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Age and sex have a profound effect on cytosine methylation levels in humans and many other species. Here we analyzed DNA methylation profiles of 2400 tissues derived from 37 primate species including 11 haplorhine species (baboons, marmosets, vervets, rhesus macaque, chimpanzees, gorillas, orangutan, humans) and 26 strepsirrhine species (suborders Lemuriformes and Lorisiformes). From these we present here, pan-primate epigenetic clocks which are highly accurate for all primates including humans (age correlation R = 0.98). We also carried out in-depth analysis of baboon DNA methylation profiles and generated five epigenetic clocks for baboons (Olive-yellow baboon hybrid), one of which, the pan-tissue epigenetic clock, was trained on seven tissue types (fetal cerebral cortex, adult cerebral cortex, cerebellum, adipose, heart, liver, and skeletal muscle) with ages ranging from late fetal life to 22.8 years of age. Using the primate data, we characterize the effect of age and sex on individual cytosines in highly conserved regions. We identify 11 sex-related CpGs on autosomes near genes (POU3F2, CDYL, MYCL, FBXL4, ZC3H10, ZXDC, RRAS, FAM217A, RBM39, GRIA2, UHRF2). Low overlap can be observed between age- and sex-related CpGs. Overall, this study advances our understanding of conserved age- and sex-related epigenetic changes in primates, and provides biomarkers of aging for all primates.
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Metilación de ADN , Epigénesis Genética , Humanos , Animales , Macaca mulatta/genética , Envejecimiento/genética , Papio , Ubiquitina-Proteína Ligasas , Proteínas PortadorasRESUMEN
In the last 300 thousand years, the genus Chlorocebus expanded from equatorial Africa into the southernmost latitudes of the continent, where colder climate was a probable driver of natural selection. We investigated population-level genetic variation in the mitochondrial uncoupling protein 1 (UCP1) gene region-implicated in non-shivering thermogenesis (NST)-in 73 wild savannah monkeys from three taxa representing this southern expansion (Chlorocebus pygerythrus hilgerti, Chlorocebus cynosuros and Chlorocebus pygerythrus pygerythrus) ranging from Kenya to South Africa. We found 17 single nucleotide polymorphisms with extended haplotype homozygosity consistent with positive selective sweeps, 10 of which show no significant linkage disequilibrium with each other. Phylogenetic generalized least-squares modelling with ecological covariates suggest that most derived allele frequencies are significantly associated with solar irradiance and winter precipitation, rather than overall low temperatures. This selection and association with irradiance is demonstrated by a relatively isolated population in the southern coastal belt of South Africa. We suggest that sunbathing behaviours common to savannah monkeys, in combination with the strength of solar irradiance, may mediate adaptations to thermal stress via NST among savannah monkeys. The variants we discovered all lie in non-coding regions, some with previously documented regulatory functions, calling for further validation and research.
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Aclimatación , Termogénesis , Animales , Chlorocebus aethiops , Filogenia , Sudáfrica , Proteína Desacopladora 1RESUMEN
The study of the mammalian microbiome serves as a critical tool for understanding host-microbial diversity and coevolution and the impact of bacterial communities on host health. While studies of specific microbial systems (e.g., in the human gut) have rapidly increased, large knowledge gaps remain, hindering our understanding of the determinants and levels of variation in microbiomes across multiple body sites and host species. Here, we compare microbiome community compositions from eight distinct body sites among 17 phylogenetically diverse species of nonhuman primates (NHPs), representing the largest comparative study of microbial diversity across primate host species and body sites. Analysis of 898 samples predominantly acquired in the wild demonstrated that oral microbiomes were unique in their clustering, with distinctive divergence from all other body site microbiomes. In contrast, all other body site microbiomes clustered principally by host species and differentiated by body site within host species. These results highlight two key findings: (i) the oral microbiome is unique compared to all other body site microbiomes and conserved among diverse nonhuman primates, despite their considerable dietary and phylogenetic differences, and (ii) assessments of the determinants of host-microbial diversity are relative to the level of the comparison (i.e., intra-/inter-body site, -host species, and -individual), emphasizing the need for broader comparative microbial analyses across diverse hosts to further elucidate host-microbial dynamics, evolutionary and biological patterns of variation, and implications for human-microbial coevolution. IMPORTANCE The microbiome is critical to host health and disease, but much remains unknown about the determinants, levels, and evolution of host-microbial diversity. The relationship between hosts and their associated microbes is complex. Most studies to date have focused on the gut microbiome; however, large gaps remain in our understanding of host-microbial diversity, coevolution, and levels of variation in microbiomes across multiple body sites and host species. To better understand the patterns of variation and evolutionary context of host-microbial communities, we conducted one of the largest comparative studies to date, which indicated that the oral microbiome was distinct from the microbiomes of all other body sites and convergent across host species, suggesting conserved niche specialization within the Primates order. We also show the importance of host species differences in shaping the microbiome within specific body sites. This large, comparative study contributes valuable information on key patterns of variation among hosts and body sites, with implications for understanding host-microbial dynamics and human-microbial coevolution.
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Microbioma Gastrointestinal , Microbiota , Animales , Bacterias/genética , Mamíferos , Filogenia , Primates/microbiologíaRESUMEN
CCR5, a chemokine receptor central for orchestrating lymphocyte/cell migration to the sites of inflammation and to the immunosurveillance, is involved in the pathogenesis of a wide spectrum of health conditions, including inflammatory diseases, viral infections, cancers and autoimmune diseases. CCR5 is also the primary coreceptor for the human immunodeficiency viruses (HIVs), supporting its entry into CD4+ T lymphocytes upon transmission and in the early stages of infection in humans. A natural loss-of-function mutation CCR5-Δ32, preventing the mutated protein expression on the cell surface, renders homozygous carriers of the null allele resistant to HIV-1 infection. This phenomenon was leveraged in the development of therapies and cure strategies for AIDS. Meanwhile, over 40 African nonhuman primate species are long-term hosts of simian immunodeficiency virus (SIV), an ancestral family of viruses that give rise to the pandemic CCR5 (R5)-tropic HIV-1. Many natural hosts typically do not progress to immunodeficiency upon the SIV infection. They have developed various strategies to minimize the SIV-related pathogenesis and disease progression, including an array of mechanisms employing modulation of the CCR5 receptor activity: (i) deletion mutations abrogating the CCR5 surface expression and conferring resistance to infection in null homozygotes; (ii) downregulation of CCR5 expression on CD4+ T cells, particularly memory cells and cells at the mucosal sites, preventing SIV from infecting and killing cells important for the maintenance of immune homeostasis, (iii) delayed onset of CCR5 expression on the CD4+ T cells during ontogenetic development that protects the offspring from vertical transmission of the virus. These host adaptations, aimed at lowering the availability of target CCR5+ CD4+ T cells through CCR5 downregulation, were countered by SIV, which evolved to alter the entry coreceptor usage toward infecting different CD4+ T-cell subpopulations that support viral replication yet without disruption of host immune homeostasis. These natural strategies against SIV/HIV-1 infection, involving control of CCR5 function, inspired therapeutic approaches against HIV-1 disease, employing CCR5 coreceptor blocking as well as gene editing and silencing of CCR5. Given the pleiotropic role of CCR5 in health beyond immune disease, the precision as well as costs and benefits of such interventions needs to be carefully considered.
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VIH-1/inmunología , Receptores CCR5/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Línea Celular , Humanos , Receptores CCR5/química , Receptores CCR5/genéticaRESUMEN
HIV emerged following cross-species transmissions of simian immunodeficiency viruses (SIVs) that naturally infect non-human primates (NHPs) from Africa. While HIV replication and CD4+ T-cell depletion lead to increased gut permeability, microbial translocation, chronic immune activation, and systemic inflammation, the natural hosts of SIVs generally avoid these deleterious consequences when infected with their species-specific SIVs and do not progress to AIDS despite persistent lifelong high viremia due to long-term coevolution with their SIV pathogens. The benign course of natural SIV infection in the natural hosts is in stark contrast to the experimental SIV infection of Asian macaques, which progresses to simian AIDS. The mechanisms of non-pathogenic SIV infections are studied mainly in African green monkeys, sooty mangabeys, and mandrills, while progressing SIV infection is experimentally modeled in macaques: rhesus macaques, pigtailed macaques, and cynomolgus macaques. Here, we focus on the distinctive features of SIV infection in natural hosts, particularly (1): the superior healing properties of the intestinal mucosa, which enable them to maintain the integrity of the gut barrier and prevent microbial translocation, thus avoiding excessive/pathologic immune activation and inflammation usually perpetrated by the leaking of the microbial products into the circulation; (2) the gut microbiome, the disruption of which is an important factor in some inflammatory diseases, yet not completely understood in the course of lentiviral infection; (3) cell population shifts resulting in target cell restriction (downregulation of CD4 or CCR5 surface molecules that bind to SIV), control of viral replication in the lymph nodes (expansion of natural killer cells), and anti-inflammatory effects in the gut (NKG2a/c+ CD8+ T cells); and (4) the genes and biological pathways that can shape genetic adaptations to viral pathogens and are associated with the non-pathogenic outcome of the natural SIV infection. Deciphering the protective mechanisms against SIV disease progression to immunodeficiency, which have been established through long-term coevolution between the natural hosts and their species-specific SIVs, may prompt the development of novel therapeutic interventions, such as drugs that can control gut inflammation, enhance gut healing capacities, or modulate the gut microbiome. These developments can go beyond HIV infection and open up large avenues for correcting gut damage, which is common in many diseases.
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Infecciones por VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Chlorocebus aethiops , Linfocitos T CD8-positivos , Macaca mulatta , InflamaciónRESUMEN
DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, we developed two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes that gain methylation with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for anti-aging studies in vervets.
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Epigénesis Genética , Epigenómica , Animales , Chlorocebus aethiops , Metilación de ADN , Longevidad , Macaca mulatta/genética , MamíferosRESUMEN
Human DNA methylation data have previously been used to develop highly accurate biomarkers of aging ("epigenetic clocks"). Subsequent studies demonstrate that similar epigenetic clocks can also be developed for mice and many other mammals. Here, we describe epigenetic clocks for common marmosets (Callithrix jacchus) based on novel DNA methylation data generated from highly conserved mammalian CpGs that were profiled using a custom Infinium array (HorvathMammalMethylChip40). From these, we developed and present here two epigenetic clocks for marmosets that are applicable to whole blood samples. We find that the human-marmoset clock for relative age exhibits moderately high age correlations in two other non-human primate species: vervet monkeys and rhesus macaques. In a separate cohort of marmosets, we tested whether intervention with rapamycin, a drug shown to extend lifespan in mice, would alter the epigenetic age of marmosets, as measured by the marmoset epigenetic clocks. These clocks did not detect significant effects of rapamycin on the epigenetic age of marmoset blood. The common marmoset stands out from other mammals in that it is not possible to build accurate estimators of sex based on DNA methylation data: the accuracy of a random forest predictor of sex (66%) was substantially lower than that observed for other mammals (which is close to 100%). Overall, the epigenetic clocks developed here for the common marmoset are expected to be useful for age estimation of wild-born animals and for anti-aging studies in this species.
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Callithrix , Metilación de ADN , Animales , Chlorocebus aethiops , Epigénesis Genética , Macaca mulatta , Ratones , Sirolimus/farmacologíaRESUMEN
Methylation levels at specific CpG positions in the genome have been used to develop accurate estimators of chronological age in humans, mice, and other species. Although epigenetic clocks are generally species-specific, the principles underpinning them appear to be conserved at least across the mammalian class. This is exemplified by the successful development of epigenetic clocks for mice and several other mammalian species. Here, we describe epigenetic clocks for the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate in biological research. Using a custom methylation array (HorvathMammalMethylChip40), we profiled n = 281 tissue samples (blood, skin, adipose, kidney, liver, lung, muscle, and cerebral cortex). From these data, we generated five epigenetic clocks for macaques. These clocks differ with regard to applicability to different tissue types (pan-tissue, blood, skin), species (macaque only or both humans and macaques), and measure of age (chronological age versus relative age). Additionally, the age-based human-macaque clock exhibits a high age correlation (R = 0.89) with the vervet monkey (Chlorocebus sabaeus), another Old World species. Four CpGs within the KLF14 promoter were consistently altered with age in four tissues (adipose, blood, cerebral cortex, skin). Future studies will be needed to evaluate whether these epigenetic clocks predict age-related conditions in the rhesus macaque.
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Metilación de ADN , Epigénesis Genética , Macaca mulatta , Envejecimiento , Animales , Chlorocebus aethiops , Epigenómica , Macaca mulatta/genética , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: The microbiota plays an important role in HIV pathogenesis in humans. Microbiota can impact health through several pathways such as increasing inflammation in the gut, metabolites of bacterial origin, and microbial translocation from the gut to the periphery which contributes to systemic chronic inflammation and immune activation and the development of AIDS. Unlike HIV-infected humans, SIV-infected vervet monkeys do not experience gut dysfunction, microbial translocation, and chronic immune activation and do not progress to immunodeficiency. Here, we provide the first reported characterization of the microbial ecosystems of the gut and genital tract in a natural nonprogressing host of SIV, wild vervet monkeys from South Africa. RESULTS: We characterized fecal, rectal, vaginal, and penile microbiomes in vervets from populations heavily infected with SIV from diverse locations across South Africa. Geographic site, age, and sex affected the vervet microbiome across different body sites. Fecal and vaginal microbiome showed marked stratification with three enterotypes in fecal samples and two vagitypes, which were predicted functionally distinct within each body site. External bioclimatic factors, biome type, and environmental temperature influenced microbiomes locally associated with vaginal and rectal mucosa. Several fecal microbial taxa were linked to plasma levels of immune molecules, for example, MIG was positively correlated with Lactobacillus and Escherichia/Shigella and Helicobacter, and IL-10 was negatively associated with Erysipelotrichaceae, Anaerostipes, Prevotella, and Anaerovibrio, and positively correlated with Bacteroidetes and Succinivibrio. During the chronic phase of infection, we observed a significant increase in gut microbial diversity, alterations in community composition (including a decrease in Proteobacteria/Succinivibrio in the gut) and functionality (including a decrease in genes involved in bacterial invasion of epithelial cells in the gut), and partial reversibility of acute infection-related shifts in microbial abundance observed in the fecal microbiome. As part of our study, we also developed an accurate predictor of SIV infection using fecal samples. CONCLUSIONS: The vervets infected with SIV and humans infected with HIV differ in microbial responses to infection. These responses to SIV infection may aid in preventing microbial translocation and subsequent disease progression in vervets, and may represent host microbiome adaptations to the virus. Video Abstract.
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Microbioma Gastrointestinal , Microbiota , Enfermedades de los Monos/microbiología , Recto/microbiología , Síndrome de Inmunodeficiencia Adquirida del Simio/microbiología , Virus de la Inmunodeficiencia de los Simios/fisiología , Vagina/microbiología , Animales , Bacterias/genética , Bacterias/aislamiento & purificación , Chlorocebus aethiops/microbiología , Heces/microbiología , Femenino , Masculino , Enfermedades de los Monos/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/virologíaRESUMEN
The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has devastated health infrastructure around the world. Both ACE2 (an entry receptor) and TMPRSS2 (used by the virus for spike protein priming) are key proteins to SARS-CoV-2 cell entry, enabling progression to COVID-19 in humans. Comparative genomic research into critical ACE2 binding sites, associated with the spike receptor binding domain, has suggested that African and Asian primates may also be susceptible to disease from SARS-CoV-2 infection. Savanna monkeys (Chlorocebus spp.) are a widespread non-human primate with well-established potential as a bi-directional zoonotic/anthroponotic agent due to high levels of human interaction throughout their range in sub-Saharan Africa and the Caribbean. To characterize potential functional variation in savanna monkey ACE2 and TMPRSS2, we inspected recently published genomic data from 245 savanna monkeys, including 163 wild monkeys from Africa and the Caribbean and 82 captive monkeys from the Vervet Research Colony (VRC). We found several missense variants. One missense variant in ACE2 (X:14,077,550; Asp30Gly), common in Ch. sabaeus, causes a change in amino acid residue that has been inferred to reduce binding efficiency of SARS-CoV-2, suggesting potentially reduced susceptibility. The remaining populations appear as susceptible as humans, based on these criteria for receptor usage. All missense variants observed in wild Ch. sabaeus populations are also present in the VRC, along with two splice acceptor variants (at X:14,065,076) not observed in the wild sample that are potentially disruptive to ACE2 function. The presence of these variants in the VRC suggests a promising model for SARS-CoV-2 infection and vaccine and therapy development. In keeping with a One Health approach, characterizing actual susceptibility and potential for bi-directional zoonotic/anthroponotic transfer in savanna monkey populations may be an important consideration for controlling COVID-19 epidemics in communities with frequent human/non-human primate interactions that, in many cases, may have limited health infrastructure.
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Chlorocebus aethiops , Infecciones por Coronavirus/veterinaria , Pandemias/veterinaria , Peptidil-Dipeptidasa A/genética , Neumonía Viral/veterinaria , Enfermedades de los Primates/genética , Serina Endopeptidasas/genética , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/metabolismo , COVID-19 , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/transmisión , Susceptibilidad a Enfermedades , Neumonía Viral/genética , Neumonía Viral/transmisión , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/metabolismo , Secuenciación Completa del Genoma , Zoonosis/transmisiónRESUMEN
Primates display a wide range of phenotypic variation underlaid by complex genetically regulated mechanisms. The links among DNA sequence, gene function, and phenotype have been of interest from an evolutionary perspective, to understand functional genome evolution and its phenotypic consequences, and from a biomedical perspective to understand the shared and human-specific roots of health and disease. Progress in methods for characterizing genetic, transcriptomic, and DNA methylation (DNAm) variation is driving the rapid development of extensive omics resources, which are now increasingly available from humans as well as a growing number of nonhuman primates (NHPs). The fast growth of large-scale genomic data is driving the emergence of integrated tools and databases, thus facilitating studies of gene functionality across primates. This review describes NHP genomic resources that can aid in exploration of how genes shape primate phenotypes. It focuses on the gene expression trajectories across development in different tissues, the identification of functional genetic variation (including variants deleterious for protein function and regulatory variants modulating gene expression), and DNAm profiles as an emerging tool to understand the process of aging. These resources enable comparative functional genomics approaches to identify species-specific and primate-shared gene functionalities associated with health and development.
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Variación Genética , Genoma , Genómica , Primates/genética , Animales , Salud , Primates/crecimiento & desarrolloRESUMEN
Psychosocial stressors - life events that challenge social support and relationships - represent powerful risk factors for human disease; included amongst these events are relocation, isolation and displacement. To evaluate the impact of a controlled psychosocial stressor on physiology and underlying molecular pathways, we longitudinally studied the influence of a 28-day period of quarantine on biomarkers of immune signalling, microbial translocation, glycaemic health and blood transcriptome in the wild-born vervet monkey. This event caused a coordinated, mostly transient, reduction of circulating levels of nine immune signalling molecules. These were paralleled by a massive dysregulation of blood transcriptome, including genes implicated in chronic pathologies and immune functions. Immune and inflammatory functions were enriched among the genes downregulated in response to stress. An upregulation of genes involved in blood coagulation, platelet activation was characteristic of the rapid response to stress induction. Stress also decreased neutrophils and increased CD4 + T cell proportions in blood. This model of psychosocial stress, characterised by an immune dysregulation at the transcriptomic, molecular and cellular levels, creates opportunities to uncover the underlying mechanisms of stress-related diseases with an immune component, including cardiovascular diseases and susceptibility to infections.
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Biomarcadores/sangre , Estrés Psicológico , Transcriptoma , Animales , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Quimiocinas/sangre , Chlorocebus aethiops , Citocinas/sangre , Regulación hacia Abajo , Estudios Longitudinales , Neutrófilos/citología , Regulación hacia ArribaRESUMEN
NHP are important translational models for understanding the genomic underpinnings of growth, development, fetal programming, and predisposition to disease, with potential for the development of early health biomarkers. Understanding how prenatal gene expression is linked to pre- and postnatal health and development requires methods for assessing the fetal transcriptome. Here we used RNAseq methodology to analyze the expression of cell-free fetal RNA in the amniotic fluid supernatant (AFS) of vervet monkeys. Despite the naturally high level of degradation of free-floating RNA, we detected more than 10,000 gene transcripts in vervet AFS. The most highly expressed genes were H19, IGF2, and TPT1, which are involved in embryonic growth and glycemic health. We noted global similarities in expression profiles between vervets and humans, with genes involved in embryonic growth and glycemic health among the genes most highly expressed in AFS. Our study demonstrates both the feasibility and usefulness of prenatal transcriptomic profiles, by using amniocentesis procedures to obtain AFS and cell-free fetal RNA from pregnant vervets.
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Líquido Amniótico , Ácidos Nucleicos Libres de Células , Chlorocebus aethiops , Desarrollo Fetal , Animales , Femenino , Embarazo , Amniocentesis , Líquido Amniótico/metabolismo , Ácidos Nucleicos Libres de Células/genética , Desarrollo Fetal/fisiología , Expresión Génica , Perfilación de la Expresión Génica , Proteína Tumoral Controlada Traslacionalmente 1RESUMEN
OBJECTIVE: Germline mutations occurring in the highly penetrant genes BRCA1 and BRCA2 are responsible for only certain cases of familial breast cancer (BC) and ovarian cancer (OC). Thus, the use of NGS multi-gene panel (MGP) testing has recently become very popular. METHODS: To estimate a reliable BC and OC risk associated with pathogenic variants in the selected candidate BC/OC predisposition genes, a comprehensive meta-analysis of 48 MGP-based studies analyzing BC/OC patients was conducted. The role of 37 genes was evaluated, comparing, in total, the mutation frequency in ~120,000 BC/OC cases and ~120,000 controls, which guaranteed strong statistical support with high confidence for most analyzed genes. RESULTS: We characterized the strategies of MGP analyses and the types and localizations of the identified mutations and showed that 13 and 11 of the analyzed genes were significantly associated with an increased BC and OC risk, respectively. The risk attributed to some of these genes (e.g., CDKN2A and PALB2 for BC) was similar to that observed for BRCA2. The analysis also showed a substantial difference in the profile of genes contributing to either BC or OC risk, including genes specifically associated with a high risk of OC but not BC (e.g., RAD51C, and RAD51D). CONCLUSIONS: Our study provides strong statistical proof, defines the risk for many genes often considered candidates for BC/OC predisposition and excludes the role of other genes frequently analyzed in the MGPs. In the context of clinical diagnostics, the results support the knowledge-based interpretation of identified mutations.
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Neoplasias de la Mama/genética , Neoplasias Ováricas/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Humanos , MutaciónRESUMEN
In the version of this article published, in the Online Methods eight citations to supplementary material refer to the wrong supplementary items. See the correction notice for full details.
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Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results: Aß1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aß1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aß1-40 and p-tau181 as potentially valuable biomarkers of these processes.
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Envejecimiento , Péptidos beta-Amiloides , Encéfalo/patología , Angiopatía Amiloide Cerebral , Chlorocebus aethiops , Enfermedades de los Monos , Fragmentos de Péptidos , Proteínas tau , Envejecimiento/líquido cefalorraquídeo , Envejecimiento/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/genética , Animales , Biomarcadores/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/genética , Cromosomas de los Mamíferos , Femenino , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Masculino , Modelos Animales , Enfermedades de los Monos/líquido cefalorraquídeo , Enfermedades de los Monos/genética , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/genética , Neuroimagen/métodos , Tamaño de los Órganos , Linaje , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/genética , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genéticaRESUMEN
Vervet monkeys are among the most widely distributed nonhuman primates, show considerable phenotypic diversity, and have long been an important biomedical model for a variety of human diseases and in vaccine research. Using whole-genome sequencing data from 163 vervets sampled from across Africa and the Caribbean, we find high diversity within and between taxa and clear evidence that taxonomic divergence was reticulate rather than following a simple branching pattern. A scan for diversifying selection across taxa identifies strong and highly polygenic selection signals affecting viral processes. Furthermore, selection scores are elevated in genes whose human orthologs interact with HIV and in genes that show a response to experimental simian immunodeficiency virus (SIV) infection in vervet monkeys but not in rhesus macaques, suggesting that part of the signal reflects taxon-specific adaptation to SIV.
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Adaptación Fisiológica/genética , Chlorocebus aethiops/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , África , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Chlorocebus aethiops/sangre , Chlorocebus aethiops/clasificación , Chlorocebus aethiops/genética , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Variación Genética , Interacciones Huésped-Patógeno , Hibridación Genética , Macaca mulatta/sangre , Macaca mulatta/genética , Macaca mulatta/virología , Filogenia , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Virus de la Inmunodeficiencia de los Simios/clasificación , Virus de la Inmunodeficiencia de los Simios/genética , Especificidad de la EspecieRESUMEN
By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.
Asunto(s)
Chlorocebus aethiops/genética , Perfilación de la Expresión Génica , Variación Genética , Sitios de Carácter Cuantitativo/genética , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Chlorocebus aethiops/crecimiento & desarrollo , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Zika virus (ZIKV) has recently spread through the Americas and has been associated with a range of health effects, including birth defects in children born to women infected during pregnancy. Although the natural reservoir of ZIKV remains poorly defined, the virus was first identified in a captive "sentinel" macaque monkey in Africa in 1947. However, the virus has not been reported in humans or nonhuman primates (NHPs) in Africa outside Gabon in over a decade. Here, we examine ZIKV infection in 239 wild baboons and African green monkeys from South Africa, the Gambia, Tanzania, and Zambia using combinations of unbiased deep sequencing, quantitative reverse transcription-PCR (qRT-PCR), and an antibody capture assay that we optimized using serum collected from captive macaque monkeys exposed to ZIKV, dengue virus, and yellow fever virus. While we did not find evidence of active ZIKV infection in wild NHPs in Africa, we found variable ZIKV seropositivity of up to 16% in some of the NHP populations sampled. We anticipate that these results and the methodology described within will help in continued efforts to determine the prevalence, natural reservoir, and transmission dynamics of ZIKV in Africa and elsewhere. IMPORTANCE Zika virus (ZIKV) is a mosquito-borne virus originally discovered in a captive monkey living in the Zika Forest of Uganda, Africa, in 1947. Recently, an outbreak in South America has shown that ZIKV infection can cause myriad health effects, including birth defects in the children of women infected during pregnancy. Here, we sought to investigate ZIKV infection in wild African primates to better understand its emergence and spread, looking for evidence of active or prior infection. Our results suggest that up to 16% of some populations of nonhuman primate were, at some point, exposed to ZIKV. We anticipate that this study will be useful for future studies that examine the spread of infections from wild animals to humans in general and those studying ZIKV in primates in particular.
RESUMEN
UNLABELLED: Staphylococcus aureus is an important pathogen of humans and animals. We genome sequenced 90 S. aureus isolates from The Gambia: 46 isolates from invasive disease in humans, 13 human carriage isolates, and 31 monkey carriage isolates. We inferred multiple anthroponotic transmissions of S. aureus from humans to green monkeys (Chlorocebus sabaeus) in The Gambia over different time scales. We report a novel monkey-associated clade of S. aureus that emerged from a human-to-monkey switch estimated to have occurred 2,700 years ago. Adaptation of this lineage to the monkey host is accompanied by the loss of phage-carrying genes that are known to play an important role in human colonization. We also report recent anthroponotic transmission of the well-characterized human lineages sequence type 6 (ST6) and ST15 to monkeys, probably because of steadily increasing encroachment of humans into the monkeys' habitat. Although we have found no evidence of transmission of S. aureus from monkeys to humans, as the two species come into ever-closer contact, there might be an increased risk of additional interspecies exchanges of potential pathogens. IMPORTANCE: The population structures of Staphylococcus aureus in humans and monkeys in sub-Saharan Africa have been previously described using multilocus sequence typing (MLST). However, these data lack the power to accurately infer details regarding the origin and maintenance of new adaptive lineages. Here, we describe the use of whole-genome sequencing to detect transmission of S. aureus between humans and nonhuman primates and to document the genetic changes accompanying host adaptation. We note that human-to-monkey switches tend to be more common than the reverse and that a novel monkey-associated clade is likely to have emerged from such a switch approximately 2,700 years ago. Moreover, analysis of the accessory genome provides important clues as to the genetic changes underpinning host adaptation and, in particular, shows that human-to-monkey switches tend to be associated with the loss of genes known to confer adaptation to the human host.