Analysis of copy number variation in the rhesus macaque genome identifies candidate loci for evolutionary and human disease studies
Arthur S. LeeMaría Gutiérrez‐ArcelusGeorge H. PerryEric J. VallenderWelkin E. JohnsonGregory M. MillerJan O. KorbelCharles Lee
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Abstract:
Copy number variants (CNVs) are heritable gains and losses of genomic DNA in normal individuals. While copy number variation is widely studied in humans, our knowledge of CNVs in other mammalian species is more limited. We have designed a custom array-based comparative genomic hybridization (aCGH) platform with 385 000 oligonucleotide probes based on the reference genome sequence of the rhesus macaque (Macaca mulatta), the most widely studied non-human primate in biomedical research. We used this platform to identify 123 CNVs among 10 unrelated macaque individuals, with 24% of the CNVs observed in multiple individuals. We found that segmental duplications were significantly enriched at macaque CNV loci. We also observed significant overlap between rhesus macaque and human CNVs, suggesting that certain genomic regions are prone to recurrent CNV formation and instability, even across a total of ∼50 million years of primate evolution (∼25 million years in each lineage). Furthermore, for eight of the CNVs that were observed in both humans and macaques, previous human studies have reported a relationship between copy number and gene expression or disease susceptibility. Therefore, the rhesus macaque offers an intriguing, non-human primate outbred model organism with which hypotheses concerning the specific functions of phenotypically relevant human CNVs can be tested.Keywords:
Rhesus macaque
Comparative genomic hybridization
Alu element
Craniosynostosis is a disorder characterized by the premature fusion of the calvarial sutures, causing an abnormal skull shape. Because this disorder occurs with a relatively high frequency, estimated at 1 in 2500 individuals, craniosynostosis represents a relevant medical problem (1). More than 100 syndromes have been shown to be associated with this disorder. It is believed that at least 20% of cases are due to single gene mutations or chromosome abnormalities (2). Although most cases can be considered both clinically and genetically heterogeneous, there is evidence that six genes are involved in many cases: MSX2, FGFR1, FGFR2, FGFR3, FBN1, and TWISTY (1).
The Msh homeobox 2 (Msx2) gene encodes a homeodomain transcription factor protein and is expressed in migrating cranial neural crest cells during development (3). Msx2 has central roles in craniofacial development (4) and limb and tissue formation (6). Furthermore, Msx2 overexpression was demonstrated to be associated with craniosynostosis in mice (5,7), indicating that normal craniofacial formation is dependent on the Msx2 dosage. Corroborating these findings, increases in the copy number in the MSX2 region have been reported in craniosynostosis patients (8-11).
In the present study, we describe the findings from a whole-genome array comparative genomic hybridization (aCGH) analysis of a four-year-old patient exhibiting craniosynostosis, microcephaly, psychomotor development delay, short stature, and cognitive impairment, among other abnormalities. We found a gain in a region of chromosome 5q35.2 that contains MSX2 and has been shown to be associated with craniosynostosis. Quantitative PCR confirmed the increase in the MSX2 copy number.
Comparative genomic hybridization
Copy number analysis
Gene dosage
Variation (astronomy)
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Objective To inspect the blood physiological and biochemiccal of Rhesus macaque and Long-tailed macaque,analyse their basic characters of biological parameters,and set up their routine.Methods Routine methods and instruments were used to determine the blood physiological and biochemical parameters with MEK-5126K(animal CMOS chip)and backman CX5.The hematophysiological indices were determinated in Rhesus macaque and Long-tailed macaque.Results There are significantly difference in AST/ALT between male and female Rhesus macaque,and significantly differece in Eosinophilla、ALP、CK、GGR、CREA between male and female Long-tailed macaque;There are also significantly difference in WBC、MCH、MCHC、Eosinophilla、Monocytosis、ALB、ALB/GLB、AST、AST/ALT、CK、LDH、GGR、CREA between Rhesus macaque and Long-tailed macaque.Conclusion Biological parameters of Rhesus macaque and Long-tailed macaque are established,which could provide basic data for further study.
Rhesus macaque
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We report a case of brain abscess after craniotomy and the placement of a recording chamber for electrophysiologic records in an adult rhesus macaque (Macaca mulatta) enrolled in visual research. Approximately 2 wk after surgery, the macaque presented with nonspecific gastrointestinal signs and showed no evidence of fever, neurologic deficits, increased intracranial pressure, suggestive alterations in the CBC, or abnormal changes in the recording chamber. The macaque responded to symptomatic and antibiotic treatment and showed no behavioral or abnormal clinical signs for 3 wk before collapsing suddenly. The macaque was euthanized, and pathologic evaluation revealed a large brain abscess immediately under the original craniotomy.
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Nonhuman primates are critical resources for biomedical research. Rhesus macaque is a popularly used laboratory nonhuman primate that share many characteristics with humans. However, rhesus macaques are the natural host of two exogenous retroviruses, SRV (simian type D retrovirus) and STLV (simian T lymphotropic virus). SRV and STLV may introduce potentially significant confounding factors into the study of AIDS model. Moreover, B virus (ceropithecine herpesvirus 1) is likely to harm not only rhesus macaque but also humans in experiments involving rhesus macaque. Yunnan province has large-scale breeding colonies of Chinese rhesus macaque. Therefore there is an urgent need for SPF Chinese rhesus macaque colonies. Here we investigated SRV, STLV and BV infections in 411 Chinese rhesus macaque by PCR technique. The results showed that the prevalence of SRV, STLV and BV among Chinese rhesus macaque breeding colony was 19.71% (81/411), 13.38% (55/411) and 23.11% (95/411), respectively. Comparison of viruses infection in different age-groups and male/female of Chinese rhesus macaque was also analyzed. This study will contribute to establishment of SPF Chinese rhesus macaque breeding colony.
Rhesus macaque
Simian
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Large animal models of implantable hearing devices are needed to assess innovative technologies before using them in humans. The rhesus macaque has cognitive abilities close to humans and has been used in the past but with noncommercial implants or no detailed radiologic descriptions of the surgical procedures. The aim of this study was to evaluate the feasibility of cochlear implantation in this animal model.We present detailed radiologic data (CT scan and Cone beam computed tomography) from 7 heads of rhesus macaque monkeys coming from autopsy materials. Several comparative measurements were performed with 10 human temporal bones to emphasize similarities and differences between the macaque and the human inner ear. The radiologic analyses helped planning the surgical approach for cochlear implant insertion in the macaque.We managed to perform one full (720 degrees) and 3 partial insertions (190-330 degrees) of cochlear implants in 4 rhesus macaque cochleae, documented by cone beam computed tomography reconstructions. We confirm that the procedure is facilitated in this animal because the cochlea dimensions are close to humans. However, marked differences in the orientation of the external auditory canal and the basal turn must be taken into account. We suggest that the removal of the inferior wall of tympanal bone provides the optimal axis for electrode array insertion.The rhesus macaque monkey is a valid and close-to-human animal model for cochlear implants insertion. Because this species is widely used in both behavioral and physiologic studies, we expect that functional implants can be coupled with electrophysiologic recordings to study the mechanisms of auditory compensation.
Rhesus macaque
Cochlear Implantation
Ossicles
Animal model
Non human primate
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Rhesus macaque
Non human primate
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Rhesus macaque
Alu element
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Rhesus macaque
Facial muscles
Non human primate
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Abstract The rhesus macaque ( Macaca mulatta ) diverged from the ancestors of Homo sapiens about 25 million years ago. The macaque's genetic and physiological similarity to human is the basis for it becoming the most widely used nonhuman primate in basic and applied biomedical research. The genome sequence of a female rhesus macaque of Indian origin has been determined and compared with the genome sequences of chimpanzee and human. Those studies have revealed the likely structure of ancestral primate genomes and provided evidence both for positive selection and for the lineage‐specific expansion and contraction of gene families during primate evolution. The complete description of the macaque genome has greatly increased the utility of this animal model for biomedical research at the same time as improving our understanding of the basic biology of this highly successful species of Old World monkey.
Rhesus macaque
Homo sapiens
Non human primate
Lineage (genetic)
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Copy number variants (CNVs) are heritable gains and losses of genomic DNA in normal individuals. While copy number variation is widely studied in humans, our knowledge of CNVs in other mammalian species is more limited. We have designed a custom array-based comparative genomic hybridization (aCGH) platform with 385 000 oligonucleotide probes based on the reference genome sequence of the rhesus macaque (Macaca mulatta), the most widely studied non-human primate in biomedical research. We used this platform to identify 123 CNVs among 10 unrelated macaque individuals, with 24% of the CNVs observed in multiple individuals. We found that segmental duplications were significantly enriched at macaque CNV loci. We also observed significant overlap between rhesus macaque and human CNVs, suggesting that certain genomic regions are prone to recurrent CNV formation and instability, even across a total of ∼50 million years of primate evolution (∼25 million years in each lineage). Furthermore, for eight of the CNVs that were observed in both humans and macaques, previous human studies have reported a relationship between copy number and gene expression or disease susceptibility. Therefore, the rhesus macaque offers an intriguing, non-human primate outbred model organism with which hypotheses concerning the specific functions of phenotypically relevant human CNVs can be tested.
Rhesus macaque
Comparative genomic hybridization
Alu element
Cite
Citations (107)