RESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) patients initially develop respiratory symptoms, but they may also suffer from neurological symptoms. People with long-lasting effects after acute infections with severe respiratory syndrome coronavirus 2 (SARS-CoV-2), i.e., post-COVID syndrome or long COVID, may experience a variety of neurological manifestations. Although we do not fully understand how SARS-CoV-2 affects the brain, neuroinflammation likely plays a role. METHODS: To investigate neuroinflammatory processes longitudinally after SARS-CoV-2 infection, four experimentally SARS-CoV-2 infected rhesus macaques were monitored for 7 weeks with 18-kDa translocator protein (TSPO) positron emission tomography (PET) using [18F]DPA714, together with computed tomography (CT). The baseline scan was compared to weekly PET-CTs obtained post-infection (pi). Brain tissue was collected following euthanasia (50 days pi) to correlate the PET signal with TSPO expression, and glial and endothelial cell markers. Expression of these markers was compared to brain tissue from uninfected animals of comparable age, allowing the examination of the contribution of these cells to the neuroinflammatory response following SARS-CoV-2 infection. RESULTS: TSPO PET revealed an increased tracer uptake throughout the brain of all infected animals already from the first scan obtained post-infection (day 2), which increased to approximately twofold until day 30 pi. Postmortem immunohistochemical analysis of the hippocampus and pons showed TSPO expression in cells expressing ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and collagen IV. In the hippocampus of SARS-CoV-2 infected animals the TSPO+ area and number of TSPO+ cells were significantly increased compared to control animals. This increase was not cell type specific, since both the number of IBA1+TSPO+ and GFAP+TSPO+ cells was increased, as well as the TSPO+ area within collagen IV+ blood vessels. CONCLUSIONS: This study manifests [18F]DPA714 as a powerful radiotracer to visualize SARS-CoV-2 induced neuroinflammation. The increased uptake of [18F]DPA714 over time implies an active neuroinflammatory response following SARS-CoV-2 infection. This inflammatory signal coincides with an increased number of TSPO expressing cells, including glial and endothelial cells, suggesting neuroinflammation and vascular dysregulation. These results demonstrate the long-term neuroinflammatory response following a mild SARS-CoV-2 infection, which potentially precedes long-lasting neurological symptoms.
Assuntos
COVID-19 , SARS-CoV-2 , Animais , Humanos , Macaca mulatta , Doenças Neuroinflamatórias , COVID-19/diagnóstico por imagem , Células Endoteliais , Síndrome de COVID-19 Pós-Aguda , Tomografia por Emissão de Pósitrons , Inflamação/diagnóstico por imagem , Colágeno Tipo IV , Receptores de GABARESUMO
MHC class I molecules play an important role in adaptive immune responses against intracellular pathogens. These molecules are highly polymorphic, and many allotypes have been characterized. In a transplantation setting, a mismatch between MHC allotypes may initiate an alloimmune response. Rhesus macaques (Macaca mulatta, Mamu) are valuable as a preclinical model species in transplantation research as well as to evaluate the safety and efficacy of vaccine candidates. In both lines of research, the availability of nonhuman primate MHC-reactive mAbs may enable in vitro monitoring and detection of presence of particular Mamu molecules. In this study, we screened a collection of thoroughly characterized HLA class I-specific human mAbs for cross-reactivity with rhesus macaque MHC class I allotypes. Two mAbs, OK4F9 and OK4F10, recognize an epitope that is defined by isoleucine (I) at amino acid position 142 that is present on the Indian rhesus macaque Mamu-B*008:01 allotype, which is an allotype known to be associated with elite control of SIV replication. The reactive pattern of a third mAb, MUS4H4, is more complex and includes an epitope shared on Mamu-A2*05:01 and -B*001:01-encoded Ags. This is the first description, to our knowledge, of human HLA-reactive mAbs that can recognize Mamu allotypes, and these can be useful tools for in vitro monitoring the presence of the relevant allelic products. Moreover, OK4F9 and OK4F10 can be powerful mAbs for application in SIV-related research.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , HIV-1/fisiologia , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/fisiologia , Síndrome da Imunodeficiência Adquirida/genética , Alelos , Animais , Anticorpos Monoclonais/metabolismo , Reações Cruzadas , Predisposição Genética para Doença , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Alótipos de Imunoglobulina , Células K562 , Macaca mulatta , Polimorfismo Genético , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Replicação ViralRESUMO
The major histocompatibility complex (MHC) plays a key role in immune defense, and the Mhc genes of cynomolgus macaque display a high degree of polymorphism. Based on their geographic distribution, different populations of cynomolgus macaques are recognized. Here we present the characterization of the Mhc class I and II repertoire of a large pedigreed group of cynomolgus macaques originating from the mainland north of the isthmus of Kra (N = 42). Segregation analyses resulted in the definition of 81 unreported Mafa-A/B/DRB/DQ/DP haplotypes, which include 32 previously unknown DRB regions. In addition, we report 13 newly defined Mafa-A/B/DRB/DQ/DP haplotypes in a group of cynomolgus macaques originating from the mainland south of the isthmus of Kra/Maritime Southeast Asia (N = 16). A relatively high level of sharing of Mafa-A (51%) and Mafa-B (40%) lineage groups is observed between the populations native to the north and the south of isthmus of Kra. At the allelic level, however, the Mafa-A/B haplotypes seem to be characteristic of a population. An overall comparison of all currently known data revealed that each geographic population has its own specific combinations of Mhc class I and II haplotypes. This illustrates the dynamic evolution of the cynomolgus macaque Mhc region, which was most likely generated by recombination and maintained by selection due to the differential pathogenic pressures encountered in different geographic areas.
Assuntos
Genes MHC Classe I , Complexo Principal de Histocompatibilidade , Alelos , Animais , Genes MHC Classe I/genética , Haplótipos/genética , Macaca fascicularis/genética , Complexo Principal de Histocompatibilidade/genéticaRESUMO
The role of natural killer (NK) cells is tightly modulated by interactions of killer cell immunoglobulin-like receptors (KIR) with their ligands of the MHC class I family. Several characteristics of the KIR gene products are conserved in primate evolution, like the receptor structures and the variegated expression pattern. At the genomic level, however, the clusters encoding the KIR family display species-specific diversity, reflected by differential gene expansions and haplotype architecture. The human KIR cluster is extensively studied in large cohorts from various populations, which revealed two KIR haplotype groups, A and B, that represent more inhibitory and more activating functional profiles, respectively. So far, genomic KIR analyses in large outbred populations of non-human primate species are lacking. In this study, we roughly quadrupled the number of rhesus macaques studied for their KIR transcriptome (n = 298). Using segregation analysis, we defined 112 unique KIR region configurations, half of which display a more inhibitory profile, whereas the other half has a more activating potential. The frequencies and functional potential of these profiles might mirror the human KIR haplotype groups. However, whereas the human group A and B KIR haplotypes are confined to largely fixed organizations, the haplotypes in macaques feature highly variable gene content. Moreover, KIR homozygosity was hardly encountered in this panel of macaques. This study exhibits highly diverse haplotype architectures in humans and macaques, which nevertheless might have an equivalent effect on the modulation of NK cell activity.
Assuntos
Hominidae , Receptores KIR , Animais , Haplótipos/genética , Humanos , Células Matadoras Naturais/metabolismo , Macaca mulatta/genética , Receptores KIR/genética , Receptores KIR/metabolismoRESUMO
The killer cell Ig-like receptors (KIR) modulate immune responses through interactions with MHC class I molecules. The KIR region in large cohorts of rhesus and cynomolgus macaque populations were characterized, and the experimental design enabled the definition of a considerable number of alleles (n = 576) and haplotypes, which are highly variable with regard to architecture. Although high levels of polymorphism were recorded, only a few alleles are shared between species and populations. The rapid evolution of allelic polymorphism, accumulated by point mutations, was further confirmed by the emergence of a novel KIR allele in a rhesus macaque family. In addition to allelic variation, abundant orthologous and species-specific KIR genes were identified, the latter of which are frequently generated by fusion events. The concerted action of both genetic mechanisms, in combination with differential selective pressures at the population level, resulted in the unparalleled rapid evolution of the KIR gene region in two closely related macaque species. The variation of the KIR gene repertoire at the species and population level might have an impact on the outcome of preclinical studies with macaque models.
Assuntos
Macaca fascicularis/genética , Macaca mulatta/genética , Receptores KIR/genética , Alelos , Animais , Evolução Molecular , Haplótipos/genética , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo Genético/genéticaRESUMO
The major histocompatibility complex (MHC) class I region of humans, chimpanzees (Pan troglodytes), and bonobos (Pan paniscus) is highly similar, and orthologues of HLA-A, -B, and -C are present in both Pan species. Based on functional characteristics, the different HLA-A allotypes are classified into different supertypes. One of them, the HLA A03 supertype, is widely distributed among different human populations. All contemporary known chimpanzee and bonobo MHC class I A allotypes cluster genetically into one of the six HLA-A families, the HLA-A1/A3/A11/A30 family. We report here that the peptide-binding motif of the Patr-A*05:01 allotype, which is commonly present in a cohort of western African chimpanzees, has a strong preference for binding peptides with basic amino acids at the carboxyl terminus. This phenomenon is shared with the family members of the HLA A03 supertype. Based on the chemical similarities in the peptide-binding pocket, we inferred that the preference for binding peptides with basic amino acids at the carboxyl terminus is widely present among the human, chimpanzee, and bonobo MHC-A allotypes. Subsequent in silico peptide-binding predictions illustrated that these allotypes have the capacity to target conserved parts of the proteome of human immunodeficiency virus type 1 (HIV-1) and the simian immunodeficiency virus SIVcpz.IMPORTANCE Most experimentally infected chimpanzees seem to control an HIV-1 infection and are therefore considered to be relatively resistant to developing AIDS. Contemporary free-ranging chimpanzees may carry SIVcpz, and there is evidence for AIDS-like symptoms in these free-ranging animals, whereas SIV infections in bonobos appear to be absent. In humans, the natural control of an HIV-1 infection is strongly associated with the presence of particular HLA class I allotypes. The ancestor of the contemporary living chimpanzees and bonobos survived a selective sweep targeting the MHC class I repertoire. We have put forward a hypothesis that this may have been caused by an ancestral retroviral infection similar to SIVcpz. Characterization of the relevant MHC allotypes may contribute to understanding the shaping of their immune repertoire. The abundant presence of MHC-A allotypes that prefer peptides with basic amino acids at the C termini suggests that these molecules may contribute to the control of retroviral infections in humans, chimpanzees, and bonobos.
Assuntos
Genes MHC Classe I/imunologia , Antígeno HLA-A3/imunologia , Primatas/imunologia , Alelos , Sequência de Aminoácidos , Animais , HIV-1/imunologia , Antígeno HLA-A3/metabolismo , Antígenos de Histocompatibilidade , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Pan paniscus/imunologia , Pan troglodytes/imunologia , Peptídeos/metabolismo , Filogenia , Ligação Proteica/imunologia , Infecções por Retroviridae/imunologia , Vírus da Imunodeficiência Símia/imunologiaRESUMO
The immunological factors that could explain the near absence of malaria parasites in bonobos are not yet understood. The MHC class I system, however, may play an important role, as particular bonobo allotypes show functional similarities to HLA-B*53/B*78, which are considered to confer protection against malaria in humans.
Assuntos
Genótipo , Antígenos HLA/genética , Antígenos HLA-B/genética , Antígenos de Histocompatibilidade Classe I/genética , Malária/genética , Pan paniscus/imunologia , Alelos , Animais , Predisposição Genética para Doença , Humanos , Malária/imunologia , Polimorfismo Genético , Alinhamento de SequênciaRESUMO
BACKGROUND: Many species are threatened with extinction as their population sizes decrease with changing environments or face novel pathogenic threats. A reduction of genetic diversity at major histocompatibility complex (MHC) genes may have dramatic effects on populations' survival, as these genes play a key role in adaptive immunity. This might be the case for chimpanzees, the MHC genes of which reveal signatures of an ancient selective sweep likely due to a viral epidemic that reduced their population size a few million years ago. To better assess how this past event affected MHC variation in chimpanzees compared to humans, we analysed several indexes of genetic diversity and linkage disequilibrium across seven MHC genes on four cohorts of chimpanzees and we compared them to those estimated at orthologous HLA genes in a large set of human populations. RESULTS: Interestingly, the analyses uncovered similar patterns of both molecular diversity and linkage disequilibrium across the seven MHC genes in chimpanzees and humans. Indeed, in both species the greatest allelic richness and heterozygosity were found at loci A, B, C and DRB1, the greatest nucleotide diversity at loci DRB1, DQA1 and DQB1, and both significant global linkage disequilibrium and the greatest proportions of haplotypes in linkage disequilibrium were observed at pairs DQA1 ~ DQB1, DQA1 ~ DRB1, DQB1 ~ DRB1 and B ~ C. Our results also showed that, despite some differences among loci, the levels of genetic diversity and linkage disequilibrium observed in contemporary chimpanzees were globally similar to those estimated in small isolated human populations, in contrast to significant differences compared to large populations. CONCLUSIONS: We conclude, first, that highly conserved mechanisms shaped the diversity of orthologous MHC genes in chimpanzees and humans. Furthermore, our findings support the hypothesis that an ancient demographic decline affecting the chimpanzee populations - like that ascribed to a viral epidemic - exerted a substantial effect on the molecular diversity of their MHC genes, albeit not more pronounced than that experienced by HLA genes in human populations that underwent rapid genetic drift during humans' peopling history. We thus propose a model where chimpanzees' MHC genes regenerated molecular variation through recombination/gene conversion and/or balancing selection after the selective sweep.
Assuntos
Evolução Molecular , Variação Genética , Antígenos HLA-D/genética , Hominidae/genética , Desequilíbrio de Ligação , Pan troglodytes , Alelos , Animais , Frequência do Gene , Genética Populacional , Haplótipos , Humanos , Pan troglodytes/genéticaRESUMO
The Killer-cell Immunoglobulin-like Receptors (KIR) are encoded by a diverse group of genes, which are characterized by allelic polymorphism, gene duplications, and recombinations, which may generate recombinant entities. The number of reported macaque KIR sequences is steadily increasing, and these data illustrate a gene system that may match or exceed the complexity of the human KIR cluster. This report lists the names of quality controlled and annotated KIR genes/alleles with all the relevant references for two different macaque species: rhesus and cynomolgus macaques. Numerous recombinant KIR genes in these species necessitate a revision of some of the earlier-published nomenclature guidelines. In addition, this report summarizes the latest information on the Immuno Polymorphism Database (IPD)-NHKIR Database, which contains annotated KIR sequences from four non-human primate species.
Assuntos
Bases de Dados Factuais , Imunogenética , Macaca mulatta/genética , Polimorfismo Genético , Receptores KIR/genética , Receptores KIR/imunologia , Terminologia como Assunto , AnimaisRESUMO
The major histocompatibility complex (MHC) is central to the innate and adaptive immune responses of jawed vertebrates. Characteristic of the MHC are high gene density, gene copy number variation, and allelic polymorphism. Because apes and monkeys are the closest living relatives of humans, the MHCs of these non-human primates (NHP) are studied in depth in the context of evolution, biomedicine, and conservation biology. The Immuno Polymorphism Database (IPD)-MHC NHP Database (IPD-MHC NHP), which curates MHC data of great and small apes, as well as Old and New World monkeys, has been upgraded. The curators of the database are responsible for providing official designations for newly discovered alleles. This nomenclature report updates the 2012 report, and summarizes important nomenclature issues and relevant novel features of the IPD-MHC NHP Database.
Assuntos
Bases de Dados Genéticas , Complexo Principal de Histocompatibilidade/genética , Primatas/genética , Primatas/imunologia , Alelos , Animais , Cercopithecidae/genética , Hominidae/genética , Complexo Principal de Histocompatibilidade/fisiologia , Filogenia , Platirrinos/genética , Polimorfismo Genético , Terminologia como AssuntoRESUMO
The original version of this article contained a spelling error in the Acknowledgments regarding the name of the funding organisation supporting GM and JAH. UKRI-BBSCR should have been UKRI-BBSRC, as is now indicated correctly below.
RESUMO
The killer-cell Ig-like receptors (KIRs) play a central role in the immune recognition in infection, pregnancy, and transplantation through their interactions with MHC class I molecules. KIR genes display abundant copy number variation as well as high levels of polymorphism. As a result, it is challenging to characterize this structurally dynamic region. KIR haplotypes have been analyzed in different species using conventional characterization methods, such as Sanger sequencing and Roche/454 pyrosequencing. However, these methods are time-consuming and often failed to define complete haplotypes, or do not reach allele-level resolution. In addition, most analyses were performed on genomic DNA, and thus were lacking substantial information about transcription and its corresponding modifications. In this paper, we present a single-molecule real-time sequencing approach, using Pacific Biosciences Sequel platform to characterize the KIR transcriptomes in human and rhesus macaque (Macaca mulatta) families. This high-resolution approach allowed the identification of novel Mamu-KIR alleles, the extension of reported allele sequences, and the determination of human and macaque KIR haplotypes. In addition, multiple recombinant KIR genes were discovered, all located on contracted haplotypes, which were likely the result of chromosomal rearrangements. The relatively high number of contracted haplotypes discovered might be indicative of selection on small KIR repertoires and/or novel fusion gene products. This next-generation method provides an improved high-resolution characterization of the KIR cluster in humans and macaques, which eventually may aid in a better understanding and interpretation of KIR allele-associated diseases, as well as the immune response in transplantation and reproduction.
Assuntos
Haplótipos/genética , Receptores KIR/genética , Transcriptoma/genética , Alelos , Animais , Variações do Número de Cópias de DNA/genética , Rearranjo Gênico/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Macaca mulatta , Polimorfismo Genético/genéticaRESUMO
The major histocompatibility complex (MHC) is one of the most gene-dense regions of the mammalian genome. Multiple genes within the human MHC (HLA) show extensive polymorphism, and currently, more than 26,000 alleles divided over 39 different genes are known. Nonhuman primate (NHP) species are grouped into great and lesser apes and Old and New World monkeys, and their MHC is studied mostly because of their important role as animal models in preclinical research or in connection with conservation biology purposes. The evolutionary equivalents of many of the HLA genes are present in NHP species, and these genes may also show abundant levels of polymorphism. This review is intended to provide a comprehensive comparison relating to the organization and polymorphism of human and NHP MHC regions.
Assuntos
Evolução Molecular , Hominidae/genética , Complexo Principal de Histocompatibilidade/genética , Alelos , Animais , Hominidae/classificação , Hominidae/imunologia , Humanos , Complexo Principal de Histocompatibilidade/imunologia , Filogenia , PrimatasRESUMO
Chimpanzees have been used for some time as an animal model in research on immune-related diseases in humans. The major histocompatibility complex (MHC) region of the chimpanzee has also been the subject of studies in which the attention was mainly on the class I genes. Although full-length sequence information is available on the DRB region genes, such detailed information is lacking for the other class II genes and, if present, is based mainly on exon 2 sequences. In the present study, full-length sequencing was performed on DQ, DP, and DRA genes in a cohort of 67 pedigreed animals, thereby allowing a thorough analysis of the MHC class II repertoire. The results demonstrate that the number of MHC class II lineages and alleles is relatively low, whereas haplotype diversity (combination of genes/alleles on a chromosome) seems to have been maximised by crossing-over processes.
Assuntos
Genes MHC da Classe II , Haplótipos , Pan troglodytes/genética , Alelos , Animais , Variação Genética , Antígenos HLA-DP/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Pan troglodytes/imunologiaRESUMO
Butyrophilins (BTN), specifically BTN3A, play a central role in the modulation of γδ T cells, which are mainly present in gut and mucosal tissues. BTN3A1 is known, for example, to activate Vγ9Vδ2 T cells by means of a phosphoantigen interaction. In the extended HLA region, three genes are located, designated BTN3A1, BTN3A2 and BTN3A3, which were also defined in rhesus macaques. In contrast to humans, rhesus monkeys have an additional gene, BTN3A3Like, which has the features of a pseudogene. cDNA analysis of 32 Indian rhesus and 16 cynomolgus macaques originating from multiple-generation families revealed that all three genes are oligomorphic, and the deduced amino acids display limited variation. The macaque BTN3A alleles segregated together with MHC alleles, proving their location in the extended (Major Histocompatibility Complex) MHC. BTN3A nearly full-length transcripts of macaques and humans cluster tightly together in the phylogenetic tree, suggesting that the genes represent true orthologs of each other. Despite the limited level of polymorphism, 15 Mamu- and 14 Mafa-BTN3A haplotypes were defined, and, as in humans, all three BTN3A genes are transcribed in PBMCs and colon tissues. In addition to regular full-length transcripts, a high number of various alternative splicing (AS) products were observed for all BTN3A alleles, which may result in different isoforms. The comparable function of certain subsets of γδ T cells in human and non-human primates in concert with high levels of sequence conservation observed for the BTN3A transcripts presents the opportunity to study these not yet well understood molecules in macaques as a model species.
Assuntos
Antígenos CD/genética , Butirofilinas/genética , Antígenos de Histocompatibilidade/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Sequência de Aminoácidos , Animais , Butirofilinas/metabolismo , Sequência Conservada , Feminino , Haplótipos , Humanos , Macaca mulatta , Masculino , Filogenia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Homologia de Sequência , Linfócitos T/metabolismoRESUMO
The major histocompatibility complex (MHC) is a highly polymorphic and polygenic genomic region that plays a crucial role in immune-related diseases. Given the need for comparative studies on the variability of immunologically important genes among wild populations and species, we investigated the allelic variation of MHC class II DRB among three congeneric true lemur species: the red-fronted lemur (Eulemur rufifrons), red-bellied lemur (Eulemur rubriventer), and black lemur (Eulemur macaco). We noninvasively collected hair and faecal samples from these species across different regions in Madagascar. We assessed DRB exon 2 polymorphism with a newly developed primer set, amplifying nearly all non-synonymous codons of the antigen-binding sites. We defined 26 DRB alleles from 45 individuals (17 alleles from E. rufifrons (N = 18); 5 from E. rubriventer (N = 7); and 4 from E. macaco (N = 20). All detected alleles are novel and show high levels of nucleotide (26.8%) and non-synonymous codon polymorphism (39.4%). In these lemur species, we found neither evidence of a duplication of DRB genes nor a sharing of alleles among sympatric groups or allopatric populations of the same species. The non-sharing of alleles may be the result of a geographical separation over a long time span and/or different pathogen selection pressures. We found dN/dS rates > 1 in the functionally important antigen recognition sites, providing evidence for balancing selection. Especially for small and isolated populations, quantifying and monitoring DRB variation are recommended to establish successful conservation plans that mitigate the possible loss of immunogenetic diversity in lemurs.
Assuntos
Cadeias beta de HLA-DR/genética , Lemur/imunologia , Alelos , Animais , Éxons , Feminino , Masculino , FilogeniaRESUMO
The immune and reproductive functions of human NK cells are regulated by interactions of the C1 and C2 epitopes of HLA-C with C1-specific and C2-specific lineage III killer cell Ig-like receptors (KIR). This rapidly evolving and diverse system of ligands and receptors is restricted to humans and great apes. In this context, the orangutan has particular relevance because it represents an evolutionary intermediate, one having the C1 epitope and corresponding KIR but lacking the C2 epitope. Through a combination of direct sequencing, KIR genotyping, and data mining from the Great Ape Genome Project, we characterized the KIR alleles and haplotypes for panels of 10 Bornean orangutans and 19 Sumatran orangutans. The orangutan KIR haplotypes have between 5 and 10 KIR genes. The seven orangutan lineage III KIR genes all locate to the centromeric region of the KIR locus, whereas their human counterparts also populate the telomeric region. One lineage III KIR gene is Bornean specific, one is Sumatran specific, and five are shared. Of 12 KIR gene-content haplotypes, 5 are Bornean specific, 5 are Sumatran specific, and 2 are shared. The haplotypes have different combinations of genes encoding activating and inhibitory C1 receptors that can be of higher or lower affinity. All haplotypes encode an inhibitory C1 receptor, but only some haplotypes encode an activating C1 receptor. Of 130 KIR alleles, 55 are Bornean specific, 65 are Sumatran specific, and 10 are shared.
Assuntos
Evolução Molecular , Pongo/genética , Pongo/imunologia , Receptores KIR/genética , Alelos , Animais , Cromossomos Artificiais Bacterianos , Haplótipos , Filogenia , Reação em Cadeia da Polimerase , Especificidade da EspécieRESUMO
In different macaque species, the MHC A2*05 gene is present in abundance, and its gene products are characterized by low cell-surface expression and a highly conserved peptide-binding cleft. We have characterized the peptide-binding motif of Mamu-A2*05:01, and elucidated the binding capacity for virus-derived peptides. The macaque A2*05 allotype prefers the basic amino acid arginine at the second position of the peptide, and hydrophobic and polar amino acids at the C-terminal end. These preferences are shared with HLA-B*27 and Mamu-B*008, molecules shown to be involved in elite control in human HIV type 1 and macaque SIV infections, respectively. In contrast, however, Mamu-A2*05 preferentially binds 8-mer peptides. Retention in the endoplasmic reticulum seems to be the cause of the lower cell-surface expression. Subsequent peptide-binding studies have illustrated that Mamu-A2*05:01 is able to bind SIV-epitopes known to evoke a strong CD8+ T cell response in the context of the Mamu-B*008 allotype in SIV-infected rhesus macaques. Thus, the macaque A2*05 gene encodes a specialized MHC class I molecule, and is most likely transported to the cell surface only when suitable peptides become available.
Assuntos
Epitopos de Linfócito T/metabolismo , Infecções por HIV/imunologia , HIV/fisiologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/fisiologia , Linfócitos T Citotóxicos/imunologia , Animais , Apresentação de Antígeno , Linhagem Celular , Epitopos de Linfócito T/genética , Predisposição Genética para Doença , Antígenos HIV/metabolismo , Infecções por HIV/genética , Antígeno HLA-B27/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunidade Celular , Macaca , Peptídeos/metabolismo , Ligação Proteica , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Carga Viral , Replicação ViralRESUMO
Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.
Assuntos
Variação Genética , Hominidae/genética , África , Animais , Animais Selvagens/genética , Animais de Zoológico/genética , Sudeste Asiático , Evolução Molecular , Fluxo Gênico/genética , Genética Populacional , Genoma/genética , Gorilla gorilla/classificação , Gorilla gorilla/genética , Hominidae/classificação , Humanos , Endogamia , Pan paniscus/classificação , Pan paniscus/genética , Pan troglodytes/classificação , Pan troglodytes/genética , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Densidade DemográficaRESUMO
Epigenetic changes have likely contributed to the large size and enhanced cognitive abilities of the human brain which evolved within the last 2 million years after the human-chimpanzee split. Using reduced representation bisulfite sequencing, we have compared the methylomes of neuronal and non-neuronal cells from 3 human and 3 chimpanzee cortices. Differentially methylated regions (DMRs) with genome-wide significance were enriched in specific genomic regions. Intraspecific methylation differences between neuronal and non-neuronal cells were approximately 3 times more abundant than interspecific methylation differences between human and chimpanzee cell types. The vast majority (>90%) of human intraspecific DMRs (including DMRs in retrotransposons) were hypomethylated in neurons, compared with glia. Intraspecific DMRs were enriched in genes associated with different neuropsychiatric disorders. Interspecific DMRs were enriched in genes showing human-specific brain histone modifications. Human-chimpanzee methylation differences were much more frequent in non-neuronal cells (n. DMRs = 666) than in neurons (n. DMRs = 96). More than 95% of interspecific DMRs in glia were hypermethylated in humans. Although without an outgroup we cannot assign whether a change in methylation occurred in the human or chimpanzee lineage, our results are consistent with a wave of methylation affecting several hundred non-neuronal genes during human brain evolution.