Analysis of Simian Endogenous Retrovirus (SERV) Full-Length Proviruses in Old World Monkey Genomes

Simian endogenous retrovirus, SERV, is a successful germ line invader restricted to Old World monkey (OWM) species. (1) Background: The availability of high-quality primate genomes warrants a study of the characteristics, evolution, and distribution of SERV proviruses. (2) Methods: Cercopithecinae OWM genomes from public databases were queried for the presence of full-length SERV proviruses. A dataset of 81 Cer-SERV genomes was generated and analyzed. (3) Results: Full-length Cer-SERV proviruses were mainly found in terrestrial OWM, and less so in arboreal, forest- dwelling monkeys. Phylogenetic analysis confirmed the existence of two genotypes, Cer-SERV-1 and Cer-SERV-2, with Cer-SERV-1 showing evidence of recent germ-line expansions. Long Terminal Repeat (LTR) variation indicated that most proviruses were of a similar age and were estimated to be between <0.3 and 10 million years old. Integrations shared between species were relatively rare. Sequence analysis further showed extensive CpG methylation-associated mutations, variable Primer Binding Site (PBS) use with Cer-SERV-1 using PBSlys3 and Cer-SERV-2 using PBSlys1,2, and the recent gain of LTR motifs for transcription factors active during embryogenesis in Cer-SERV-1. (4) Conclusions: sequence analysis of 81 SERV proviruses from Cercopithecinae OWM genomes provides evidence for the adaptation of this retrovirus to germ line reproduction.

HIV-1 Vif gained breadth in APOBEC3G specificity after cross-species transmission of its precursors

APOBEC3G (A3G) is a host-encoded cytidine deaminase that potently restricts retroviruses, such as HIV-1, and depends on its ability to package into virions. As a consequence of this, HIV-1 protein Vif has evolved to antagonize human A3G by targeting it for ubiquitination and subsequent degradation. There is an ancient arms-race between Vif and A3G highlighted by amino acids 128 and 130 in A3G that have evolved under positive selection due to Vif-mediated selective pressure in Old World primates. Nonetheless, not all possible amino acid combinations at these sites have been sampled by nature and it is not clear the evolutionary potential of species to resist Vif antagonism. To explore the evolutionary space of positively selected sites in the Vif-binding region of A3G, we designed a combinatorial mutagenesis screen to introduce all 20 amino acids at sites 128 and 130. Our screen uncovered mutants of A3G with several interesting phenotypes, including loss of antiviral activity and resistance of Vif antagonism. However, HIV-1 Vif exhibited remarkable flexibility in antagonizing A3G 128 and 130 mutants, which significantly reduces viable Vif resistance strategies for hominid primates. Importantly, we find that broadened Vif specificity was conferred through Loop 5 adaptations that were required for cross-species adaptation from Old World monkey A3G to hominid A3G. Our evidence suggests that Vif adaptation to novel A3G interfaces during cross-species transmission may train Vif towards broadened specificity that can further facilitate cross-species transmissions and raise the barrier to host resistance. Importance APOBEC3G (A3G) is an antiviral protein that potently restricts retroviruses like HIV. In turn, the HIV-1 protein Vif has evolved to antagonize A3G through degradation. Two rapidly evolving sites in A3G confer resistance to unadapted Vif and act as a barrier to cross-species transmission of retroviruses. We recently identified a single amino acid mutation in an SIV Vif that contributed to the cross-species origins of SIV infecting chimpanzee, and ultimately the HIV-1 pandemic. This mutation broadened specificity of this Vif to both antagonize the A3G of its host while simultaneously overcoming the A3G barrier in the great apes. In this work, we explore the evolutionary space of human A3G at these rapidly evolving sites to understand if the broadened Vif specificity gained during cross-species transmission confers an advantage to HIV-1 Vif in its host-virus arms race with A3G.

Analysis of Simian Endogenous Retrovirus (SERV) proviruses in Old World Monkey Genomes: Evidence for a Transition to Replication during Embryogenesis

Simian endogenous retrovirus, SERV, is a successful germ line invader restricted to Old World monkey (OWM) species. (1) Background: The availability of high quality primate genomes warrants a study of the characteristics, evolution and distribution of SERV proviruses; (2) Methods: Cercopithecinae OWM genomes from public databases were queried for the presence of full length SERV proviruses. A dataset of 81 Cer-SERV genomes was generated and analyzed; (3) Results: Full length Cer-SERV proviruses were mainly found in terrestrial OWM, and less so in arboreal, forest- dwelling monkeys. Phylogenetic analysis confirmed the existence of two genotypes, Cer-SERV-1 and Cer-SERV-2, with Cer-SERV-1 showing evidence of recent germ line expansions. Long Terminal Repeat (LTR) variation indicated that most proviruses were of a similar age, and were estimated to be between &amp;lt;0.3 and 10 million years old. Integrations shared between species were relatively rare. Sequence analysis further showed extensive CpG methylation-associated mutation, variable Primer Binding Site (PBS) use with Cer-SERV-1 using PBSlys3 and Cer-SERV-2 using PBSlys1,2, and the recent gain of LTR motifs for transcription factors active during embryogenesis in Cer-SERV-1; (4) Conclusions: sequence analysis of 81 SERV proviruses from Cercopithecinae OWM genomes provides evidence for the adaptation of this retrovirus to germ line reproduction.

The Genomic Organization of the LILR Region Remained Largely Conserved Throughout Primate Evolution: Implications for Health And Disease

The genes of the leukocyte immunoglobulin-like receptor (LILR) family map to the leukocyte receptor complex (LRC) on chromosome 19, and consist of both activating and inhibiting entities. These receptors are often involved in regulating immune responses, and are considered to play a role in health and disease. The human LILR region and evolutionary equivalents in some rodent and bird species have been thoroughly characterized. In non-human primates, the LILR region is annotated, but a thorough comparison between humans and non-human primates has not yet been documented. Therefore, it was decided to undertake a comprehensive comparison of the human and non-human primate LILR region at the genomic level. During primate evolution the organization of the LILR region remained largely conserved. One major exception, however, is provided by the common marmoset, a New World monkey species, which seems to feature a substantial contraction of the number of LILR genes in both the centromeric and the telomeric region. Furthermore, genomic analysis revealed that the killer-cell immunoglobulin-like receptor gene KIR3DX1, which maps in the LILR region, features one copy in humans and great ape species. A second copy, which might have been introduced by a duplication event, was observed in the lesser apes, and in Old and New World monkey species. The highly conserved gene organization allowed us to standardize the LILR gene nomenclature for non-human primate species, and implies that most of the receptors encoded by these genes likely fulfill highly preserved functions.

Pulmonary granuloma is not always the tuberculosis hallmark: pathological findings of different tuberculosis stages in New and Old World Nonhuman Primates naturally infected with the Mycobacterium tuberculosis Complex

Herein we present the pathological findings of different tuberculosis stages in Old and New World monkeys kept under human care in Rio de Janeiro, Brazil and naturally infected with Mycobacterium tuberculosis Complex. Fifteen nonhuman primates from five different colonies were incorporated into the study. There are 60% (9/15) Old World Monkeys and 40% (6/15) New World Monkeys. According to the gross and histopathologic findings, the lesions in nonhuman primates of this study are classified into the chronic-active, extrapulmonary, early-activation or latent-reactivation tuberculosis stage. Among the Old World Monkey, 66.7% (6/9) of nonhuman primates, all rhesus monkeys (Macaca mulatta), showed severe granulomatous pneumonia. In all Old World Monkeys cases, typical granulomas were seen in at least one organ regardless of the stage of the disease. In the New World Monkeys, the typical pulmonary granulomas were seen in 16.7% (1/6) of the cases, just in the latent-reactivation stage in Uta Hick’s Bearded Saki (Chiropotes utahickae). In this study, 66.7% (6/9) of Old World Monkeys (OWM) and 83.3% (5/6) of New World Monkeys (NWM) showed pulmonary changes at the histological evaluation. The tuberculosis diagnosis in the nonhuman primates in this study was based on pathological, immunohistochemical, molecular, and bacteriological culture. Although the typical presentation was observed in some cases, the absence of pulmonary granuloma did not exclude the tuberculosis occurrence in nonhuman primates of the Old and New World. Tuberculosis should be included as a cause of interstitial pneumonia with foamy macrophages infiltration in the New World nonhuman primates. Due to the high sensitivity of immunohistochemistry with Anti-Mycobacterium tuberculosis, we suggest the addition of this technique as a diagnostic tool of tuberculosis in the nonhuman primates even when the typical changes are not seen.

A New World Monkey Resembles Human in Bitter Taste Receptor Evolution and Function via a Single Parallel Amino Acid Substitution

Bitter taste receptors (Tas2Rs) serve as a vital component in the defense system against toxin intake by animals, and the family of genes encoding these receptors has been demonstrated, usually by family size variance, to correlate with dietary preference. However, few systematic studies of specific Tas2R to unveil their functional evolution have been conducted. Here, we surveyed Tas2R16 across all major clades of primates, which represent diverse feeding ecologies, and observed a rare case of a convergent change to increase sensitivity to β-glucopyranosides in human and a New World monkey, the white-faced saki (Pithecia pithecia). We combined evolutionary, 3D modeling and functional assay analyses to demonstrate that a parallel amino acid substitution (K172N) shared by these two species is responsible for this functional convergence of Tas2R16. Considering the specialized feeding preference of the white-faced saki, the K172N change likely played an important adaptive role in its early evolution to avoid potentially toxic cyanogenic glycosides, as suggested for the human TAS2R16 gene.

HIV-1 Vif gained breadth in APOBEC3G specificity after cross-species transmission of its precursors

APOBEC3G (A3G) is a host-encoded cytidine deaminase that potently restricts retroviruses, such as HIV-1, and depends on its ability to package into virions. As a consequence of this, HIV-1 protein Vif has evolved to antagonize human A3G by targeting it for ubiquitination and subsequent degradation. There is an ancient arms-race between Vif and A3G highlighted by amino acids 128 and 130 in A3G that have evolved under positive selection due to Vif-mediated selective pressure in Old World primates. Nonetheless, not all possible amino acid combinations at these sites have been sampled by nature and it is not clear the evolutionary potential of species to resist Vif antagonism. To explore the evolutionary space of positively selected sites in the Vif-binding region of A3G, we designed a combinatorial mutagenesis screen to introduce all 20 amino acids at sites 128 and 130. Our screen uncovered mutants of A3G with several interesting phenotypes, including loss of stability and resistance of Vif antagonism. However, HIV-1 Vif exhibited remarkable flexibility in antagonizing A3G 128 and 130 mutants, which significantly reduces viable Vif resistance strategies for hominid primates. Importantly, we find that broadened Vif specificity was conferred through Loop 5 adaptations that were required for cross-species adaptation from Old World monkey A3G to hominid A3G. Our evidence suggests that Vif adaptation to novel A3G interfaces during cross-species transmission may train Vif towards broadened specificity that can further facilitate cross-species transmissions and raise the barrier to host resistance.

Divergence in dimerization and activity of primate APOBEC3C

The APOBEC3 (A3) family of single-stranded DNA cytidine deaminases are host restriction factors that inhibit lentiviruses, such as HIV-1, in the absence of the Vif protein that causes their degradation. Deamination of cytidine in HIV-1 (-)DNA forms uracil that causes inactivating mutations when uracil is used as a template for (+)DNA synthesis. For APOBEC3C (A3C), the chimpanzee and gorilla orthologues are more active than human A3C, and the Old World Monkey A3C from rhesus macaque (rh) is not active against HIV-1. Multiple integrated analyses determined why rhA3C was not active against HIV-1 and how to increase this activity. Biochemical, virological, and coevolutionary analyses combined with molecular dynamics simulations showed that the key amino acids needed to promote rhA3C antiviral activity also promoted dimerization. Although rhA3C shares a similar dimer interface with hominid A3C, the key amino acid contacts were different. Overall, our results determine the basis for why rhA3C is less active than human A3C, establish the amino acid network for dimerization and increased activity, and track the loss and gain of A3C antiviral activity in primates. The coevolutionary analysis of the A3C dimerization interface provides a basis from which to analyze dimerization interfaces of other A3 family members.

A natural marmoset model of genetic generalized epilepsy.

As a common neurological disease, epilepsy has been extensively studied. Efforts have been made on rodent and other animal models to reveal the pathogenic mechanisms of epilepsy and develop new drugs as treatment . However, the features of current epilepsy models cannot fully mimic different kinds of epilepsy in human, asking for non-human primates models of epilepsy. The common marmoset (Callithrix jacchus) is a New World monkey that is widely used to study brain function. Here, we show a natural marmoset model of generalized epilepsy. In this unique marmoset family, generalized epilepsy was successfully induced by handling operation in some individuals. We mapped the marmoset family with handling-sensitive epilepsy and found that epileptic marmoset had an autosomal dominant genetic predisposition. Those marmosets were more sensitive to epilepsy inducers pentylenetetrazol (PTZ). By electrocorticogram (ECoG) recording, we detected epileptic discharge in marmoset with history of seizures. However, there was no significant change in the overall structure of epileptic marmoset brain. In summary, we report a family of marmosets with generalized seizures induced by handling operation. This epileptic marmoset family provides insights to better understand the mechanism of generalized epilepsy and helps to develop new therapeutic methods.

Marcgrave's red-tailed monkey: the earliest European depiction of a titi monkey

Among the approximately 40 species of mammals described in Historia naturalis Brasiliae by Willem Piso and Georg Marcgrave, the identity of the monkey “cagui major” has been one of the most controversial. Authors have identified Marcgrave's “cagui major” as a tamarin, a saki monkey, a squirrel monkey, a titi monkey and even as an Old-World monkey. Based on a watercolour, probably related to the original illustration that served as basis for the “cagui major” woodcut, we confirm that it depicts a titi monkey ( Callicebus). By comparing the pelage characteristics shown in the drawing and some measurements and pelage characteristics described in Historia naturalis Brasiliae, we confirm that the species depicted was Callicebus melanochir that occurs today in southern Bahia and northeastern Minas Gerais states, outside the range of the Dutch possessions in Brazil.