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BACKGROUND: In the last decade, universally available antiretroviral therapy (ART) has led to greatly improved health and survival of people living with HIV in sub-Saharan Africa, but new infections continue to appear. The design of effective prevention strategies requires the demographic characterisation of individuals acting as sources of infection, which is the aim of this study. METHODS: Between 2014 and 2018, the HPTN 071 PopART study was conducted to quantify the public health benefits of ART. Viral samples from 7124 study participants in Zambia were deep-sequenced as part of HPTN 071-02 PopART Phylogenetics, an ancillary study. We used these sequences to identify likely transmission pairs. After demographic weighting of the recipients in these pairs to match the overall HIV-positive population, we analysed the demographic characteristics of the sources to better understand transmission in the general population. FINDINGS: We identified a total of 300 likely transmission pairs. 178 (59·4%) were male to female, with 130 (95% CI 110-150; 43·3%) from males aged 25-40 years. Overall, men transmitted 2·09-fold (2·06-2·29) more infections per capita than women, a ratio peaking at 5·87 (2·78-15·8) in the 35-39 years source age group. 40 (26-57; 13·2%) transmissions linked individuals from different communities in the trial. Of 288 sources with recorded information on drug resistance mutations, 52 (38-69; 18·1%) carried viruses resistant to first-line ART. INTERPRETATION: HIV-1 transmission in the HPTN 071 study communities comes from a wide range of age and sex groups, and there is no outsized contribution to new infections from importation or drug resistance mutations. Men aged 25-39 years, underserved by current treatment and prevention services, should be prioritised for HIV testing and ART. FUNDING: National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health.
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Infecciones por VIH , Seropositividad para VIH , VIH-1 , Adulto , Femenino , Humanos , Masculino , Demografía , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , VIH-1/genética , Epidemiología Molecular , Estados Unidos , Zambia/epidemiologíaRESUMEN
Human-specific insertions play important roles in human phenotypes and diseases. Here we reported a 446-bp insertion (Insert-446) in intron 11 of the TBC1D8B gene, located on chromosome X, and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5. Interestingly, Insert-446 was present in the human Neanderthal and Denisovans genomes, and was fixed in humans after human-chimpanzee divergence. We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques. In addition, over-expression TBC1D8B promoted cell proliferation and migration through "a dual finger" catalytic mechanism (Arg538 and Gln573) in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo. Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells. Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene. These findings provide a significant insight into the effects of human-specific insertions on evolution.
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Regulación Neoplásica de la Expresión Génica , Humanos , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , IntronesRESUMEN
Coexistence and cooperation between dogs and humans over thousands of years have supported convergent evolutionary processes in the two species. Previous studies found that Eurasian dogs evolved into a distinct geographic cluster. In this study, we used the genomes of 242 European dogs, 38 Southeast Asian indigenous (SEAI) dogs, and 41 gray wolves to identify adaptation of European dogs . We report 86 unique positively selected genes in European dogs, among which is LCT (lactase). LCT encodes lactase, which is fundamental for the digestion of lactose. We found that an A-to-G mutation (chr19:38,609,592) is almost fixed in Middle Eastern and European dogs. The results of two-dimensional site frequency spectrum (2D SFS) support that the mutation is under soft sweep . We inferred that the onset of positive selection of the mutation is shorter than 6,535 years and behind the well-developed dairy economy in central Europe. It increases the expression of LCT by reducing its binding with ZEB1, which would enhance dog's ability to digest milk-based diets. Our study uncovers the genetic basis of convergent evolution between humans and dogs with respect to diet, emphasizing the import of the dog as a biomedical model for studying mechanisms of the digestive system.
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Lactasa , Selección Genética , Animales , Perros , Frecuencia de los Genes , Humanos , Lactasa/genética , Lactasa/metabolismo , Lactosa/metabolismo , Polimorfismo de Nucleótido Simple , Población BlancaRESUMEN
Domestication of the helmeted guinea fowl (HGF; Numida meleagris) in Africa remains elusive. Here we report a high-quality de novo genome assembly for domestic HGF generated by long- and short-reads sequencing together with optical and chromatin interaction mapping. Using this assembly as the reference, we performed population genomic analyses for newly sequenced whole-genomes for 129 birds from Africa, Asia, and Europe, including domestic animals (n = 89), wild progenitors (n = 34), and their closely related wild species (n = 6). Our results reveal domestication of HGF in West Africa around 1,300-5,500 years ago. Scanning for selective signals characterized the functional genes in behavior and locomotion changes involved in domestication of HGF. The pleiotropy and linkage in genes affecting plumage color and fertility were revealed in the recent breeding of Italian domestic HGF. In addition to presenting a missing piece to the jigsaw puzzle of domestication in poultry, our study provides valuable genetic resources for researchers and breeders to improve production in this species.
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Domesticación , Galliformes/genética , Genoma , Filogenia , Animales , Variación Genética , Masculino , Filogeografía , Selección GenéticaRESUMEN
Extensive global sampling and sequencing of the pandemic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have enabled researchers to monitor its spread and to identify concerning new variants. Two important determinants of variant spread are how frequently they arise within individuals and how likely they are to be transmitted. To characterize within-host diversity and transmission, we deep-sequenced 1313 clinical samples from the United Kingdom. SARS-CoV-2 infections are characterized by low levels of within-host diversity when viral loads are high and by a narrow bottleneck at transmission. Most variants are either lost or occasionally fixed at the point of transmission, with minimal persistence of shared diversity, patterns that are readily observable on the phylogenetic tree. Our results suggest that transmission-enhancing and/or immune-escape SARS-CoV-2 variants are likely to arise infrequently but could spread rapidly if successfully transmitted.
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COVID-19/transmisión , COVID-19/virología , Variación Genética , SARS-CoV-2/genética , COVID-19/inmunología , Coinfección/virología , Infecciones por Coronavirus/virología , Coronavirus Humano OC43 , Composición Familiar , Genoma Viral , Humanos , Evasión Inmune , Mutación , Filogenia , ARN Viral/genética , RNA-Seq , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiología , Selección Genética , Glicoproteína de la Espiga del Coronavirus/genética , Reino Unido , Carga ViralRESUMEN
Piao chicken, a rare Chinese native poultry breed, lacks primary tail structures, such as pygostyle, caudal vertebra, uropygial gland, and tail feathers. So far, the molecular mechanisms underlying tail absence in this breed remain unclear. In this study, we comprehensively employed comparative transcriptomic and genomic analyses to unravel potential genetic underpinnings of rumplessness in Piao chicken. Our results reveal many biological factors involved in tail development and several genomic regions under strong positive selection in this breed. These regions contain candidate genes associated with rumplessness, including Irx4, Il18, Hspb2, and Cryab. Retrieval of quantitative trait loci (QTL) and gene functions implies that rumplessness might be consciously or unconsciously selected along with the high-yield traits in Piao chicken. We hypothesize that strong selection pressures on regulatory elements might lead to changes in gene activity in mesenchymal stem cells of the tail bud. The ectopic activity could eventually result in tail truncation by impeding differentiation and proliferation of the stem cells. Our study provides fundamental insights into early initiation and genetic basis of the rumpless phenotype in Piao chicken.
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Pollos , Transcriptoma , Animales , Pollos/genética , Genómica/métodos , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter CuantitativoRESUMEN
Hunting wild African harlequin quails (Coturnix delegorguei delegorguei) using traditional methods in Western Kenya has been ongoing for generations, yet their genetic diversity and evolutionary history are largely unknown. In this study, the genetic variation and demographic history of wild African harlequin quails were assessed using a 347bp mitochondrial DNA (mtDNA) control region fragment and 119,339 single nucleotide polymorphisms (SNPs) from genotyping-by-sequencing (GBS) data. Genetic diversity analyses revealed that the genetic variation in wild African harlequin quails was predominantly among individuals than populations. Demographic analyses indicated a signal of rapid demographic expansion, and the estimated time since population expansion was found to be 150,000-350,000 years ago, corresponding to around the Pliocene-Pleistocene boundary. A gradual decline in their effective population size was also observed, which raised concerns about their conservation status. These results provide the first account of the genetic diversity of wild African harlequin quails of Siaya, thereby creating a helpful foundation in their biodiversity conservation.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Despite the substantial role that chickens have played in human societies across the world, both the geographic and temporal origins of their domestication remain controversial. To address this issue, we analyzed 863 genomes from a worldwide sampling of chickens and representatives of all four species of wild jungle fowl and each of the five subspecies of red jungle fowl (RJF). Our study suggests that domestic chickens were initially derived from the RJF subspecies Gallus gallus spadiceus whose present-day distribution is predominantly in southwestern China, northern Thailand and Myanmar. Following their domestication, chickens were translocated across Southeast and South Asia where they interbred locally with both RJF subspecies and other jungle fowl species. In addition, our results show that the White Leghorn chicken breed possesses a mosaic of divergent ancestries inherited from other subspecies of RJF. Despite the strong episodic gene flow from geographically divergent lineages of jungle fowls, our analyses show that domestic chickens undergo genetic adaptations that underlie their unique behavioral, morphological and reproductive traits. Our study provides novel insights into the evolutionary history of domestic chickens and a valuable resource to facilitate ongoing genetic and functional investigations of the world's most numerous domestic animal.
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Pollos/genética , Genoma , Filogenia , Distribución Animal , Animales , Animales Domésticos/genética , Asia , Domesticación , Pool de Genes , Geografía , Funciones de Verosimilitud , Aves de Corral/genética , Selección GenéticaRESUMEN
Genetic introgression not only provides material for adaptive evolution but also confounds our understanding of evolutionary history. This is particularly true for canids, a species complex in which genome sequencing and analysis has revealed a complex history of admixture and introgression. Here, we sequence 19 new whole genomes from high-altitude Tibetan and Himalayan wolves and dogs and combine these into a larger data set of 166 whole canid genomes. Using these data, we explore the evolutionary history and adaptation of these and other canid lineages. We find that Tibetan and Himalayan wolves are closely related to each other, and that â¼39% of their nuclear genome is derived from an as-yet-unrecognized wolf-like lineage that is deeply diverged from living Holarctic wolves and dogs. The EPAS1 haplotype, which is present at high frequencies in Tibetan dog breeds and wolves and confers an adaptive advantage to animals living at high altitudes, was probably derived from this ancient lineage. Our study underscores the complexity of canid evolution and demonstrates how admixture and introgression can shape the evolutionary trajectories of species.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Evolución Biológica , Perros/genética , Hibridación Genética , Lobos/genética , Animales , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: Yellow-feathered chickens (YFCs) have a long history in China. They are well-known for the nutritional and commercial importance attributable to their yellow color phenotype. Currently, there is a huge paucity in knowledge of the genetic determinants responsible for phenotypic and biochemical properties of these iconic chickens. This study aimed to uncover the genetic structure and the molecular underpinnings of the YFCs trademark coloration. RESULTS: The whole-genomes of 100 YFCs from 10 major traditional breeds and 10 Huaibei partridge chickens from China were re-sequenced. Comparative population genomics based on autosomal single nucleotide polymorphisms (SNPs) revealed three geographically based clusters among the YFCs. Compared to other Chinese indigenous chicken genomes incorporated from previous studies, a closer genetic proximity within YFC breeds than between YFC breeds and other chicken populations is evident. Through genome-wide scans for selective sweeps, we identified RALY heterogeneous nuclear ribonucleoprotein (RALY), leucine rich repeat containing G protein-coupled receptor 4 (LGR4), solute carrier family 23 member 2 (SLC23A2), and solute carrier family 2 member 14 (SLC2A14), besides the classical beta-carotene dioxygenase 2 (BCDO2), as major candidates pigment determining genes in the YFCs. CONCLUSION: We provide the first comprehensive genomic data of the YFCs. Our analyses show phylogeographical patterns among the YFCs and potential candidate genes giving rise to the yellow color trait of the YFCs. This study lays the foundation for further research on the genome-phenotype cross-talks that define important poultry traits and for formulating genetic breeding and conservation strategies for the YFCs.
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Proteínas Aviares/genética , Pollos/genética , Plumas/metabolismo , Estudio de Asociación del Genoma Completo/métodos , Pigmentación/genética , Selección Genética , Animales , Cruzamiento , Pollos/clasificación , China , Color , Dioxigenasas/genética , Genómica/métodos , Ribonucleoproteína Heterogénea-Nuclear Grupo C/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Transportadores de Sodio Acoplados a la Vitamina C/genéticaRESUMEN
Dingoes are wild canids living in Australia, originating from domestic dogs. They have lived isolated from both the wild and the domestic ancestor, making them a unique model for studying feralization. Here, we sequence the genomes of 10 dingoes and 2 New Guinea Singing Dogs. Phylogenetic and demographic analyses show that dingoes originate from dogs in southern East Asia, which migrated via Island Southeast Asia to reach Australia around 8300 years ago, and subsequently diverged into a genetically distinct population. Selection analysis identifies 50 positively selected genes enriched in digestion and metabolism, indicating a diet change during feralization of dingoes. Thirteen of these genes have shifted allele frequencies compared to dogs but not compared to wolves. Functional assays show that an A-to-G mutation in ARHGEF7 decreases the endogenous expression, suggesting behavioral adaptations related to the transitions in environment. Our results indicate that the feralization of the dingo induced positive selection on genomic regions correlated to neurodevelopment, metabolism and reproduction, in adaptation to a wild environment.
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Canidae/clasificación , Canidae/genética , Genómica , Filogenia , Migración Animal , Animales , Asia Sudoriental , Australia , ADN Mitocondrial/análisis , Perros/clasificación , Perros/genética , Variación Genética , Genética de Población , Genoma Mitocondrial , Nueva Guinea , Polimorfismo de Nucleótido Simple , Factores de Intercambio de Guanina Nucleótido Rho/genética , Lobos/clasificación , Lobos/genéticaRESUMEN
Indigenous chickens at the Swahili coast and other traditional migratory corridors in Kenya represent important populations that are inconclusively characterized. Using a comprehensive dataset of Kenyan indigenous chickens and additional mined data of chickens from 8 African and 5 Asian countries, we performed univariate and multivariate assessments to uncover the underlying phenotypic and morphometric variability. Kenyan indigenous chickens expressed differentiation of several qualitative and quantitative traits, both among different counties in the Swahili coast, and among coastal, western, and northern migratory corridors. There was a substantial population stratification of these chickens, particularly distinctive clustering of chickens from Marsabit, Lamu, and Kilifi counties. The pooled dataset further clarified a closer phenotypic and morphometric proximity of chickens within different geographical regions. We additionally revealed a preponderance of bantam and rumpless traits to hot and humid locales, and feathered shanks to cooler regions. Currently, most chicken breeding programs in developing countries rely on phenotypic and morphometric properties. Hence, the high chicken diversity and population stratification observed in our study, possibly shaped by natural and artificial selective pressures, reveal opportunities for complementary phenotypic and genotypic assessments to identify resources for effective breed improvement and conservation strategies of indigenous chickens in the tropics.
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Pollos/anatomía & histología , Pollos/clasificación , Animales , Pollos/genética , Femenino , Kenia , Masculino , Fenotipo , Clima TropicalRESUMEN
RNA editing is one of the most common RNA level modifications that potentially generate amino acid changes similar to those resulting from genomic nonsynonymous mutations. However, unlike DNA level allele-specific modifications such as DNA methylation, it is currently unknown whether RNA editing displays allele-specificity across tissues and species. Here, we analyzed allele-specific RNA editing in human tissues and from brain tissues of heterozygous mice generated by crosses between divergent mouse strains and found a high proportion of overlap of allele-specific RNA editing sites between different samples. We identified three allele-specific RNA editing sites cause amino acid changes in coding regions of human and mouse genes, whereas their associated SNPs yielded synonymous differences. In vitro cellular experiments confirmed that sequences differing at a synonymous SNP can have differences in a linked allele-specific RNA editing site with nonsynonymous implications. Further, we demonstrate that allele-specific RNA editing is influenced by differences in local RNA secondary structure generated by SNPs. Our study provides new insights towards a better comprehension of the molecular mechanism that link SNPs with human diseases and traits.
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Estudio de Asociación del Genoma Completo , Ratones/genética , Edición de ARN , Alelos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Secuencia de Bases , Química Encefálica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Cruzamientos Genéticos , ADN de Neoplasias/genética , Humanos , Conformación de Ácido Nucleico , Especificidad de Órganos , Polimorfismo de Nucleótido Simple , Precursores del ARN/genética , ARN Neoplásico/genética , Análisis de Secuencia de ARN , Especificidad de la Especie , TranscriptomaRESUMEN
RT-qPCR offers high sensitivity, for accurate interpretations of qPCR results however, normalisation using suitable reference genes is fundamental. Androgens can regulate transcriptional expression including reference gene expression in prostate cancer. In this study, we evaluated ten mRNA and six non-protein coding RNA reference genes in five prostate cell lines under varied dihydrotestosterone (DHT) treatments. We validated the effects of DHT-treatments using media containing charcoal-stripped serum prior to DHT stimulation on the test samples by Western blot experiments. Reference gene expression stability was analysed using three programs (geNorm, NormFinder and BestKeeper), and the recommended comprehensive ranking is provided. Our results reveal that ACTB and GAPDH, and miR-16 and miR-1228-3p are the most suitable mRNA and miRNA reference genes across all cell lines, respectively. Considering prostate cancer cell types, ACTB/GAPDH and ACTB/HPRT1 are the most suitable reference gene combinations for mRNA analysis, and miR-16/miR-1228-3p and RNU6-2/RNU43 for miRNA analysis in AR+, and AR- and normal cell lines, respectively. Comparison of relative target gene (PCA3 and miR-141) expression reveals different patterns depending on reference genes used for normalisation. To our knowledge, this is the first report on validation of reference genes under different DHT treatments in prostate cancer cells. This study provides insights for discovery of reliable DHT-regulated genes in prostate cells.
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MicroARNs/genética , Neoplasias de la Próstata/genética , ARN Mensajero/genética , Algoritmos , Línea Celular Tumoral , Dihidrotestosterona/farmacología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , MicroARNs/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Androgénicos/metabolismo , Estándares de Referencia , Reproducibilidad de los Resultados , Programas InformáticosRESUMEN
Mitochondrial abnormality is frequently reported in individuals with hepatitis B virus (HBV) infection, but the associated hosts' mitochondrial genetic factors remain obscure. We hypothesized that mitochondria may affect host susceptibility to HBV infection. In this study, we aimed to detect the association between chronic HBV infection and mitochondrial DNA in Chinese from Yunnan, Southwest China. A total of 272 individuals with chronic HBV infection (CHB), 310 who had never been infected by HBV (healthy controls, HC) and 278 with a trace of HBV infection (spontaneously recovered, SR) were analysed for mtDNA sequence variations and classified into respective haplogroups. Haplogroup frequencies were compared between HBV infected patients, HCs and SRs. Haplogroup D5 presented a higher frequency in CHBs than in HCs (P = 0.017, OR = 2.87, 95% confidence interval [CI] = (1.21-6.81)) and SRs (P = 0.049, OR = 2.90, 95% CI = 1.01-8.35). The network of haplogroup D5 revealed a distinct distribution pattern between CHBs and non-CHBs. A trend of higher viral load among CHBs with haplogroup D5 was observed. Our results indicate the risk potential of mtDNA haplogroup D5 in chronic HBV infection in Yunnan, China.
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ADN Mitocondrial , Haplotipos , Virus de la Hepatitis B , Hepatitis B Crónica/genética , Hepatitis B Crónica/virología , Adulto , Biomarcadores , Estudios de Casos y Controles , China , Femenino , Hepatitis B Crónica/metabolismo , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Carga ViralRESUMEN
The geographic origin and migration of the brown rat (Rattus norvegicus) remain subjects of considerable debate. In this study, we sequenced whole genomes of 110 wild brown rats with a diverse world-wide representation. We reveal that brown rats migrated out of southern East Asia, rather than northern Asia as formerly suggested, into the Middle East and then to Europe and Africa, thousands of years ago. Comparison of genomes from different geographical populations reveals that many genes involved in the immune system experienced positive selection in the wild brown rat.
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Filogeografía/métodos , Ratas/genética , África , Animales , Asia Sudoriental/epidemiología , Evolución Biológica , Europa (Continente) , Evolución Molecular , Variación Genética/genética , Genética de Población , Genoma/genética , Medio Oriente , Filogenia , Secuenciación Completa del Genoma/métodosRESUMEN
Natural selection in domestic dogs is of great interest in evolutionary biology since dogs have migrated to every inhabited continent of the world alongside humans, and adapted to diverse environments. Here, we explored their demographic history and genetic basis of adaptation to the tropical African environment using whole genome analyses of 19 African indigenous dogs from Nigeria. Demographic analysis suggests that the ancestors of these dogs migrated into Africa from Eurasia 14,000 years ago and underwent a severe founder effect before population expansion. Admixture analysis further reveals that African dog genomes contain about 1.88-3.50% introgression from African golden wolves (Canis anthus). Population genetic analysis identifies 50 positively selected genes linked with immunity, angiogenesis, ultraviolet protection, as well as insulin secretion and sensitivity that may contribute to adaptation to tropical conditions. One of the positively selected genes, adhesion G protein-coupled receptor E1 (ADGRE1), has also been found to be association with severe malaria resistance in African human populations. Functional assessments showed that ADGRE1 provides protective host defense against Plasmodium infections. This result, together with the fact that the inflammatory response to canine babesiosis is similar to complicated falciparum malaria in humans, support the dogs as a model for the study of malaria control and treatment.