human chromosomes 13, 16, 18, X and Y, using human bacterial artificial chromosome (BAC) probes.
Main Outcome Measure(s)
Chromosomal abnormality rates in preimplantation embryos from young rhesus macaque females were established.
Fifty preimplantation embryos, displaying good morphology and normal development, from 11 young rhesus macaque females were analyzed. Overall, 27 embryos (54%) were normal, 11 embryos (22%) mosaic, 3 embryos (6%) chaotic, 2 embryos (4%) aneuploid, 3 embryos (6%) haploid and 4 embryos (8%) triploid.
These data indicate that IVP rhesus macaque and human preimplantation embryos exhibit similar numerical chromosomal aberrations. Rhesus macaques appear to be a suitable animal model for investigating the origin of chromosomal instability observed in human preimplantation embryos.
Aneuploidy; ART; Cytogenetics; Embryo; FISH; IVF; Non-human primate; PGD
Rationale, aims and objectives
Scarring is a significant cause of dissatisfaction for women who undergo breast surgery. Scar tissue may be clinically distinguished from normal skin by aberrant color, rough surface texture, increased thickness (hypertrophy), and firmness. Colorimeters or spectrophotometers can be used to quantitatively assess scar color, but they require direct patient interaction and can cost thousands of dollars By comparison, digital photography is already in widespread use to document clinical outcomes and requires less patient interaction. Thus, assessment of scar coloration by digital photography is an attractive alternative. The goal of this study was to compare color measurements obtained by digital photography and colorimetry.
Agreement between photographic and colorimetric measurements of color were evaluated. Experimental conditions were controlled by performing measurements on artificial scars created by a makeup artist. The colorimetric measurements of the artificial scars were compared to those reported in the literature for real scars in order to confirm the validity of this approach. We assessed the agreement between the colorimetric and photographic measurements of color using a hypothesis test for equivalence, the intra-class correlation coefficient (ICC), and the Bland-Altman method.
Overall, good agreement was obtained for three parameters (L*a*b*) measured by colorimetry and photography from the results of three statistical analyses.
Color measurements obtained by digital photography were equivalent to those obtained using colorimetry. Thus, digital photography is a reliable, cost-effective measurement method of skin color and should be further investigated for quantitative analysis of surgical outcomes.
Aesthetics; Breast Neoplasm; Clinical Photography; Reconstructive Surgical Procedures; Surgical Scars; Treatment Outcome
Adults, preschool children, and nonhuman primates detect and categorize food objects according to substance information, conveyed primarily by color and texture. In contrast, they perceive and categorize artifacts primarily by shape and rigidity. The present experiments investigated the origins of this distinction. Using a looking time procedure, Experiment 1 extended previous findings that rhesus macaques (Macaca mulatta) generalize learning about novel food objects by color over changes in shape. Six additional experiments then investigated whether human infants show the same signature patterns of perception and generalization. Nine-month-old infants failed to detect food objects in accord with their intrinsic properties, in contrast to rhesus monkeys tested in previous research with identical displays. Eight-month-old infants did not privilege substance information over other features when categorizing foods, even though they detected and remembered this information. Moreover, infants showed the same property generalization patterns when presented with foods and tools. The category-specific patterns of perception and categorization shown by human adults, children, and adult monkeys therefore were not found in human infants, providing evidence for limits to infants’ domains of knowledge.
The ability to recognize kin is an important social skill for primates. Humans are adept at using facial similarity to recognize likely kin, and there is evidence that nonhuman primates are also able to use facial similarity to make judgments about kinship. However, if and how nonhuman primate faces actually contain kinship information remains unclear. To test whether there is objectively measurable facial similarity in related nonhuman primates, we compared facial measurements from related (paternal half-sisters) and unrelated adult female rhesus macaques (Macaca mulatta). Facial measurements were first summarized into 5 factors using a principal component analysis. Differences in these factors between the faces of related macaques were compared with differences between the faces of random unrelated macaques and of age-matched unrelated macaques. The difference in facial measurements between related macaques was significantly smaller than the difference in facial measurements of either group of unrelated macaques, constituting an objective measure of facial similarity in macaque kin. These results indicate that kinship information is contained in the rhesus macaque face and suggest that nonhuman primates may rely in part on facial similarity to distinguish kin.
kin recognition; facial similarity; rhesus macaque; principal component analysis
Macaca fascicularis (cynomolgus or longtail macaques) is the most commonly used non-human primate in biomedical research. Little is known about the genomic variation in cynomolgus macaques or how the sequence variants compare to those of the well-studied related species, Macaca mulatta (rhesus macaque). Previously we identified single nucleotide polymorphisms (SNPs) in portions of 94 rhesus macaque genes and reported that Indian and Chinese rhesus had largely different SNPs. Here we identify SNPs from some of the same genomic regions of cynomolgus macaques (from Indochina, Indonesia, Mauritius and the Philippines) and compare them to the SNPs found in rhesus.
We sequenced a portion of 10 genes in 20 cynomolgus macaques. We identified 69 SNPs in these regions, compared with 71 SNPs found in the same genomic regions of 20 Indian and Chinese rhesus macaques. Thirty six (52%) of the M. fascicularis SNPs were overlapping in both species. The majority (70%) of the SNPs found in both Chinese and Indian rhesus macaque populations were also present in M. fascicularis. Of the SNPs previously found in a single rhesus population, 38% (Indian) and 44% (Chinese) were also identified in cynomolgus macaques. In an alternative approach, we genotyped 100 cynomolgus DNAs using a rhesus macaque SNP array representing 53 genes and found that 51% (29/57) of the rhesus SNPs were present in M. fascicularis. Comparisons of SNP profiles from cynomolgus macaques imported from breeding centers in China (where M. fascicularis are not native) showed they were similar to those from Indochina.
This study demonstrates a surprisingly high conservation of SNPs between M. fascicularis and M. mulatta, suggesting that the relationship of these two species is closer than that suggested by morphological and mitochondrial DNA analysis alone. These findings indicate that SNP discovery efforts in either species will generate useful resources for both macaque species. Identification of SNPs that are unique to regional populations of cynomolgus macaques indicates that location-specific SNPs could be used to distinguish monkeys of uncertain origin. As an example, cynomolgus macaques obtained from 2 different breeding centers in China were shown to have Indochinese ancestry.
The use of calibrated, commercial digital cameras for dental applications is promising. The color accuracy of various calibration models were evaluated as applied to three commercial digital cameras for use in dental color matching.
CIE LAB values of 264 color patches and 65 shade tabs were measured with a spectroradiometer. Digital images of the samples were taken with the Nikon D100, Canon D60 and Sigma SD9 cameras. Four regression models were formulated from the color patch CIE LAB and the digital image values. Shade tab CIE LAB colors were predicted by applying the digital image values into the calibration models and were compared to the measured CIE LAB values. The Wilcoxon Rank-Sum test determined if the 12 camera/calibration models differed significantly from the color measurement setup.
Every camera/calibration model (ΔE’s ranging from 1.79 to 5.25) showed a statistically significant difference from the color measurement setup.
Commercial SLR digital cameras when combined with the appropriate calibration protocols showed potential for use in the color replication process of clinical dentistry.
Digital cameras; Calibration models; Color measurement; Translucent material
Researchers studying individual variation in conspicuous skin coloration in primates have suggested that color indicates male quality. Although primate fur color can also be flamboyant, the potential condition dependence and thus signaling function of fur remains poorly studied. We studied sources of variation in sexually dichromatic facial hair coloration in red-fronted lemurs (Eulemur fulvus rufus). We collected data on 13 adult males in Kirindy Forest, Madagascar, during two study periods in 2006 and 2007, to determine whether variation in facial hair coloration correlates with male age, rank, androgen status, and reproductive success. We quantified facial hair coloration via standardized digital photographs of each male, assessed androgen status using fecal hormone measurements, and obtained data on reproductive success through genetic paternity analyses. Male facial hair coloration showed high individual variation, and baseline coloration was related to individual androgen status but not to any other parameter tested. Color did not reflect rapid androgen changes during the mating season. However, pronounced long-term changes in androgen levels between years were accompanied by changes in facial hair coloration. Our data suggest that facial hair coloration in red-fronted lemur males is under proximate control of androgens and may provide some information about male quality, but it does not correlate with dominance rank or male reproductive success.
androgen; coloration; condition-dependent trait; Eulemur fulvus rufus; facial hair
To use contrast enhanced ultrasound (CEU) to quantify blood flow in the macaque uterus during early pregnancy.
Prospective nonhuman primate study.
National Primate Research Center.
Naturally cycling female rhesus macaques (Macaca mulatta).
Female macaques were mated on days 11–14 of the cycle. Females were then imaged by CEU and Doppler ultrasound (DUS) once every 3 days from day 21 through day 39 of the fertile cycle.
Main Outcome Measures
Visualization and quantification of uterine vascular perfusion.
CEU identified the primary placental disc and underlying vessels ~2 days earlier than DUS was able to observe endometrial thickening. CEU revealed spatial differences in vascular perfusion between the endometrium, myometrium, and the endometrial-myometrial (junctional) zone. Myometrium displayed the highest rate of blood flow (>10 mL/min/g tissue). There was less blood flow in the endometrium and junctional zone (<3 mL/min/g). A brief fall in progesterone was observed during early implantation, which was correlated with reduced blood flow to all three uterine compartments, but did not reduce flow to the placenta.
CEU provides a sensitive, non-invasive method to assess vascular perfusion of the uterus during embryo implantation in macaques. We propose CEU as a new diagnostic tool to monitor vascular changes associated with early pregnancy in women.
contrast enhanced ultrasound; Doppler ultrasound; endometrium; implantation; macaque; pregnancy; progesterone; uterus; vascular perfusion
Male animals of many species use conspicuous coloration to attract mates. Among mammals, primates possess the most brilliant secondary sexual coloration. However, whether colour plays a part in primate female mate choice remains unknown. Adult male rhesus macaques undergo a hormonally regulated increased reddening of facial and anogenital skin during their mating season. We experimentally investigated whether red male facial coloration is preferred by simultaneously presenting female rhesus macaques (n = 6) with computer-manipulated pale and red versions of 24 different male faces. The duration and direction of gaze were measured to discern visual preferences. Females exhibited preferences for the red versions of male faces. It is proposed that male coloration might provide a cue to male quality.
Although the rhesus macaque (Macaca mulatta) is commonly used for biomedical research and becoming a preferred model for translational medicine, quantification of genome-wide variation has been slow to follow the publication of the genome in 2007. Here we report the properties of 4040 single nucleotide polymorphisms discovered and validated in Chinese and Indian rhesus macaques from captive breeding colonies in the United States. Frequency-matched measures of linkage disequilibrium were much greater in the Indian sample. Although the majority of polymorphisms were shared between the two populations, rare alleles were over twice as common in the Chinese sample. Indian rhesus had higher rates of heterozygosity, as well as previously undetected substructure, potentially due to admixture from Burma in wild populations and demographic events post-captivity.
Macaca mulatta; nonhuman primate; SNP; Linkage Disequilibrium
Linear dominance hierarchies organize and maintain stability in female rhesus macaque (Macaca mulatta) social groups regardless of group size. As a consequence of their low social status, subordinate females suffer from an array of adverse outcomes including reproductive compromise, impaired immune function, and poor cardiovascular health. However, data that differentiate limbic-hypothalamic-pituitary adrenal axis (LHPA) parameters between dominant from subordinate female monkeys are inconsistent, bringing into question whether social subordination alters the LHPA axis in female macaques. One difficulty in examining LHPA function in macaques may be the confounding effects of cycling ovarian steroids that are known to modulate LHPA activity. The current study used ovariectomized dominant and subordinate female rhesus monkeys to examine the effect that social subordination has on LHPA function by measuring morning and diurnal serum cortisol levels, dexamethasone (Dex) suppression of cortisol, metabolic clearance of Dex, and ACTH stimulation of adrenal cortisol release and cortisol response following exposure to acute social isolation. Compared to dominant females, subordinate females showed diminished morning peak cortisol secretion, weakened glucocorticoid negative feedback, and decreased adrenal cortisol response to an ACTH challenge as well as a restrained cortisol response following social isolation. However, the metabolism of Dex did not account for differences in Dex suppression between dominant and subordinate females. These results indicate that the ability to mount and limit glucocorticoid release is significantly reduced by psychosocial stress in female rhesus macaques, suggesting a hyporesponsive LHPA phenotype which resembles that observed in several human psychopathologies.
social subordination; dexamethasone; cortisol; ACTH; psychosocial stress; monkeys
CD8α exodomain protein, a crucial immune-system factor in rhesus macaque (M. mulatta), one of the best animal models for vaccine design, was assembled and crystallized. The full structure data will contribute to future studies of immune responses in rhesus macaques.
As a T-cell co-receptor, CD8 binds to MHC class I molecules and plays a pivotal role in the activation of cytotoxic T lymphocytes. To date, structures of CD8 have been solved for two different mammals: human and mouse. The infection of rhesus macaques (Macaca mulatta) by simian immunodeficiency virus (SIV) is the best animal model for studying HIV. In this study, the rhesus macaque CD8 (rCD8) αα homodimer was obtained and rCD8α exodomain protein crystals were successfully obtained for further structural analysis. Diffraction data were collected to a resolution of 2.4 Å. The crystal belonged to space group P212121, with unit-cell parameters a = 46.52, b = 56.28, c = 82.40 Å. These data will facilitate further studies on the structural differences between these CD8 structures and the cellular immune responses of rhesus macaque.
CD8α exodomain protein; Macaca mulatta; CD8; T-cell co-receptors
Soft-copy presentation of medical images is becoming more and more important as medical imaging is strongly moving toward digital technology, and health care facilities are converting to filmless hospital and radiological information management. Although most medical images are monochrome, frequently they are displayed on color CRTs, particularly if general-purpose workstations or PCs are used for medical viewing. In the present report, general measurement and modeling procedures for the characterization of color CRT monitors for monochrome presentation are introduced. The contributions from the three color channels (red, green, and blue) are weighted according to the spectral sensitivity of the human eye for photopic viewing. The luminance behavior and the resolution capabilities of color CRT monitors are analyzed with the help of photometer and charge-coupled device (CCD) camera measurements. For the evaluation of spatial resolution, a two-dimensional Fourier analysis of special test images containing white noise (broadband response) is employed. A stage model for a color CRT monitor is developed to discuss the effects of scanning and dot sampling. Furthermore, display intrinsic veiling glare and reflectivity of typical color CRT monitors are measured and compared with those of monochrome CRT monitors. The developed methods and models allow one to describe the image quality aspects of color monitors if they are applied for medical monochrome image presentation. Particularly, because of the reduced luminance and dynamic range of color monitors, the calibration and control of their luminance curves is a very important task. For present color CRT monitors, 1,280×1,024 turns out to be an intrinsic limit for the displayable matrix of medical images.
monitor characterization; color CRT monitors; soft-copy viewing; image quality
The appearance of a chromatic stimulus depends on more than the wavelengths composing it. The scientific literature has countless examples showing that spatial and temporal features of light influence the colors we see. Studying chromatic stimuli that vary over space, time or direction of motion has a further benefit beyond predicting color appearance: the unveiling of otherwise concealed neural processes of color vision. Spatial or temporal stimulus variation uncovers multiple mechanisms of brightness and color perception at distinct levels of the visual pathway. Spatial variation in chromaticity and luminance can change perceived three-dimensional shape, an example of chromatic signals that affect a percept other than color. Chromatic objects in motion expose the surprisingly weak link between the chromaticity of objects and their physical direction of motion, and the role of color in inducing an illusory motion direction. Space, time and motion – color’s colleagues – reveal the richness of chromatic neural processing.
Of the two rhesus macaque subspecies used for AIDS studies, the Simian immunodeficiency virus-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection, providing both insight into pathogenesis and a system for testing novel vaccines. Despite the Chinese rhesus macaque potentially being a more relevant model for AIDS outcomes than the Indian rhesus macaque, the Chinese-origin rhesus macaques have not been well-characterized for their major histocompatibility complex (MHC) composition and function, reducing their greater utilization. In this study, we characterized a total of 50 unique Chinese rhesus macaques from several varying origins for their entire MHC class I allele composition and identified a total of 58 unique complete MHC class I sequences. Only nine of the sequences had been associated with Indian rhesus macaques, and 28/58 (48.3%) of the sequences identified were novel. From all MHC alleles detected, we prioritized Mamu-A1*02201 for functional characterization based on its higher frequency of expression. Upon the development of MHC/peptide binding assays and definition of its associated motif, we revealed that this allele shares peptide binding characteristics with the HLA-B7 supertype, the most frequent supertype in human populations. These studies provide the first functional characterization of an MHC class I molecule in the context of Chinese rhesus macaques and the first instance of HLA-B7 analogy for rhesus macaques.
Electronic supplementary material
The online version of this article (doi:10.1007/s00251-010-0450-3) contains supplementary material, which is available to authorized users.
Rhesus macaque; MHC; HLA; CTL
In contrast to most mammalian species, female sexual activity is not limited to the fertile phase of the ovarian cycle in anthropoid primates, which has long been proposed to conceal the timing of ovulation to males. It is now generally believed that females are still most attractive during the fertile phase, leading to high-ranking males successfully mate-guarding them specifically during this period. While studies conducted in species exhibiting exaggerated sexual swellings (probabilistic signal of the fertile phase) have generally supported this hypothesis, mixed support comes from others. Here, we investigated whether high-ranking males timed mate-guarding effort towards female fertile phases in rhesus macaques (Macaca mulatta). In this species, adult females do not exhibit sexual swellings, but undergo facial skin colour variation, an alternative oestrogens-dependent graded-signal of female reproductive status. We collected behavioural, hormonal and genetic paternity data during two mating seasons for one group of the free-ranging population of Cayo Santiago. Our results show that mate-guarding by top-ranking males did not completely cover the entire female fertile phase and that this tactic accounted for only 30-40% of all fertilisations observed. Males tended to prolong mate-guarding into the luteal phase (null probability of fertilisation), which mirrors the pattern of male attraction to female facial colour reported in an earlier study. These findings suggest that males may have limited knowledge regarding the exact timing of females’ fertile phase in rhesus macaques, which presumably allows females to gain more control over reproduction relative to other anthropoid primate species.
Prolonged sexual receptivity; concealed ovulation; mate-guarding; fecal steroids; reproductive strategies; fertile phase; genetic paternity analysis; primates; rhesus macaques
Most primates are both highly visual and highly social. These qualities predict that visual cues to social variables, such as identity, sex, social status, and reproductive quality, would be intrinsically valuable and systematically attract attention. Supporting this idea, thirsty male rhesus macaques (Macaca mulatta) will forego fluid reward to view images of the faces of high-ranking males and the sexual skin of females. Whether female rhesus macaques, who experience dramatically different social pressures and reproductive costs than male macaques, also systematically and spontaneously value visual cues to social information remains untested experimentally. We probed the preferences of female rhesus macaques, given the opportunity to display an image from a known class of social stimuli or touch a second target to display a blank screen. We found that females preferred faces of high-status males and also images of the perinea of both males and females, but were not motivated to display images of subordinate males or control stimuli. These findings endorse the view that both male and female rhesus macaques—and presumably other highly social primates—seek information about other individuals in a way that matches the adaptive value of that information for guiding social behavior.
Macaca mulatta; Social; Dominant; Subordinate; Status; Hierarchy
Rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate animal in biomedical research. A global map of genetic variations in rhesus macaque is valuable for both evolutionary and functional studies.
Using next-generation sequencing technology, we sequenced a Chinese rhesus macaque genome with 11.56-fold coverage. In total, 96% of the reference Indian macaque genome was covered by at least one read, and we identified 2.56 million homozygous and 2.94 million heterozygous SNPs. We also detected a total of 125,150 structural variations, of which 123,610 were deletions with a median length of 184 bp (ranging from 25 bp to 10 kb); 63% of these deletions were located in intergenic regions and 35% in intronic regions. We further annotated 5,187 and 962 nonsynonymous SNPs to the macaque orthologs of human disease and drug-target genes, respectively. Finally, we set up a genome-wide genetic variation database with the use of Gbrowse.
Genome sequencing and construction of a global sequence variation map in Chinese rhesus macaque with the concomitant database provide applicable resources for evolutionary and biomedical research.
Different subspecies of rhesus monkeys (Macaca mulatta) that are derived from different geographical locations, primarily Indian and China, are commonly employed in vision research. Substantial morphological and behavioral differences have been reported between Chinese- and Indian-derived subspecies. The purpose of this study was to compare refractive development in Chinese- and Indian-derived rhesus monkeys.
The subjects were 216 Indian-derived and 78 Chinese-derived normal infant rhesus monkeys. Cross-sectional data were obtained at 3 weeks of age for all subjects. In addition, longitudinal data were obtained from 10 Indian-derived (male = 5, female = 5) and 5 Chinese-derived monkeys (male =3, female =2) that were reared with unrestricted vision. Ocular and refractive development was assessed by retinoscopy, keratometry, video-based ophthalmophakometry, and A-scan ultrasonography.
Although the course of emmetropization was very similar in these two groups of rhesus monkeys, there were consistent and significant inter-group differences in ocular dimensions and refractive error. Throughout the observation period, the Chinese-derived monkeys were on average about 0.4 D less hyperopic than the Indian-derived monkeys and the Chinese-derived monkeys had longer overall axial lengths, deeper anterior and vitreous chamber depths, thicker crystalline lenses, flatter corneas and lower powered crystalline lenses.
The ocular differences observed in this study presumably reflect genetic differences between subspecies but could reflect the differences in the genetic pool between isolated colonies rather than true subspecies differences. Nonetheless, the substantial ocular differences that we observed emphasize that caution must be exercised when comparing and/or pooling data from rhesus monkeys obtained from different colonies. These inter-subspecies differences might be analogous to the ethnic differences in ocular parameters that have been observed in humans.
refractive error; axial length; emmetropization; corneal power; crystalline lens
The rhesus macaque (Macaca mulatta) is the most utilized primate model in the biomedical and psychological sciences. Expressive behavior is of interest to scientists studying these animals, both as a direct variable (modeling neuropsychiatric disease, where expressivity is a primary deficit), as an indirect measure of health and welfare, and also in order to understand the evolution of communication. Here, intramuscular electrical stimulation of facial muscles was conducted in the rhesus macaque in order to document the relative contribution of each muscle to the range of facial movements and to compare the expressive function of homologous muscles in humans and macaques. Despite published accounts that monkeys possess less differentiated and less complex facial musculature, the majority of muscles previously identified in humans were stimulated successfully in the rhesus macaque and caused similar appearance changes to human facial movements. These observations suggest that the facial muscular apparatus of the monkey has extensive homology to the human face. The muscles of the human face, therefore, do not represent a significant evolutionary departure from that of monkey species. Thus, facial expressions can be compared between humans and rhesus macaques at the level of the facial musculature, facilitating the systematic investigation of comparative facial communication.
Monkey; primate; FACS; facial expression; emotion; intramuscular electrical stimulation
The use of Chinese-origin rhesus macaques (Macaca mulatta) for infectious disease immunity research is increasing despite the relative lack of major histocompatibility complex (MHC) class I immunogenetics information available for this population. We determined transcript-based MHC class I haplotypes for 385 Chinese rhesus macaques from five different experimental cohorts, providing a concise representation of the full complement of MHC class I major alleles expressed by each animal. In total, 123 Mamu-A and Mamu-B haplotypes were defined in the full Chinese rhesus macaque cohort. We then performed an analysis of haplotype frequencies across the experimental cohorts of Chinese rhesus macaques, as well as a comparison against a group of 96 Indian rhesus macaques. Notably, 35 of the 51 Mamu-A and Mamu-B haplotypes observed in Indian rhesus macaques were also detected in the Chinese population, with 85% of the 385 Chinese-origin rhesus macaques expressing at least one of these class I haplotypes. This unexpected conservation of Indian rhesus macaque MHC class I haplotypes in the Chinese rhesus macaque population suggests that immunologic insights originally gleaned from studies using Indian rhesus macaques may be more applicable to Chinese rhesus macaques than previously appreciated and may provide an opportunity for studies of CD8+ T-cell responses between populations. It may also be possible to extend these studies across multiple species of macaques, as we found evidence of shared ancestral haplotypes between Chinese rhesus and Mauritian cynomolgus macaques.
Macaca mulatta; MHC class I; RNA transcript-based haplotypes; immunogenetics
Genotypes for 13 short tandem repeats (STRs) were used to assess the genetic diversity within and differentiation among populations of rhesus macaques (Macaca mulatta) from mainland Asia and long-tailed macaques (M. fascicularis) from mainland and insular Southeast Asia. These animals were either recently captured in the wild or derived from wild-caught founders maintained in captivity for biomedical research.
A large number of alleles is shared between the two macaque species but a significant genetic division between them persists. This distinction is more clear-cut among populations that are not, or are unlikely to have recently been, geographically contiguous. Our results suggest there has been significant interspecies nuclear gene flow between rhesus macaques and long-tailed macaques on the mainland. Comparisons of mainland and island populations of long-tailed macaques reflect marked genetic subdivisions due to barriers to migration. Geographic isolation has restricted gene flow, allowing island populations to become subdivided and genetically differentiated. Indonesian long-tailed macaques show evidence of long-term separation and genetic isolation from the mainland populations, while long-tailed macaques from the Philippines and Mauritius both display evidence of founder effects and subsequent isolation, with the impact from genetic drift being more profound in the latter.
Introgression; hybridization; microsatellites; gene flow; genetic structure
Because most studies of AIDS pathogenesis in nonhuman primates have been performed in Indian-origin rhesus macaques (Macaca mulatta), little is known about lentiviral pathogenicity and control of virus replication following infection of alternative macaque species. Here, we report the consequences of simian-human immunodeficiency virus SHIV-89.6P and SIVmac251 infection in cynomolgus (Macaca fascicularis) and rhesus macaques of Chinese origin. Compared to the pathogenicity of the same viruses in Indian rhesus macaques, both cynomolgus and Chinese rhesus macaques showed lower levels of plasma virus. By 9 to 10 months after infection, both viruses became undetectable in plasma more frequently in cynomolgus than in either Chinese or Indian rhesus macaques. Furthermore, after SHIV-89.6P infection, CD4+ T-cell numbers declined less and survival was longer in cynomolgus and Chinese rhesus macaques than in Indian rhesus macaques. This attenuated pathogenicity was associated with gamma interferon ELISPOT responses to Gag and Env that were generated earlier and of higher frequency in cynomolgus than in Indian rhesus macaques. Cynomolgus macaques also developed higher titer neutralizing antibodies against SHIV-89.6 at 10 and 20 weeks postinoculation than Indian rhesus macaques. These studies demonstrate that the pathogenicity of nonhuman primate lentiviruses varies markedly based on the species or geographic origin of the macaques infected and suggest that the cellular immune responses may contribute to the control of pathogenicity in cynomolgus macaques. While cynomolgus and Chinese rhesus macaques provide alternative animal models of lentiviral infection, the lower levels of viremia in cynomolgus macaques limit the usefulness of infection of this species for vaccine trials that utilize viral load as an experimental endpoint.
The genetic background of the cynomolgus macaque (Macaca fascicularis) is made complex by the high genetic diversity, population structure, and gene introgression from the closely related rhesus macaque (Macaca mulatta). Herein we report the whole-genome sequence of a Malaysian cynomolgus macaque male with more than 40-fold coverage, which was determined using a resequencing method based on the Indian rhesus macaque genome.
We identified approximately 9.7 million single nucleotide variants (SNVs) between the Malaysian cynomolgus and the Indian rhesus macaque genomes. Compared with humans, a smaller nonsynonymous/synonymous SNV ratio in the cynomolgus macaque suggests more effective removal of slightly deleterious mutations. Comparison of two cynomolgus (Malaysian and Vietnamese) and two rhesus (Indian and Chinese) macaque genomes, including previously published macaque genomes, suggests that Indochinese cynomolgus macaques have been more affected by gene introgression from rhesus macaques. We further identified 60 nonsynonymous SNVs that completely differentiated the cynomolgus and rhesus macaque genomes, and that could be important candidate variants for determining species-specific responses to drugs and pathogens. The demographic inference using the genome sequence data revealed that Malaysian cynomolgus macaques have experienced at least three population bottlenecks.
This list of whole-genome SNVs will be useful for many future applications, such as an array-based genotyping system for macaque individuals. High-quality whole-genome sequencing of the cynomolgus macaque genome may aid studies on finding genetic differences that are responsible for phenotypic diversity in macaques and may help control genetic backgrounds among individuals.