Comparison of research cost: man--primate animal--other animal models

The costs of research in human subjects are compared to those in primate animals and in other animal models on the basis of data available from a U.S. institution. The cost of experimentation in a chimpanzee is 3.59% of the per diem cost of clinical research in man. The cost for the dog is 37.1% of that of the chimpanzee, and the mouse costs 2.02% of the cost of the dog.     

'Chumanzee' evolution: the urge to diverge and merge

A recent analysis of the human and chimpanzee genomes compared with portions of other primate genomes suggests that the divergence of the human and chimpanzee lineages beginning around 6 million years ago was not a simple clean split.     

Chimpanzee Down syndrome: a case study of trisomy 22 in a captive chimpanzee

We report a case of chimpanzee trisomy 22 in a captive-born female. Because chromosome 22 in great apes is homologous to human chromosome 21, the present case is analogous to human trisomy 21, also called Down syndrome. The chimpanzee in the present case experienced retarded growth; infantile cataract and vision problems, including nystagmus, strabismus, and keratoconus; congenital atrial septal defect; and hypodontia. All of these symptoms are common in human Down syndrome. This case was the second reported case of trisomy 22 in the chimpanzee. The chimpanzee in our case became blind by 7 years old, making social life with other chimpanzees difficult, but opportunities to interact with other conspecific individuals have been offered routinely. We believe that providing her with the best care over the course of her life will be essential.     

Mass spectral analyses of the two major apolipoproteins of great ape high density lipoproteins

The two major apolipoproteins associated with human and chimpanzee (Pan troglodytes) high density lipoproteins (HDL) are apoA-I and dimeric apoA-II. Although humans are closely related to great apes, apolipoprotein data do not exist for bonobos (Pan paniscus), western lowland gorillas (Gorilla gorilla gorilla) and the Sumatran orangutans (Pongo abelii). In the absence of any data, other great apes simply have been assumed to have dimeric apoA-II while other primates and most other mammals have been shown to have monomeric apoA-II. Using mass spectrometry, we have measured the molecular masses of apoA-I and apoA-II associated with the HDL of these great apes. Each was observed to have dimeric apoA-II. Being phylogenetically related, one would anticipate these apolipoproteins having a high percentage of invariant sequences when compared with human apolipoproteins. However, the orangutan, which diverged from the human lineage between 16 and 21 million years ago, had an apoA-II with the lowest monomeric mass, 8031.3 Da and the highest apoA-I value, 28,311.7 Da, currently reported for various mammals. Interestingly, the gorilla that diverged from the lineage leading to the human–chimpanzee branch after the orangutan had almost identical mass values to those reported for human apoA-I and apoA-II. But chimpanzee and the bonobo that diverged more recently had identical apoA-II mass values that were slightly larger than reported for the human apolipoprotein. The chimpanzee A-I mass values were very close to those of humans; however, the bonobo had values intermediate to the molecular masses of orangutan and the other great apes. With the already existing genomic data for chimpanzee and the recent entries for the orangutan and gorilla, we were able to demonstrate a close agreement between our mass spectral data and the calculated molecular weights determined from the predicted primary sequences of the respective apolipoproteins. Post-translational modification of these apolipoproteins, involving truncation and oxidation of methionine, are also reported.     

The chimpanzee GH locus: composition, organization, and evolution

In most mammals the growth hormone (GH) locus comprises a single gene expressed primarily in the anterior pituitary gland. However, in higher primates multiple duplications of the GH gene gave rise to a complex locus containing several genes. In man this locus comprises five genes, including GH-N (expressed in pituitary) and four genes expressed in the placenta, but in other species the number and organization of these genes vary. The situation in chimpanzee has been unclear, with suggestions of up to seven GH-like genes. We have re-examined the GH locus in chimpanzee and have deduced the complete sequence. The locus includes five genes apparently organized in a fashion similar to that in human, with two of these genes encoding GH-like proteins, and three encoding chorionic somatomammotropins/placental lactogens (CSHs/PLs). There are notable differences between the human and chimpanzee loci with regard to the expressed proteins, gene regulation, and gene conversion events. In particular, one human gene (hCSH-L) has changed substantially since the chimpanzee/human split, potentially becoming a pseudogene, while the corresponding chimpanzee gene (CSH-A1) has been conserved, giving a product almost identical to the adjacent CSH-A2. Chimpanzee appears to produce two CSHs, with potentially differing biological properties, whereas human produces a single CSH. The pattern of gene conversion in human has been quite different from that in chimpanzee. The region around the GH-N gene in chimpanzee is remarkably polymorphic, unlike the corresponding region in human. The results shed new light on the complex evolution of the GH locus in higher primates.     

A novel chimpanzee adenovirus vector with low human seroprevalence: improved systems for vector derivation and comparative immunogenicity

Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, the development of new vectors has focused on serotypes to which the human population is less exposed in order to circumvent pre-existing anti vector immunity. This study describes the derivation of a new vaccine vector based on a chimpanzee adenovirus, Y25, together with a comparative assessment of its potential to elicit transgene product specific immune responses in mice. The vector was constructed in a bacterial artificial chromosome to facilitate genetic manipulation of genomic clones. In order to conduct a fair head-to-head immunological comparison of multiple adenoviral vectors, we optimised a method for accurate determination of infectious titre, since this parameter exhibits profound natural variability and can confound immunogenicity studies when doses are based on viral particle estimation. Cellular immunogenicity of recombinant E1 E3-deleted vector ChAdY25 was comparable to that of other species E derived chimpanzee adenovirus vectors including ChAd63, the first simian adenovirus vector to enter clinical trials in humans. Furthermore, the prevalence of virus neutralizing antibodies (titre >1:200) against ChAdY25 in serum samples collected from two human populations in the UK and Gambia was particularly low compared to published data for other chimpanzee adenoviruses. These findings support the continued development of new chimpanzee adenovirus vectors, including ChAdY25, for clinical use.     

Reexamination of the African hominoid trichotomy with additional sequences from the primate beta-globin gene cluster.

Additional DNA sequence information from a range of primates, including 13.7 kb from pygmy chimpanzee (Pan paniscus), was added to data sets of beta-globin gene cluster sequence alignments that span the gamma 1, gamma 2, and psi eta loci and their flanking and intergenic regions. This enlarged body of data was used to address the issue of whether the ancestral separations of gorilla, chimpanzee, and human lineages resulted from only one trichotomous branching or from two dichotomous branching events. The degree of divergence, corrected for superimposed substitutions, seen in the beta-globin gene cluster between human alleles is about a third to a half that observed between two species of chimpanzee and about a fourth that between human and chimpanzee. The divergence either between chimpanzee and gorilla or between human and gorilla is slightly greater than that between human and chimpanzee, suggesting that the ancestral separations resulted from two closely spaced dichotomous branchings. Maximum parsimony analysis further strengthened the evidence that humans and chimpanzees share the longest common ancestry. Support for this human-chimpanzee clade is statistically significant at P = 0.002 over a human-gorilla clade or a chimpanzee-gorilla clade. An analysis of expected and observed homoplasy revealed that the number of sequence changes uniquely shared by human and chimpanzee lineages is too large to be attributed to homoplasy. Molecular clock calculations that accommodated lineage variations in rates of molecular evolution yielded hominoid branching times that ranged from 17-19 million years ago (MYA) for the separation of gibbon from the other hominoids to 5-7 MYA for the separation of chimpanzees from humans. Based on the relatively late dates and mounting corroborative evidence from unlinked nuclear genes and mitochondrial DNA for the close sister grouping of humans and chimpanzees, a cladistic classification would place all apes and humans in the same family. Within this family, gibbons would be placed in one subfamily and all other extant hominoids in another subfamily. The later subfamily would be divided into a tribe for orangutans and another tribe for gorillas, chimpanzees, and humans. Finally, gorillas would be placed in one subtribe with chimpanzees and humans in another, although this last division is not as strongly supported as the other divisions.     

Increased neutralization sensitivity and reduced replicative capacity of human immunodeficiency virus type 1 after short-term in vivo or in vitro passage through chimpanzees

Development of disease is extremely rare in chimpanzees when inoculated with either T-cell-line-adapted neutralization-sensitive or primary human immunodeficiency virus type 1 (HIV-1), at first excluding a role for HIV-1 neutralization sensitivity in the clinical course of infection. Interestingly, we observed that short-term in vivo and in vitro passage of primary HIV-1 isolates through chimpanzee peripheral blood mononuclear cells (PBMC) resulted in a neutralization-sensitive phenotype. Furthermore, an HIV-1 variant reisolated from a chimpanzee 10 years after experimental infection was still sensitive to neutralization by soluble CD4, the CD4 binding site recognizing antibody IgG1b12 and autologous chimpanzee serum samples, but had become relatively resistant to neutralization by polyclonal human sera and neutralizing monoclonal antibodies. The initial adaptation of HIV-1 to replicate in chimpanzee PBMC seemed to coincide with a selection for viruses with low replicative kinetics. Neither coreceptor usage nor the expression level of CD4, CCR5, or CXCR4 on chimpanzee PBMC compared to human cells could explain the phenotypic changes observed in these chimpanzee-passaged viruses. Our data suggest that the increased neutralization sensitivity of HIV-1 after replication in chimpanzee cells may in part contribute to the long-term asymptomatic HIV-1 infection in experimentally infected chimpanzees.     

P‐glycoprotein (ABCB1) inhibited network of mitochondrion transport along microtubule and BMP signal‐induced cell shape in chimpanzee left cerebrum by systems‐theoretical analysis

We constructed the significant low‐expression P‐glycoprotein (ABCB1) inhibited transport and signal network in chimpanzee compared with high‐expression (fold change ≥2) the human left cerebrum in GEO data set, by using integration of gene regulatory activated and inhibited network inference method with gene ontology (GO) analysis. Our result showed that ABCB1 transport and signal upstream network RAB2A inhibited ABCB1, and downstream ABCB1‐inhibited SMAD1_2, NCK2, SLC25A46, GDF10, RASGRP1, EGFR, LRPPRC, RASSF2, RASA4, CA2, CBLB, UBR5, SLC25A16, ITGB3BP, DDIT4, PDPN, RAB2A in chimpanzee left cerebrum. We obtained that the different biological processes of ABCB1 inhibited transport and signal network repressed carbon dioxide transport, ER to Golgi vesicle‐mediated transport, folic acid transport, mitochondrion transport along microtubule, water transport, BMP signaling pathway, Ras protein signal transduction, transforming growth factor beta receptor signaling pathway in chimpanzee compared with the inhibited network of the human left cerebrum, as a result of inducing inhibition of mitochondrion transport along microtubule and BMP signal‐induced cell shape in chimpanzee left cerebrum. Our hypothesis was verified by the same and different biological processes of ABCB1 inhibited transport and signal network of chimpanzee compared with the corresponding activated network of chimpanzee and the human left cerebrum, respectively. Copyright © 2012 John Wiley & Sons, Ltd.     

Vocal responsiveness in male wild chimpanzees: implications for the evolution of language

Several captive chimpanzees and bonobos have learned to use symbols and to comprehend syntax. Thus, compared with other nonhumans, these animals appear to have unusual cognitive powers that can be recruited for communicative behavior. This raises the possibility that wild chimpanzee vocal communication is more complex than heretofore demonstrated. To examine this possibility, I investigated whether wild chimpanzee vocal exchanges exhibit uniquely human conversational attributes. The results indicate that wild chimpanzees vocalize at low rates, tend not to respond to calls that they hear, and, when they do respond, tend to give calls that are similar to the ones they have heard. Thus, chimpanzee vocal interactions resemble those of other primate species, and show no special similarity to human conversations. The results support the view that we need to explore cognitive and social continuities and discontinuities with nonhuman primates to understand the origin and evolution of language, but also emphasize the need for fine-grained analyses of wild chimpanzee vocal interactions.     

Alu recombination-mediated structural deletions in the chimpanzee genome

With more than 1.2 million copies, Alu elements are one of the most important sources of structural variation in primate genomes. Here, we compare the chimpanzee and human genomes to determine the extent of Alu recombination-mediated deletion (ARMD) in the chimpanzee genome since the divergence of the chimpanzee and human lineages (~6 million y ago). Combining computational data analysis and experimental verification, we have identified 663 chimpanzee lineage-specific deletions (involving a total of ~771 kb of genomic sequence) attributable to this process. The ARMD events essentially counteract the genomic expansion caused by chimpanzee-specific Alu inserts. The RefSeq databases indicate that 13 exons in six genes, annotated as either demonstrably or putatively functional in the human genome, and 299 intronic regions have been deleted through ARMDs in the chimpanzee lineage. Therefore, our data suggest that this process may contribute to the genomic and phenotypic diversity between chimpanzees and humans. In addition, we found four independent ARMD events at orthologous loci in the gorilla or orangutan genomes. This suggests that human orthologs of loci at which ARMD events have already occurred in other nonhuman primate genomes may be “at-risk” motifs for future deletions, which may subsequently contribute to human lineage-specific genetic rearrangements and disorders.     

Growth rates and phylogeny in primates

There is sufficient evidence to indicate that man grows for a longer period of time than chimpanzee who in turn has a greater duration of growth than rhesus monkey. The problem of this paper was to determine if there was a concomitant decrease in a rate of growth. Using the relative growth rate of Fisher ('21), it appears that for most of their period of growth, the rate of change is the same. Immediately after birth, when we have no data for children, rhesus monkey grows significantly faster than chimpanzee. By a year and a half their rates are the same, and neither species shows a sex difference. From seven years (age of youngest children) until children start through puberty, there is no sex difference in Homo sapiens, and the human rate does not differ from the chimpanzee rate. Because of the resemblance between the primate curve for rate and that for dairy cattle, it is postulated that this curve is more mammalian than primate and that during phylogeny the primates have merely increased the duration of time when growth is possible. Man does show one new feature, the puberal growth spurt, which is not found in the non-human data considered. The implications of these conclusions for primate phylogeny and for growth are discussed.     

Reconstruction of molecular phylogeny of extant hominoids from DNA sequence data

Evolutionary distance matrices of the extant hominoids are computed from DNA sequence data, and hominoid DNA phylogenies are reconstructed by applying the neighbor-joining method to these distance matrices. The chimpanzee is clustered with the human in most of the phylogenetic trees thus obtained. The proportion of the distance between human and chimpanzee to that between human/chimpanzee and orangutan is estimated. Both mitochondrial DNA and nuclear DNA show a similar value (0.44), which is close to values derived from DNA-DNA hybridization data.     

A comparison of TSPY genes from Y-chromosomal DNA of the great apes and humans: Sequence,evolution, and phylogeny

The genes for testis-specific protein Y (TSPY) were sequenced from chimpanzee (Pan troglodytes), gorilla (Gorilla gorilla), orangutan (Pongo pygmaeus), and baboon (Papio hamadryas). The sequences were compared with each other and with the published human sequence. Substitutions were detected at 144 of the 755 nucleotide positions compared. In overviewing five sequences, one deletion in human, four successive nucleotide insertions in orangutan, and seven deletions/insertions in baboon sequence were noted. The present sequences differed from that of human by 1.9% (chimpanzee), 4.0% (gorilla), 8.2% (orangutan), and 16.8% (baboon), respectively. The phylogenetic tree constructed by the neighbor-joining method suggests that human and chimpanzee are more closely related to each other than either of them is to gorilla, and this result is also supported by maximum likelihood and strict consensus maximum parsimony trees. The number of nucleotide substitutions per site between human and chimpanzee, gorilla, and orangutan for TSPY intron were 0.024, 0.048, and 0.094, respectively. The rates of nucleotide substitutions per site per year were higher in the TSPY intron than in the TSPY exon, and higher in the TSPY intron than in the ZFY (Zinc Finger Y) intron in human and apes. © 1996 Wiley-Liss, Inc.     

Dynamic evolution of the CYP2ABFGST gene cluster in primates

We have annotated and analyzed sequences from the CYP2ABFGST gene cluster for the chimpanzee and the Rhesus macaque, and compared them in detail to the complete map of the syntenic human cluster. While the macaque cluster has accumulated substantial differences in gene number and organization relative to the other two species, the chimpanzee cluster has remained surprisingly similar to the human cluster, given the evolutionary volatility of this gene family. The comparison will allow us to further refine our model of the evolution of this gene family in mammals.     

Effect of species-specificity in auditory-visual intermodal matching in a chimpanzee (Pan troglodytes) and humans

The goal of this study was to compare the performance of a chimpanzee and humans on auditory-visual intermodal matching of conspecifics and non-conspecifics. The task consisted of matching vocal samples to facial images of the corresponding vocalizers. We tested the chimpanzee and human subjects with both chimpanzee and human stimuli to assess the involvement of species-specificity in the recognition process. All subjects were highly familiar with the stimuli. The chimpanzee subject, named Pan, had had extensive previous experience in auditory-visual intermodal matching tasks. We found clear evidence of a species-specific effect: the chimpanzee and human subjects both performed better at recognizing conspecifics than non-conspecifics. Our results suggest that Pan's early exposure to human caretakers did not seem to favor a perceptual advantage in better discriminating familiar humans compared to familiar conspecifics. The results also showed that Pan's recognition of non-conspecifics did not significantly improve over the course of the experiment. In contrast, human subjects learned to better discriminate non-conspecific stimuli, suggesting that the processing of recognition might differ across species. Nevertheless, this comparative study demonstrates that species-specificity significantly affects intermodal individual recognition of highly familiar individuals in both chimpanzee and human subjects.     

Lessons from chimpanzee-based research on human disease: the implications of genetic differences

Assertions that the use of chimpanzees to investigate human diseases is valid scientifically are frequently based on a reported 98-99% genetic similarity between the species. Critical analyses of the relevance of chimpanzee studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for the chimpanzee to constitute a good model for research, and furthermore, that chimpanzee data do not translate well to progress in clinical practice for humans. Leading examples include the minimal citations of chimpanzee research that is relevant to human medicine, the highly different pathology of HIV/AIDS and hepatitis C virus infection in the two species, the lack of correlation in the efficacy of vaccines and treatments between chimpanzees and humans, and the fact that chimpanzees are not useful for research on human cancer. The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology - there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and chimpanzee genetic sequences is of little consequence for biomedical research. The extrapolation of biomedical data from the chimpanzee to the human is therefore highly unreliable, and the use of the chimpanzee must be considered of little value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to science.     

Chimpanzee vocal signaling points to a multimodal origin of human language

The evolutionary origin of human language and its neurobiological foundations has long been the object of intense scientific debate. Although a number of theories have been proposed, one particularly contentious model suggests that human language evolved from a manual gestural communication system in a common ape-human ancestor. Consistent with a gestural origins theory are data indicating that chimpanzees intentionally and referentially communicate via manual gestures, and the production of manual gestures, in conjunction with vocalizations, activates the chimpanzee Broca's area homologue--a region in the human brain that is critical for the planning and execution of language. However, it is not known if this activity observed in the chimpanzee Broca's area is the result of the chimpanzees producing manual communicative gestures, communicative sounds, or both. This information is critical for evaluating the theory that human language evolved from a strictly manual gestural system. To this end, we used positron emission tomography (PET) to examine the neural metabolic activity in the chimpanzee brain. We collected PET data in 4 subjects, all of whom produced manual communicative gestures. However, 2 of these subjects also produced so-called attention-getting vocalizations directed towards a human experimenter. Interestingly, only the two subjects that produced these attention-getting sounds showed greater mean metabolic activity in the Broca's area homologue as compared to a baseline scan. The two subjects that did not produce attention-getting sounds did not. These data contradict an exclusive "gestural origins" theory for they suggest that it is vocal signaling that selectively activates the Broca's area homologue in chimpanzees. In other words, the activity observed in the Broca's area homologue reflects the production of vocal signals by the chimpanzees, suggesting that this critical human language region was involved in vocal signaling in the common ancestor of both modern humans and chimpanzees.