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Strong ultraviolet (UV) radiation at high altitude imposes a serious selective pressure, which may induce skin pigmentation adaptation of indigenous populations. We conducted skin pigmentation phenotyping and genome-wide analysis of Tibetans in order to understand the underlying mechanism of adaptation to UV radiation. We observe that Tibetans have darker baseline skin color compared with lowland Han Chinese, as well as an improved tanning ability, suggesting a two-level adaptation to boost their melanin production. A genome-wide search for the responsible genes identifies GNPAT showing strong signals of positive selection in Tibetans. An enhancer mutation (rs75356281) located in GNPAT intron 2 is enriched in Tibetans (58%) but rare in other world populations (0 to 18%). The adaptive allele of rs75356281 is associated with darker skin in Tibetans and, under UVB treatment, it displays higher enhancer activities compared with the wild-type allele in in vitro luciferase assays. Transcriptome analyses of gene-edited cells clearly show that with UVB treatment, the adaptive variant of GNPAT promotes melanin synthesis, likely through the interactions of CAT and ACAA1 in peroxisomes with other pigmentation genes, and they act synergistically, leading to an improved tanning ability in Tibetans for UV protection.
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Adaptação Fisiológica , Altitude , Pigmentação da Pele , Aciltransferases/genética , Adaptação Fisiológica/genética , Etnicidade , Humanos , Melaninas/genética , Fenótipo , Pigmentação da Pele/genética , Tibet , Transcriptoma , Raios UltravioletaRESUMO
During the origin of great apes about 14 million years ago, a series of phenotypic innovations emerged, such as the increased body size, the enlarged brain volume, the improved cognitive skill, and the diversified diet. Yet, the genomic basis of these evolutionary changes remains unclear. Utilizing the high-quality genome assemblies of great apes (including human), gibbon, and macaque, we conducted comparative genome analyses and identified 15,885 great ape-specific structural variants (GSSVs), including eight coding GSSVs resulting in the creation of novel proteins (e.g., ACAN and CMYA5). Functional annotations of the GSSV-related genes revealed the enrichment of genes involved in development and morphogenesis, especially neurogenesis and neural network formation, suggesting the potential role of GSSVs in shaping the great ape-shared traits. Further dissection of the brain-related GSSVs shows great ape-specific changes of enhancer activities and gene expression in the brain, involving a group of GSSV-regulated genes (such as NOL3) that potentially contribute to the altered brain development and function in great apes. The presented data highlight the evolutionary role of structural variants in the phenotypic innovations during the origin of the great ape lineage.
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Hominidae , Animais , Humanos , Hominidae/genética , Evolução Biológica , Genoma , Genômica , FenótipoRESUMO
BACKGROUND: Domestication and introduction of dairy animals facilitated the permanent human occupation of the Tibetan Plateau. Yet the history of dairy pastoralism in the Tibetan Plateau remains poorly understood. Little is known how Tibetans adapted to milk and dairy products. RESULTS: We integrated archeological evidence and genetic analysis to show the picture that the dairy ruminants, together with dogs, were introduced from West Eurasia into the Tibetan Plateau since ~ 3600 years ago. The genetic admixture between the exotic and indigenous dogs enriched the candidate lactase persistence (LP) allele 10974A > G of West Eurasian origin in Tibetan dogs. In vitro experiments demonstrate that - 13838G > A functions as a LP allele in Tibetans. Unlike multiple LP alleles presenting selective signatures in West Eurasians and South Asians, the de novo origin of Tibetan-specific LP allele - 13838G > A with low frequency (~ 6-7%) and absence of selection corresponds - 13910C > T in pastoralists across eastern Eurasia steppe. CONCLUSIONS: Results depict a novel scenario of genetic and cultural adaptations to diet and expand current understanding of the establishment of dairy pastoralism in the Tibetan Plateau.
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Criação de Animais Domésticos , Povo Asiático , Dieta , Leite , Animais , Cães/genética , Humanos , Tibet , RuminantesRESUMO
Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of EPAS1, a gene encoding hypoxia inducible factor 2α (HIF-2α) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed that the Tibetan-enriched EPAS1 variants down-regulate expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia, mirroring the situation in Tibetans. Furthermore, we found that the Tibetan version of EPAS1 is not only associated with the relatively low hemoglobin level as a polycythemia protectant, but also is associated with a low pulmonary vasoconstriction response in Tibetans. We propose that the down-regulation of EPAS1 contributes to the molecular basis of Tibetans' adaption to high-altitude hypoxia.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia/genética , Aclimatação/genética , Adaptação Biológica/genética , Adaptação Fisiológica/genética , Adulto , Altitude , Doença da Altitude/genética , Doença da Altitude/metabolismo , Animais , Regulação para Baixo , Etnicidade/genética , Feminino , Variação Genética/genética , Hemoglobinas , Humanos , Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Desequilíbrio de Ligação/genética , Masculino , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Seleção Genética , TibetRESUMO
Tibetans are well adapted to high-altitude environments. Among the adaptive traits in Tibetans, the relatively low hemoglobin level is considered a blunted erythropoietic response to hypoxic challenge. Previously, EPAS1 and EGLN1, the major upstream regulators in the hypoxic pathway, were reportedly involved in the hemoglobin regulation in Tibetans. In this study, we report a downstream gene (HMOX2) involved in heme catabolism, which harbors potentially adaptive variants in Tibetans. We first resequenced the entire genomic region (45.6 kb) of HMOX2 in Tibetans, which confirmed the previously suspected signal of positive selection on HMOX2 in Tibetans. Subsequent association analyses of hemoglobin levels in two independent Tibetan populations (a total of 1,250 individuals) showed a male-specific association between the HMOX2 variants and hemoglobin levels. Tibetan males with the derived C allele at rs4786504:T>C displayed lower hemoglobin level as compared with the T allele carriers. Furthermore, our in vitro experiments indicated that the C allele of rs4786504 could increase the expression of HMOX2, presumably leading to a more efficient breakdown of heme that may help maintain a relatively low hemoglobin level at high altitude. Collectively, we propose that HMOX2 contributes to high-altitude adaptation in Tibetans by functioning as a modifier in the regulation of hemoglobin metabolism.
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Adaptação Fisiológica/genética , Heme Oxigenase (Desciclizante)/genética , Hemoglobinas/genética , Hipóxia/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Altitude , Etnicidade , Éxons , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Heme/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hemoglobinas/metabolismo , Humanos , Hipóxia/etnologia , Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Fatores Sexuais , Transdução de Sinais , TibetRESUMO
Compared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence between Tibetans and Han, and Tibetans show decreased immune response and endoplasmic reticulum stress. Remarkably, we detected a sex-biased expression divergence, where the male-infant placentas show a greater between-population difference than the female-infant placentas. The umbilical cord plays a key role in the sex-biased expression divergence, which is associated with the higher birth weight of the male newborns of Tibetans. We also identified adaptive histological changes in the male-infant placentas of Tibetans, including larger umbilical artery wall and umbilical artery intima and media, and fewer syncytial knots. These findings provide valuable insights into the sex-biased adaptation of human populations, with significant implications for medical and genetic studies of human reproduction.
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Desenvolvimento Fetal , Placenta , Humanos , Feminino , Placenta/metabolismo , Masculino , Gravidez , Desenvolvimento Fetal/genética , Tibet , Recém-Nascido , Transcriptoma , Altitude , Fatores Sexuais , Caracteres SexuaisRESUMO
The crab-eating macaques ( Macaca fascicularis ) and rhesus macaques ( M. mulatta ) are widely studied nonhuman primates in biomedical and evolutionary research. Despite their significance, the current understanding of the complex genomic structure in macaques and the differences between species requires substantial improvement. Here, we present a complete genome assembly of a crab-eating macaque and 20 haplotype-resolved macaque assemblies to investigate the complex regions and major genomic differences between species. Segmental duplication in macaques is â¼42% lower, while centromeres are â¼3.7 times longer than those in humans. The characterization of â¼2 Mbp fixed genetic variants and â¼240 Mbp complex loci highlights potential associations with metabolic differences between the two macaque species (e.g., CYP2C76 and EHBP1L1 ). Additionally, hundreds of alternative splicing differences show post-transcriptional regulation divergence between these two species (e.g., PNPO ). We also characterize 91 large-scale genomic differences between macaques and humans at a single-base-pair resolution and highlight their impact on gene regulation in primate evolution (e.g., FOLH1 and PIEZO2 ). Finally, population genetics recapitulates macaque speciation and selective sweeps, highlighting potential genetic basis of reproduction and tail phenotype differences (e.g., STAB1 , SEMA3F , and HOXD13 ). In summary, the integrated analysis of genetic variation and population genetics in macaques greatly enhances our comprehension of lineage-specific phenotypes, adaptation, and primate evolution, thereby improving their biomedical applications in human diseases.
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Introduction: Berberine is an isoquinoline alkaloid extracted from Berberis vulgaris, which possesses a variety of pharmacological activities. Alzheimer's disease (AD) is a complex disease with multiple pathologic factors, with cognitive decline being the main manifestation of AD. The neuroprotective effects of berberine in animal models of Alzheimer's disease (AD) have been widely reported, exhibiting protective effects against risk factors associated with AD. In this study, we summarize and evaluate the effects of berberine on cognitive function and ß-amyloid precursor protein in animal models of AD. Material and methods: Eligible studies were retrieved from PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Library databases up to 1 June 2023. Risk of bias was assessed by the Systematic Review Center for Laboratory Animal Experiments (SYRCLE). Statistical analyses were performed using STATA 14.0 and Review Manger 5.4 software to calculate weighted standardized mean difference (SMD) and 95% confidence intervals (CI), Morris water maze (MWM) test and ß-amyloid precursor protein as outcome measures. Heterogeneity was tested using the I2 test. Sensitivity analysis and publication bias were also assessed. Results: 19 studies involving 360 animals met the inclusion criteria, and the results of the meta-analysis showed that berberine decreased escape latency (SMD = -2.19, 95% CI: (-2.50, -1.88), p < 0.00001), increased the number of platform crossings (SMD = 4.27, 95% CI (3.38, 5.17), p < 0.00001), time in the target quadrant (SMD = 5.92, 95% CI (4.43, 7.41), p < 0.00001) and APP expression (SMD = 0.73, 95% CI: (0.25, 1.21), p = 0.003). Conclusion: Berberine can regulate APP expression and improve cognitive function in animal models of AD, and the mechanism may be related to the involvement of berberine in APP processing and influence the expression of its related factors. Systematic review registration: PROSPERO, CRD42023437445.
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Blood oxygen saturation (SpO2) is a key indicator of oxygen availability in the body. It is known that a low SpO2 at high altitude is associated with morbidity and mortality risks due to physiological hypoxemia. Previously, it was proposed that the lowlander immigrants living at high altitude should have a lower SpO2 level compared to the highlander natives, but this proposal has not been rigorously tested due to the lack of data from the lowlander immigrants living at high altitude. In this study, we compared arterial oxygen saturation of 5929 Tibetan natives and 1034 Han Chinese immigrants living at altitudes ranging from 1120 m to 5020 m. Unexpectedly, the Han immigrants had a higher SpO2 than the Tibetan natives at the same high altitudes. At the same time, there is a higher prevalence of chronic mountain sickness in Han than in Tibetans at the same altitude. This result suggests that the relatively higher SpO2 level of the acclimatized Han is associated with a physiological cost, and the SpO2 level of Tibetans tends to be sub-optimal. Consequently, SpO2 alone is not a robust indicator of physiological performance at high altitude. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00117-x.
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Tibetans are the ideal population to study genetic adaptation in extreme environments. Here, we performed systematic phenotyping of 11,880 highlanders, covering 133 quantitative traits of 13 organ systems. We provided a comprehensive phenotypic atlas by comparing altitude adaptation and altitude acclimatization. We found the differences between adaptation and acclimatization are quantitative rather than qualitative, with a whole-system "blunted effect" seen in the adapted Tibetans. We characterized twelve different functional changes between adaptation and acclimatization. More importantly, we established a landscape of adaptive phenotypes of indigenous Tibetans, including 45 newly identified Tibetan adaptation-nominated traits, involving specific changes of Tibetans in internal organ state, metabolism, eye morphology, and skin pigmentation. In addition, we observed a sex-biased pattern between altitude acclimatization and adaptation. The generated atlas of phenotypic landscape provides new insights into understanding of human adaptation to high-altitude environments, and it serves as a valuable blueprint for future medical and physiological studies.
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The adaptation of Tibetans to high-altitude environments has been studied extensively. However, the direct assessment of evolutionary adaptation, i.e., the reproductive fitness of Tibetans and its genetic basis, remains elusive. Here, we conduct systematic phenotyping and genome-wide association analysis of 2,252 mother-newborn pairs of indigenous Tibetans, covering 12 reproductive traits and 76 maternal physiological traits. Compared with the lowland immigrants living at high altitudes, indigenous Tibetans show better reproductive outcomes, reflected by their lower abortion rate, higher birth weight, and better fetal development. The results of genome-wide association analyses indicate a polygenic adaptation of reproduction in Tibetans, attributed to the genomic backgrounds of both the mothers and the newborns. Furthermore, the EPAS1-edited mice display higher reproductive fitness under chronic hypoxia, mirroring the situation in Tibetans. Collectively, these results shed new light on the phenotypic pattern and the genetic mechanism of human reproductive fitness in extreme environments.
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BACKGROUND: Tibetans are genetically adapted to high-altitude environments. Though many studies have been conducted, the genetic basis of the adaptation remains elusive due to the poor reproducibility for detecting selective signatures in the Tibetan genomes. RESULTS: Here, we present whole-genome sequencing (WGS) data of 1001 indigenous Tibetans, covering the major populated areas of the Qinghai-Tibetan Plateau in China. We identify 35 million variants, and more than one-third of them are novel variants. Utilizing the large-scale WGS data, we construct a comprehensive map of allele frequency and linkage disequilibrium and provide a population-specific genome reference panel, referred to as 1KTGP. Moreover, with the use of a combined approach, we redefine the signatures of Darwinian-positive selection in the Tibetan genomes, and we characterize a high-confidence list of 4320 variants and 192 genes that have undergone selection in Tibetans. In particular, we discover four new genes, TMEM132C, ATP13A3, SANBR, and KHDRBS2, with strong signals of selection, and they may account for the adaptation of cardio-pulmonary functions in Tibetans. Functional annotation and enrichment analysis indicate that the 192 genes with selective signatures are likely involved in multiple organs and physiological systems, suggesting polygenic and pleiotropic effects. CONCLUSIONS: Overall, the large-scale Tibetan WGS data and the identified adaptive variants/genes can serve as a valuable resource for future genetic and medical studies of high-altitude populations.
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Adaptação Fisiológica , Altitude , Adaptação Fisiológica/genética , Reprodutibilidade dos Testes , Seleção Genética , Humanos , Genoma HumanoAssuntos
Doença da Altitude/epidemiologia , Altitude , Policitemia/epidemiologia , Seleção Genética , Aclimatação/genética , Adulto , Doença da Altitude/sangue , Doença da Altitude/genética , Etnicidade/genética , Feminino , Hemoglobinas/análise , Humanos , Masculino , Policitemia/sangue , Policitemia/etiologia , Policitemia/genética , Prevalência , Tibet/epidemiologiaRESUMO
Systems genetics holds the promise to decipher complex traits by interpreting their associated SNPs through gene regulatory networks derived from comprehensive multi-omics data of cell types, tissues, and organs. Here, we propose SpecVar to integrate paired chromatin accessibility and gene expression data into context-specific regulatory network atlas and regulatory categories, conduct heritability enrichment analysis with genome-wide association studies (GWAS) summary statistics, identify relevant tissues, and estimate relevance correlation to depict common genetic factors acting in the shared regulatory networks between traits. Our method improves power upon existing approaches by associating SNPs with context-specific regulatory elements to assess heritability enrichments and by explicitly prioritizing gene regulations underlying relevant tissues. Ablation studies, independent data validation, and comparison experiments with existing methods on GWAS of six phenotypes show that SpecVar can improve heritability enrichment, accurately detect relevant tissues, and reveal causal regulations. Furthermore, SpecVar correlates the relevance patterns for pairs of phenotypes and better reveals shared SNP-associated regulations of phenotypes than existing methods. Studying GWAS of 206 phenotypes in UK Biobank demonstrates that SpecVar leverages the context-specific regulatory network atlas to prioritize phenotypes' relevant tissues and shared heritability for biological and therapeutic insights. SpecVar provides a powerful way to interpret SNPs via context-specific regulatory networks and is available at https://github.com/AMSSwanglab/SpecVar, copy archived at swh:1:rev:cf27438d3f8245c34c357ec5f077528e6befe829.
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Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Fenótipo , Regulação da Expressão Gênica , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Birth weight (BW) is a key determinant of infant mortality. Previous studies have reported seasonal fluctuation of BW. However, the responsible environmental factors remain disputable. High-altitude environment provides a great opportunity to test the current hypotheses due to its distinctive climate conditions. We collected BW data of ~ 9000 Tibetan singletons born at Lhasa (elevation: 3660 m) from 2014 to 2018. Using regression models, we analyzed BW seasonality of highland Tibetans. Multivariate models with meteorological factors as independent variables were employed to examine responsible environmental factors accounting for seasonal variation. We compared BW, low-BW prevalence and sex ratio between highland and lowland populations, and we observed a significant seasonal pattern of BW in Tibetans, with a peak in winter and a trough in summer. Notably, there is a marked sex-biased pattern of BW seasonality (more striking in males than in females). Sunlight exposure in the 3rd trimester and barometric pressure exposure in the 2nd trimester are significantly correlated with BW, and the latter can be explained by seasonal change of oxygen partial pressure. In particular, due to the male-biased BW seasonality, we found a more serious BW reduction and higher prevalence of low-BW in males, and a skewed sex ratio in highlanders. The infant BW of highland Tibetans has a clear pattern of seasonality. The winter BW is larger than the summer BW, due to the longer sunlight exposure during the late-trimester. Male infants are more sensitive to hypoxia than female infants during the 2nd trimester, leading to more BW reduction and higher mortality. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-021-00038-7.
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Southern East Asia is the dispersal center regarding the prehistoric settlement and migrations of modern humans in Asia-Pacific regions. However, the settlement pattern and population structure of paleolithic humans in this region remain elusive, and ancient DNA can provide direct information. Here, we sequenced the genome of a Late Pleistocene hominin (MZR), dated â¼14.0 thousand years ago from Red Deer Cave located in Southwest China, which was previously reported possessing mosaic features of modern and archaic hominins. MZR is the first Late Pleistocene genome from southern East Asia. Our results indicate that MZR is a modern human who represents an early diversified lineage in East Asia. The mtDNA of MZR belongs to an extinct basal lineage of the M9 haplogroup, reflecting a rich matrilineal diversity in southern East Asia during the Late Pleistocene. Combined with the published data, we detected clear genetic stratification in ancient southern populations of East/Southeast Asia and some degree of south-versus-north divergency during the Late Pleistocene, and MZR was identified as a southern East Asian who exhibits genetic continuity to present day populations. Markedly, MZR is linked deeply to the East Asian ancestry that contributed to First Americans.
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Cervos , Hominidae , Animais , China , Fósseis , Genoma Humano , HumanosRESUMO
Structural variants (SVs) may play important roles in human adaptation to extreme environments such as high altitude but have been under-investigated. Here, combining long-read sequencing with multiple scaffolding techniques, we assembled a high-quality Tibetan genome (ZF1), with a contig N50 length of 24.57 mega-base pairs (Mb) and a scaffold N50 length of 58.80 Mb. The ZF1 assembly filled 80 remaining N-gaps (0.25 Mb in total length) in the reference human genome (GRCh38). Markedly, we detected 17 900 SVs, among which the ZF1-specific SVs are enriched in GTPase activity that is required for activation of the hypoxic pathway. Further population analysis uncovered a 163-bp intronic deletion in the MKL1 gene showing large divergence between highland Tibetans and lowland Han Chinese. This deletion is significantly associated with lower systolic pulmonary arterial pressure, one of the key adaptive physiological traits in Tibetans. Moreover, with the use of the high-quality de novo assembly, we observed a much higher rate of genome-wide archaic hominid (Altai Neanderthal and Denisovan) shared non-reference sequences in ZF1 (1.32%-1.53%) compared to other East Asian genomes (0.70%-0.98%), reflecting a unique genomic composition of Tibetans. One such archaic hominid shared sequence-a 662-bp intronic insertion in the SCUBE2 gene-is enriched and associated with better lung function (the FEV1/FVC ratio) in Tibetans. Collectively, we generated the first high-resolution Tibetan reference genome, and the identified SVs may serve as valuable resources for future evolutionary and medical studies.
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High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.
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Aclimatação/genética , Cromatina/metabolismo , Etnicidade/genética , Redes Reguladoras de Genes , Modelos Genéticos , Altitude , Doença da Altitude/etnologia , Doença da Altitude/genética , Doença da Altitude/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia Celular/genética , Células Cultivadas , Cromatina/genética , Sequenciamento de Cromatina por Imunoprecipitação , Resistência à Doença/genética , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Oxigênio/metabolismo , Polimorfismo de Nucleotídeo Único , Gravidez , Cultura Primária de Células , RNA-Seq , Elementos Reguladores de Transcrição/genética , Seleção Genética , Tibet/etnologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do GenomaRESUMO
We present a high-quality de novo genome assembly (rheMacS) of the Chinese rhesus macaque (Macaca mulatta) using long-read sequencing and multiplatform scaffolding approaches. Compared to the current Indian rhesus macaque reference genome (rheMac8), rheMacS increases sequence contiguity 75-fold, closing 21,940 of the remaining assembly gaps (60.8 Mbp). We improve gene annotation by generating more than two million full-length transcripts from ten different tissues by long-read RNA sequencing. We sequence resolve 53,916 structural variants (96% novel) and identify 17,000 ape-specific structural variants (ASSVs) based on comparison to ape genomes. Many ASSVs map within ChIP-seq predicted enhancer regions where apes and macaque show diverged enhancer activity and gene expression. We further characterize a subset that may contribute to ape- or great-ape-specific phenotypic traits, including taillessness, brain volume expansion, improved manual dexterity, and large body size. The rheMacS genome assembly serves as an ideal reference for future biomedical and evolutionary studies.
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Genoma , Hominidae/genética , Macaca mulatta/genética , Animais , China , Evolução Molecular , Hominidae/classificação , Humanos , Macaca mulatta/classificação , Masculino , Anotação de Sequência Molecular , Fenótipo , Análise de Sequência de RNA , Especificidade da EspécieRESUMO
CRISPR-Cas9 is a widely-used genome editing tool, but its off-target effect and on-target complex mutations remain a concern, especially in view of future clinical applications. Non-human primates (NHPs) share close genetic and physiological similarities with humans, making them an ideal preclinical model for developing Cas9-based therapies. However, to our knowledge no comprehensive in vivo off-target and on-target assessment has been conducted in NHPs. Here, we perform whole genome trio sequencing of Cas9-treated rhesus monkeys. We only find a small number of de novo mutations that can be explained by expected spontaneous mutations, and no unexpected off-target mutations (OTMs) were detected. Furthermore, the long-read sequencing data does not detect large structural variants in the target region.