257 research outputs found

    Inferring human evolutionary history

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    Genomes are invaluable tools for inferring the demographic and adaptive history of human populations, including migrations, population splits, admixture, and genetic adaptations. Growing datasets of modern and ancient genomes make this possible, but their massive size comes with important challenges, demanding techniques that analyze immense amounts of data in reasonable amounts of time while using as much information as possible. Combining genomes from different datasets poses perhaps an even greater challenge, especially when it comes to integrating ancient and modern genomes. On page 836 of this issue, Wohns et al. (1) report surmounting some of these challenges to construct the largest human genealogy to date, integrating modern and ancient genomes from multiple datasets to infer key events in human history together with their timings and geographical locations

    Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors

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    Pathogens and the diseases they cause have been among the most important selective forces experienced by humans during their evolutionary history. Although adaptive alleles generally arise by mutation, introgression can also be a valuable source of beneficial alleles. Archaic humans, who lived in Europe and Western Asia for more than 200,000 years, were probably well adapted to this environment and its local pathogens. It is therefore conceivable that modern humans entering Europe and Western Asia who admixed with them obtained a substantial immune advantage from the introgression of archaic alleles. Here we document a cluster of three Toll-like receptors (TLR6-TLR1-TLR10) in modern humans that carries three distinct archaic haplotypes, indicating repeated introgression from archaic humans. Two of these haplotypes are most similar to the Neandertal genome, and the third haplotype is most similar to the Denisovan genome. The Toll-like receptors are key components of innate immunity and provide an important first line of immune defense against bacteria, fungi, and parasites. The unusually high allele frequencies and unexpected levels of population differentiation indicate that there has been local positive selection on multiple haplotypes at this locus. We show that the introgressed alleles have clear functional effects in modern humans; archaic-like alleles underlie differences in the expression of the TLR genes and are associated with Increased microbial resistance and increased allergic disease in large cohorts. This provides strong evidence for recurrent adaptive introgression at the TLR6-TLR1-TLR10 locus, resulting in differences in disease phenotypes in modern humans

    Identification of Structural Variation in Chimpanzees Using Optical Mapping and Nanopore Sequencing.

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    Recent efforts to comprehensively characterize great ape genetic diversity using short-read sequencing and single-nucleotide variants have led to important discoveries related to selection within species, demographic history, and lineage-specific traits. Structural variants (SVs), including deletions and inversions, comprise a larger proportion of genetic differences between and within species, making them an important yet understudied source of trait divergence. Here, we used a combination of long-read and -range sequencing approaches to characterize the structural variant landscape of two additional Pan troglodytes verus individuals, one of whom carries 13% admixture from Pan troglodytes troglodytes. We performed optical mapping of both individuals followed by nanopore sequencing of one individual. Filtering for larger variants (>10 kbp) and combined with genotyping of SVs using short-read data from the Great Ape Genome Project, we identified 425 deletions and 59 inversions, of which 88 and 36, respectively, were novel. Compared with gene expression in humans, we found a significant enrichment of chimpanzee genes with differential expression in lymphoblastoid cell lines and induced pluripotent stem cells, both within deletions and near inversion breakpoints. We examined chromatin-conformation maps from human and chimpanzee using these same cell types and observed alterations in genomic interactions at SV breakpoints. Finally, we focused on 56 genes impacted by SVs in >90% of chimpanzees and absent in humans and gorillas, which may contribute to chimpanzee-specific features. Sequencing a greater set of individuals from diverse subspecies will be critical to establish the complete landscape of genetic variation in chimpanzees

    Genetic adaptations to SIV across chimpanzee populations

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    Central and eastern chimpanzees are infected with Simian Immunodeficiency Virus (SIV) in the wild, typically without developing acute immunodeficiency. Yet the recent zoonotic transmission of chimpanzee SIV to humans, which were naïve to the virus, gave rise to the Human Immunodeficiency Virus (HIV), which causes AIDS and is responsible for one of the deadliest pandemics in human history. Chimpanzees have been infected with SIV for tens of thousands of years and have likely evolved to reduce its pathogenicity, becoming semi-natural hosts that largely tolerate the virus. In support of this view, central and eastern chimpanzees show evidence of positive selection in genes involved in SIV/HIV cell entry and immune response to SIV, respectively. We hypothesise that the population first infected by SIV would have experienced the strongest selective pressure to control the lethal potential of zoonotic SIV, and that population genetics will reveal those first critical adaptations. With that aim we used population genomics to investigate signatures of positive selection in the common ancestor of central-eastern chimpanzees. The genes with signatures of positive selection in the ancestral population are significantly enriched in SIV-related genes, especially those involved in the immune response to SIV and those encoding for host genes that physically interact with SIV/HIV (VIPs). This supports a scenario where SIV first infected the central-eastern ancestor and where this population was under strong pressure to adapt to zoonotic SIV. Interestingly, integrating these genes with candidates of positive selection in the two infected subspecies reveals novel patterns of adaptation to SIV. Specifically, we observe evidence of positive selection in numerous steps of the biological pathway responsible for T-helper cell differentiation, including CD4 and multiple genes that SIV/HIV use to infect and control host cells. This pathway is active only in CD4+ cells which SIV/HIV infects, and it plays a crucial role in shaping the immune response so it can efficiently control the virus. Our results confirm the importance of SIV as a selective factor, identify specific genetic changes that may have allowed our closest living relatives to reduce SIV's pathogenicity, and demonstrate the potential of population genomics to reveal the evolutionary mechanisms used by naïve hosts to reduce the pathogenicity of zoonotic pathogens

    Inferring Balancing Selection From Genome-Scale Data

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    The identification of genomic regions and genes that have evolved under natural selection is a fundamental objective in the field of evolutionary genetics. While various approaches have been established for the detection of targets of positive selection, methods for identifying targets of balancing selection, a form of natural selection that preserves genetic and phenotypic diversity within populations, have yet to be fully developed. Despite this, balancing selection is increasingly acknowledged as a significant driver of diversity within populations, and the identification of its signatures in genomes is essential for understanding its role in evolution. In recent years, a plethora of sophisticated methods has been developed for the detection of patterns of linked variation produced by balancing selection, such as high levels of polymorphism, altered allele-frequency distributions, and polymorphism sharing across divergent populations. In this review, we provide a comprehensive overview of classical and contemporary methods, offer guidance on the choice of appropriate methods, and discuss the importance of avoiding artifacts and of considering alternative evolutionary processes. The increasing availability of genome-scale datasets holds the potential to assist in the identification of new targets and the quantification of the prevalence of balancing selection, thus enhancing our understanding of its role in natural populations

    Identificació electrònica animal

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    Treball presentat a l'assignatura de Deontologia i Veterinària Legal (21223

    The LRRC8-mediated volume-regulated anion channel is altered in glaucoma

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    LRRC8; Anion channel; GlaucomaLRRC8; Canal Aniònic; GlaucomaLRRC8; Canal Aniónico; GlaucomaRegulation of cellular volume is an essential process to balance volume changes during cell proliferation and migration or when intracellular osmolality increases due to transepithelial transport. We previously characterized the key role of volume-regulated anion channels (VRAC) in the modulation of the volume of trabecular meshwork (TM) cells and, in turn, the aqueous humour (AH) outflow from the eye. The balance between the secretion and the drainage of AH determines the intraocular pressure (IOP) that is the major casual risk factor for glaucoma. Glaucoma is an ocular disease that causes irreversible blindness due to the degeneration of retinal ganglion cells. The recent identification of Leucine-Rich Repeat-Containing 8 (LRRC8A-E) proteins as the molecular components of VRAC opens the field to elucidate their function in the physiology of TM and glaucoma. Human TM cells derived from non-glaucomatous donors and from open-angle glaucoma patients were used to determine the expression and the functional activity of LRRC8-mediated channels. Expression levels of LRRC8A-E subunits were decreased in HTM glaucomatous cells compared to normotensive HTM cells. Consequently, the activity of VRAC currents and volume regulation of TM cells were significantly affected. Impaired cell volume regulation will likely contribute to altered aqueous outflow and intraocular pressure

    Adaptation and psychometric validation of Diabetes Health Profile (DHP-18) in patients with type 2 diabetes in Quito, Ecuador: a cross-sectional study

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    Diabetes mellitus; Ecuador; FiabilidadDiabetis mellitus; Equador; FiabilitatDiabetes mellitus; Ecuador; ReliabilityIntroduction The Diabetes Health Profile (DHP‐18), structured in three dimensions (psychological distress (PD), barriers to activity (BA) and disinhibited eating (DE)), assesses the psychological and behavioural burden of living with type 2 diabetes. The objectives were to adapt the DHP‐18 linguistically and culturally for use with patients with type 2 DM in Ecuador, and to evaluate its psychometric properties. Methods Participants were recruited using purposive sampling through patient clubs at primary health centres in Quito, Ecuador. The DHP-18 validation consisted in the linguistic validation made by two Ecuadorian doctors and eight patient interviews. And in the psychometric validation, where participants provided clinical and sociodemographic data and responded to the SF-12v2 health survey and the linguistically and culturally adapted version of the DHP-18. The original measurement model was evaluated with confirmatory factor analysis (CFA). Reliability was assessed through internal consistency using Cronbach’s alpha and test–retest reproducibility by administering DHP-18 in a random subgroup of the participants two weeks after (n = 75) using intraclass correlation coefficient (ICC). Convergent validity was assessed by establishing previous hypotheses of the expected correlations with the SF12v2 using Spearman’s coefficient. Results Firstly, the DHP-18 was linguistically and culturally adapted. Secondly, in the psychometric validation, we included 146 participants, 58.2% female, the mean age was 56.8 and 31% had diabetes complications. The CFA indicated a good fit to the original three factor model (χ2 (132) = 162.738, p  −0.40 in two of three hypotheses). Conclusions The original three factor model showed good fit to the data. Although reliability parameters were adequate for PD and DE dimensions, the BA presented lower internal consistency and future analysis should verify the applicability and cultural equivalence of some of the items of this dimension to Ecuador.This research was funded by a H2020 European Research Council 2018 Starting Grant, Grant Number 804761—CEAD

    Diseño de un modelo de negocio que permita crear una ventaja competitiva para la empresa de cambio y calidad organizacional Ecco Consulting SAS

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    84 Páginas.Aunque el diseño y puesta en marcha de modelos de negocio no es una actividad estratégica nueva, tampoco en el pasado se le prestaba la atención necesaria. Esto se debe particularmente a que los cambios introducidos en las organizaciones tenían más relación con el diseño de nuevos productos o servicios. Por otro lado, los cambios a nivel administrativo, técnico y tecnológico que se dieron en el siglo XX generaron las condiciones para la construcción de un mercado caracterizado por la competitividad, la globalización y la innovación. Por lo anterior, las empresas actuales sin importar el tamaño o el objeto social de las mismas, han debido adaptarse al cambio permanente de acuerdo a las exigencias del mercado, a través de múltiples estrategias basadas en el marketing, los planes de negocios, el rediseño de estructuras organizacionales y la innovación en la oferta de productos y servicios. Para todo esto, el direccionamiento estratégico juega un papel significativo y esencial, pues las organizaciones requieren un sistema estratégico flexible que se enfoque en aquellos aspectos que le permitan construir una ventaja competitiva. En este orden de ideas, cualquier organización debe partir de una serie de cuestionamientos: ¿Cuál es nuestro negocio? ¿Cuál es nuestra misión? ¿A dónde queremos llegar como empresa

    Nomenclatura de sustancias inorgánicas y la vida: un nexo necesario/Nomenclature of inorganic substances and life: a necessary nexus

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    El artículo tiene como objetivo revelar la unidad del lenguaje químico, como contenido del proceso de enseñanza-aprendizaje de la Química y en particular de la nomenclatura de las sustancias inorgánicas,  con la vida, el medio social y el trabajo, en función de lograr aprendizajes que satisfagan las necesidades sociales. Está investigación parte de los resultados del diagnóstico a 94 estudiantes del décimo grado de la Escuela Militar “Camilo Cienfuegos” en Ciego de Ávila. Se emplearon como métodos investigativos: el analítico-sintético, el inductivo-deductivo, el histórico-lógico y el análisis de documentos. Como resultado se proponen actividades experimentales y ejercicios variados dirigidos a sistematizar la nomenclatura química en vínculo con la vida
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