RESUMEN
Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which may lead to the development of rhesus disease models. Through phenotyping of macaques carrying a pathogenic OPA1:p.A8S variant, we identify a genetic model of autosomal dominant optic atrophy. Finally, we present a public website housing variant and genotype data from over two thousand rhesus macaques.
Asunto(s)
Modelos Animales de Enfermedad , Variación Genética , Macaca mulatta , Animales , Macaca mulatta/genética , Humanos , Frecuencia de los Genes , Atrofia Óptica Autosómica Dominante/genética , Polimorfismo de Nucleótido Simple , Fenotipo , Aprendizaje Automático , Genotipo , Mutación MissenseRESUMEN
Mauritian-origin cynomolgus macaques (MCMs) serve as a powerful nonhuman primate model in biomedical research due to their unique genetic homogeneity, which simplifies experimental designs. Despite their extensive use, a comprehensive understanding of crucial immune-regulating gene families, particularly killer Ig-like receptors (KIR) and NK group 2 (NKG2), has been hindered by the lack of detailed genomic reference assemblies. In this study, we employ advanced long-read sequencing techniques to completely assemble eight KIR and seven NKG2 genomic haplotypes, providing an extensive insight into the structural and allelic diversity of these immunoregulatory gene clusters. Leveraging these genomic resources, we prototype a strategy for genotyping KIR and NKG2 using short-read, whole-exome capture data, illustrating the potential for cost-effective multilocus genotyping at colony scale. These results mark a significant enhancement for biomedical research in MCMs and underscore the feasibility of broad-scale genetic investigations.
Asunto(s)
Haplotipos , Macaca fascicularis , Receptores KIR , Animales , Receptores KIR/genética , Macaca fascicularis/genética , Subfamília C de Receptores Similares a Lectina de Células NK/genética , Genómica/métodos , GenotipoRESUMEN
While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of "natural" hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from "natural hosts," which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections.
Asunto(s)
Infecciones por VIH , Inflamasomas , Síndrome de Inmunodeficiencia Adquirida del Simio , Animales , Humanos , Ratones , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Progresión de la Enfermedad , Infecciones por VIH/patología , Inflamasomas/metabolismo , Proteínas de Neoplasias/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/fisiología , Viremia , VIH/fisiologíaRESUMEN
Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3-9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.
Asunto(s)
Secuencia Conservada , Evolución Molecular , Genoma , Primates , Animales , Femenino , Humanos , Embarazo , Secuencia Conservada/genética , Desoxirribonucleasa I/metabolismo , ADN/genética , ADN/metabolismo , Genoma/genética , Mamíferos/clasificación , Mamíferos/genética , Placenta , Primates/clasificación , Primates/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Reproducibilidad de los Resultados , Factores de Transcripción/metabolismo , Proteínas/genética , Regulación de la Expresión Génica/genéticaRESUMEN
The common marmoset (Callithrix jacchus) is one of the most widely used nonhuman primate models of human disease. Owing to limitations in sequencing technology, early genome assemblies of this species using short-read sequencing suffered from gaps. In addition, the genetic diversity of the species has not yet been adequately explored. Using long-read genome sequencing and expert annotation, we generated a high-quality genome resource creating a 2.898 Gb marmoset genome in which most of the euchromatin portion is assembled contiguously (contig N50 = 25.23 Mbp, scaffold N50 = 98.2 Mbp). We then performed whole genome sequencing on 84 marmosets sampling the genetic diversity from several marmoset research centers. We identified a total of 19.1 million single nucleotide variants (SNVs), of which 11.9 million can be reliably mapped to orthologous locations in the human genome. We also observed 2.8 million small insertion/deletion variants. This dataset includes an average of 5.4 million SNVs per marmoset individual and a total of 74,088 missense variants in protein-coding genes. Of the 4956 variants orthologous to human ClinVar SNVs (present in the same annotated gene and with the same functional consequence in marmoset and human), 27 have a clinical significance of pathogenic and/or likely pathogenic. This important marmoset genomic resource will help guide genetic analyses of natural variation, the discovery of spontaneous functional variation relevant to human disease models, and the development of genetically engineered marmoset disease models.
Asunto(s)
Callithrix , Genómica , Animales , Humanos , Callithrix/genética , Mapeo Cromosómico , Genoma HumanoRESUMEN
Baboons (genus Papio) are a morphologically and behaviorally diverse clade of catarrhine monkeys that have experienced hybridization between phenotypically and genetically distinct phylogenetic species. We used high-coverage whole-genome sequences from 225 wild baboons representing 19 geographic localities to investigate population genomics and interspecies gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal patterns of population structure within and among species, including differential admixture among conspecific populations. We describe the first example of a baboon population with a genetic composition that is derived from three distinct lineages. The results reveal processes, both ancient and recent, that produced the observed mismatch between phylogenetic relationships based on matrilineal, patrilineal, and biparental inheritance. We also identified several candidate genes that may contribute to species-specific phenotypes.
Asunto(s)
Evolución Biológica , Flujo Génico , Papio , Animales , Masculino , Papio/anatomía & histología , Papio/genética , Fenotipo , Filogenia , Especificidad de la Especie , Caracteres SexualesRESUMEN
The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human specific. This study will open a wide range of research avenues for future primate genomic research.
Asunto(s)
Evolución Biológica , Variación Genética , Primates , Animales , Humanos , Genoma , Tasa de Mutación , Filogenia , Primates/genética , Densidad de PoblaciónRESUMEN
Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.
Asunto(s)
Variación Genética , Primates , Animales , Humanos , Secuencia de Bases , Frecuencia de los Genes , Primates/genética , Secuenciación Completa del GenomaRESUMEN
Baboons (genus Papio ) are a morphologically and behaviorally diverse clade of catarrhine monkeys that have experienced hybridization between phenotypically and genetically distinct phylogenetic species. We used high coverage whole genome sequences from 225 wild baboons representing 19 geographic localities to investigate population genomics and inter-species gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal novel patterns of population structure within and among species, including differential admixture among conspecific populations. We describe the first example of a baboon population with a genetic composition that is derived from three distinct lineages. The results reveal processes, both ancient and recent, that produced the observed mismatch between phylogenetic relationships based on matrilineal, patrilineal, and biparental inheritance. We also identified several candidate genes that may contribute to species-specific phenotypes. One-Sentence Summary: Genomic data for 225 baboons reveal novel sites of inter-species gene flow and local effects due to differences in admixture.
RESUMEN
Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases. One Sentence Summary: Deep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.
RESUMEN
BACKGROUND: Recent population studies are ever growing in number of samples to investigate the diversity of a population or species. These studies reveal new polymorphism that lead to important insights into the mechanisms of evolution, but are also important for the interpretation of these variations. Nevertheless, while the full catalog of variations across entire species remains unknown, we can predict which regions harbor additional not yet detected variations and investigate their properties, thereby enhancing the analysis for potentially missed variants. RESULTS: To achieve this we developed SVhound ( https://github.com/lfpaulin/SVhound ), which based on a population level SVs dataset can predict regions that harbor unseen SV alleles. We tested SVhound using subsets of the 1000 genomes project data and showed that its correlation (average correlation of 2800 tests r = 0.7136) is high to the full data set. Next, we utilized SVhound to investigate potentially missed or understudied regions across 1KGP and CCDG. Lastly we also apply SVhound on a small and novel SV call set for rhesus macaque (Macaca mulatta) and discuss the impact and choice of parameters for SVhound. CONCLUSIONS: SVhound is a unique method to identify potential regions that harbor hidden diversity in model and non model organisms and can also be potentially used to ensure high quality of SV call sets.
Asunto(s)
Variación Estructural del Genoma , Polimorfismo Genético , Programas Informáticos , Animales , Humanos , Alelos , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Macaca mulatta/genéticaRESUMEN
A male mutation bias is observed across vertebrates, and, where data are available, this bias is accompanied by increased per-generation mutation rates with parental age. While continuing mitotic cell division in the male germline post puberty has been proposed as the major cellular mechanism underlying both patterns, little direct evidence for this role has been found. Understanding the evolution of the per-generation mutation rate among species requires that we identify the molecular mechanisms that change between species. Here, we study the per-generation mutation rate in an extended pedigree of the brown (grizzly) bear, Ursus arctos horribilis. Brown bears hibernate for one-third of the year, a period during which spermatogenesis slows or stops altogether. The reduction of spermatogenesis is predicted to lessen the male mutation bias and to lower the per-generation mutation rate in this species. However, using whole-genome sequencing, we find that both male bias and per-generation mutation rates are highly similar to that expected for a non-hibernating species. We also carry out a phylogenetic comparison of substitution rates along the lineage leading to brown bear and panda (a non-hibernating species) and find no slowing of the substitution rate in the hibernator. Our results contribute to accumulating evidence that suggests that male germline cell division is not the major determinant of mutation rates and mutation biases. The results also provide a quantitative basis for improved estimates of the timing of carnivore evolution.
Asunto(s)
Hibernación , Ursidae , Animales , Masculino , Ursidae/genética , Hibernación/genética , Tasa de Mutación , Filogenia , Mutación de Línea Germinal , Células GerminativasRESUMEN
The mutation rate is a fundamental evolutionary parameter with direct and appreciable effects on the health and function of individuals. Here, we examine this important parameter in the domestic cat, a beloved companion animal as well as a valuable biomedical model. We estimate a mutation rate of 0.86 × 10-8 per bp per generation for the domestic cat (at an average parental age of 3.8 years). We find evidence for a significant paternal age effect, with more mutations transmitted by older sires. Our analyses suggest that the cat and the human have accrued similar numbers of mutations in the germline before reaching sexual maturity. The per-generation mutation rate in the cat is 28% lower than what has been observed in humans, but is consistent with the shorter generation time in the cat. Using a model of reproductive longevity, which takes into account differences in the reproductive age and time to sexual maturity, we are able to explain much of the difference in per-generation rates between species. We further apply our reproductive longevity model in a novel analysis of mutation spectra and find that the spectrum for the cat resembles the human mutation spectrum at a younger age of reproduction. Together, these results implicate changes in life-history as a driver of mutation rate evolution between species. As the first direct observation of the paternal age effect outside of rodents and primates, our results also suggest a phenomenon that may be universal among mammals.
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Longevidad , Tasa de Mutación , Animales , Gatos/genética , Preescolar , Humanos , Longevidad/genética , Mamíferos , Mutación , Edad Paterna , Reproducción/genéticaRESUMEN
BACKGROUND: The Syrian hamster (Mesocricetus auratus) has been suggested as a useful mammalian model for a variety of diseases and infections, including infection with respiratory viruses such as SARS-CoV-2. The MesAur1.0 genome assembly was generated in 2013 using whole-genome shotgun sequencing with short-read sequence data. Current more advanced sequencing technologies and assembly methods now permit the generation of near-complete genome assemblies with higher quality and greater continuity. FINDINGS: Here, we report an improved assembly of the M. auratus genome (BCM_Maur_2.0) using Oxford Nanopore Technologies long-read sequencing to produce a chromosome-scale assembly. The total length of the new assembly is 2.46 Gb, similar to the 2.50-Gb length of a previous assembly of this genome, MesAur1.0. BCM_Maur_2.0 exhibits significantly improved continuity, with a scaffold N50 that is 6.7 times greater than MesAur1.0. Furthermore, 21,616 protein-coding genes and 10,459 noncoding genes are annotated in BCM_Maur_2.0 compared to 20,495 protein-coding genes and 4,168 noncoding genes in MesAur1.0. This new assembly also improves the unresolved regions as measured by nucleotide ambiguities, where â¼17.11% of bases in MesAur1.0 were unresolved compared to BCM_Maur_2.0, in which the number of unresolved bases is reduced to 3.00%. CONCLUSIONS: Access to a more complete reference genome with improved accuracy and continuity will facilitate more detailed, comprehensive, and meaningful research results for a wide variety of future studies using Syrian hamsters as models.
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Cromosomas de los Mamíferos , Mesocricetus , Animales , Cromosomas de los Mamíferos/genética , Genoma , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mesocricetus/genética , Secuenciación Completa del GenomaRESUMEN
Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029CAsunto(s)
Neoplasias del Colon
, Neoplasias Colorrectales Hereditarias sin Poliposis
, Neoplasias Colorrectales
, Animales
, Neoplasias del Colon/genética
, Neoplasias Colorrectales/genética
, Neoplasias Colorrectales/patología
, Neoplasias Colorrectales Hereditarias sin Poliposis/genética
, Neoplasias Colorrectales Hereditarias sin Poliposis/patología
, Metilación de ADN/genética
, Reparación de la Incompatibilidad de ADN/genética
, Genómica
, Humanos
, Macaca mulatta/genética
, Ratones
, Inestabilidad de Microsatélites
, Homólogo 1 de la Proteína MutL/genética
RESUMEN
Nonhuman primates and especially rhesus macaques (Macaca mulatta) have been indispensable animal models for studies of various aspects of neurobiology, developmental psychology, and other aspects of neuroscience. While remarkable progress has been made in our understanding of influences on atypical human social behavior, such as that observed in autism spectrum disorders (ASD), many significant questions remain. Improved understanding of the relationships among variation in specific genes and variation in expressed social behavior in a nonhuman primate would benefit efforts to investigate risk factors, developmental mechanisms, and potential therapies for behavioral disorders including ASD. To study genetic influences on key aspects of social behavior and interactions-individual competence and/or motivation for specific aspects of social behavior-we quantified individual variation in social interactions among juvenile rhesus macaques using both a standard macaque ethogram and a macaque-relevant modification of the human Social Responsiveness Scale. Our analyses demonstrate that various aspects of juvenile social behavior exhibit significant genetic heritability, with estimated quantitative genetic effects similar to that described for ASD in human children. We also performed exome sequencing and analyzed variants in 143 genes previously suggested to influence risk for human ASD. We find preliminary evidence for genetic association between specific variants and both individual behaviors and multi-behavioral factor scores. To our knowledge, this is the first demonstration that spontaneous social behaviors performed by free-ranging juvenile rhesus macaques display significant genetic heritability and then to use exome sequencing data to examine potential macaque genetic associations in genes associated with human ASD.
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Trastorno del Espectro Autista , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/psicología , Humanos , Macaca mulatta/psicología , Fenotipo , Conducta Social , Secuenciación del ExomaRESUMEN
This report describes the clinical and histological findings, genetic study, and treatment in a 1.3-year-old rhesus macaque with bilateral cataracts and unilateral secondary glaucoma. Intravitreal injection of gentamicin decreased the intraocular pressure from 56 to <2 mm Hg. A putative genetic cause of the cataracts was not identified.
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Catarata , Glaucoma , Animales , Catarata/diagnóstico , Catarata/genética , Catarata/veterinaria , Glaucoma/genética , Glaucoma/veterinaria , Presión Intraocular , Macaca mulatta/genéticaRESUMEN
Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.
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Endometriosis , Receptores Acoplados a Proteínas G/genética , Animales , Endometriosis/tratamiento farmacológico , Endometriosis/genética , Endometrio , Femenino , Humanos , Macaca mulatta , Ratones , Factor de Necrosis Tumoral alfaRESUMEN
An anxious or inhibited temperament (IT) early in life is a major risk factor for the later development of stress-related psychopathology. Starting in infancy, nonhuman primates, like humans, begin to reveal their temperament when exposed to novel situations. Here, in Study 1 we demonstrate this infant IT predicts adult behavior. Specifically, in over 600 monkeys, we found that individuals scored as inhibited during infancy were more likely to refuse treats offered by potentially-threatening human experimenters as adults. In Study 2, using a sample of over 4000 monkeys from a large multi-generational family pedigree, we demonstrate that infant IT is partially heritable. The data revealed infant IT to reflect a co-inherited substrate that manifests across multiple latent variables. Finally, in Study 3 we performed whole-genome sequencing in 106 monkeys to identify IT-associated single-nucleotide variations (SNVs). Results demonstrated a genome-wide significant SNV near CTNNA2, suggesting a molecular target worthy of additional investigation. Moreover, we observed lower p values in genes implicated in human association studies of neuroticism and depression. Together, these data demonstrate the utility of our model of infant inhibited temperament in the rhesus monkey to facilitate discovery of genes that are relevant to the long-term inherited risk to develop anxiety and depressive disorders.
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Ansiedad , Temperamento , Animales , Ansiedad/genética , Trastornos de Ansiedad/genética , Variación Genética/genética , Macaca mulattaRESUMEN
Sifakas (genus Propithecus) are critically endangered, large-bodied diurnal lemurs that eat leaf-based diets and show corresponding anatomical and microbial adaptations to folivory. We report on the genome assembly of Coquerel's sifaka (P. coquereli) and the resequenced genomes of Verreaux's (P. verreauxi), the golden-crowned (P. tattersalli), and the diademed (P. diadema) sifakas. We find high heterozygosity in all sifakas compared with other primates and endangered mammals. Demographic reconstructions nevertheless suggest declines in effective population size beginning before human arrival on Madagascar. Comparative genomic analyses indicate pervasive accelerated evolution in the ancestral sifaka lineage affecting genes in several complementary pathways relevant to folivory, including nutrient absorption and xenobiotic and fatty acid metabolism. Sifakas show convergent evolution at the level of the pathway, gene family, gene, and amino acid substitution with other folivores. Although sifakas have relatively generalized diets, the physiological challenges of habitual folivory likely led to strong selection.