Mostrando recursos 1 - 20 de 452

  1. Deciphering genetic associations using genome-wide epigenomics approaches

    Wang, Xinchen, Ph. D. Massachusetts Institute of Technology
    Genetic mapping of the drivers of complex human phenotypes and disease through the genome-wide association study (GWAS) has identified thousands of causal genetic loci in the human population. However, genetic mapping approaches can often only reveal a particular causal locus, not the molecular mechanism through which it acts. Biological interpretation of these genetic results is thus a bottleneck for turning results from GWAS into meaningful biological insights for human biology. Genetic mapping of complex human traits has revealed that most common variants influencing human phenotypes have weak effect sizes and reside outside protein-coding regions, complicating biological interpretation of their function....

  2. Plasmodium malariae and P. ovale genomes provide insights into malaria parasite evolution

    Rutledge, Gavin G; Böhme, Ulrike; Sanders, Mandy; Reid, Adam J; Cotton, James A; Maiga-Ascofare, Oumou; Djimdé, Abdoulaye A; Apinjoh, Tobias O; Amenga-Etego, Lucas; Manske, Magnus; Barnwell, John W; Renaud, François; Ollomo, Benjamin; Prugnolle, Franck; Anstey, Nicholas M; Auburn, Sarah; Price, Ric N; McCarthy, James S; Kwiatkowski, Dominic P; Newbold, Chris I; Berriman, Matthew; Otto, Thomas D
    Elucidation of the evolutionary history and interrelatedness of Plasmodium species that infect humans has been hampered by a lack of genetic information for three human-infective species: P. malariae and two P. ovale species (P. o. curtisi and P. o. wallikeri). These species are prevalent across most regions in which malaria is endemic and are often undetectable by light microscopy, rendering their study in human populations difficult. The exact evolutionary relationship of these species to the other human-infective species has been contested. Using a new reference genome for P. malariae and a manually curated draft P. o. curtisi genome, we are...

  3. Systematic dissection of genomic features determining transcription factor binding and enhancer function

    Zhang, Xiaolan; Wang, Li; Melnikov, Alexandre; Rogov, Peter; Tewhey, Ryan; Isakova, Alina; Deplancke, Bart; Bernstein, Bradley E.; Mikkelsen, Tarjei S.; Grossman, Sharon Rachel; Engreitz, Jesse Michael; Lander, Eric Steven
    Enhancers regulate gene expression through the binding of sequence-specific transcription factors (TFs) to cognate motifs. Various features influence TF binding and enhancer function—including the chromatin state of the genomic locus, the affinities of the binding site, the activity of the bound TFs, and interactions among TFs. However, the precise nature and relative contributions of these features remain unclear. Here, we used massively parallel reporter assays (MPRAs) involving 32,115 natural and synthetic enhancers, together with high-throughput in vivo binding assays, to systematically dissect the contribution of each of these features to the binding and activity of genomic regulatory elements that contain...

  4. Sustentabilidade dos recursos florestais em Portugal: o que aprendemos com o pinheiro-bravo

    Ribeiro, M.M.A.
    O desenvolvimento sustentável de uma espécie depende da diversidade genética presente nas populações. A conservação dos recursos genéticos, devido à maior resiliência da espécie quando a sua variabilidade genética é maior, promoverá a salvaguarda da existência das espécies e evolução, o aumento da sustentabilidade dos ecossistemas, a manutenção da capacidade produtiva das florestas, a futura utilização de genes (resistência a doenças, entre outras) e a proteção das espécies negligenciadas e das sobre exploradas. As atuais ameaças à diversidade genética incluem a influência antropogénica (alteração do habitat, desflorestação, fragmentação e domesticação), a globalização (agentes patogénicos, insetos, espécies exóticas e movimentação de...

  5. Genética humana

  6. Massively parallel high-order combinatorial genetics in human cells

    Wong, Siu Lun; Choi, Ching Gee; Cheng, Allen; Purcell, Oliver; Lu, Timothy K
    The systematic functional analysis of combinatorial genetics has been limited by the throughput that can be achieved and the order of complexity that can be studied. To enable massively parallel characterization of genetic combinations in human cells, we developed a technology for rapid, scalable assembly of high-order barcoded combinatorial genetic libraries that can be quantified with high-throughput sequencing. We applied this technology, combinatorial genetics en masse (CombiGEM), to create high-coverage libraries of 1,521 two-wise and 51,770 three-wise barcoded combinations of 39 human microRNA (miRNA) precursors. We identified miRNA combinations that synergistically sensitize drug-resistant cancer cells to chemotherapy and/or inhibit cancer...

  7. Esclerosis múltiple: encrucijada entre genética, inmunología y virología

    Hera Hernanz, Belén de la
    La esclerosis múltiple (EM) es una enfermedad crónica progresiva caracterizada por inflamación en el sistema nervioso central acompañado por desmielinización, daño axonal y disfunción neurológica progresiva. Se trata de una enfermedad compleja, cuya incidencia parece haber incrementado en los últimos tiempos, afectando actualmente a 2.3 millones de personas en el mundo. Sin embargo, muchos de los aspectos de su etiopatogenia continúan sin ser conocidos hoy en día. Es comúnmente aceptado que surge de la interacción de una serie de factores ambientales en individuos genéticamente susceptibles. Los estudios de barrido genómicos (GWAS) junto con el proyecto InmunoChip han permitido identificar un...

  8. The genetics of human migration: Tracing migrations through the genome

    Comas, David
    Various academic disciplines shed light on human migrations, helping us to reconstruct the past. Studying the genetic diversity of human populations today reveals past demographic and migratory events that have left an imprint on our genome. Armed with knowledge of migrations in prehistoric times, we can test hypotheses put forward in other scientific disciplines. Similarly, the distribution of genetic diversity in the future will largely depend on today’s extensive human migrations, facilitated by technological advances.

  9. The genetics of East African populations: a Nilo-Saharan component in the African genetic landscape

    Dobon, Begoña; Hassan, Hissam Y.; Laayouni, Hafid; Luisi, Pierre; Ricaño- Ponce, Isis; Zhernakova, Alexandra; Wijmenga, Cisca; Tahir, Hanan; Comas, David; Netea, Mihai G.; Bertranpetit, Jaume
    East Africa is a strategic region to study human genetic diversity due to the presence of ethnically, linguistically, and geographically diverse populations. Here, we provide new insight into the genetic history of populations living in the Sudanese region of East Africa by analysing nine ethnic groups belonging to three African linguistic families: Niger-Kordofanian, Nilo-Saharan and Afro-Asiatic. A total of 500 individuals were genotyped for 200,000 single-nucleotide polymorphisms. Principal component analysis, clustering analysis using ADMIXTURE, FST statistics, and the three-population test were used to investigate the underlying genetic structure and ancestry of the different ethno-linguistic groups. Our analyses revealed a genetic...

  10. MicroRNA Genetic Variation: From Population Analysis to Functional Implications of Three Allele Variants Associated with Cancer

    Torruella-Loran. Ignasi; Laayouni, Hafid; Dobon, Begoña; Gallego, Alicia; Balcells, Ingrid; García-Ramallo, Eva; Espinosa-Parrilla, Yolanda
    Nucleotide variants in microRNA regions have been associated with disease; nevertheless, few studies still have addressed the allele-dependent effect of these changes. We studied microRNA genetic variation in human populations and found that while low-frequency variants accumulate indistinctly in microRNA regions, the mature and seed regions tend to be depleted of high-frequency variants, probably as a result of purifying selection. Comparison of pairwise population fixation indexes among regions showed that the seed had higher population fixation indexes than the other regions, suggesting the existence of local adaptation in the seed region. We further performed functional studies of three microRNA variants...

  11. Inference of Evolutionary Forces Acting on Human Biological Pathways

    Daub, Josephine T.; Dupanloup, Isabelle; Robinson-Rechavi, Michael; Excoffier, Laurent
    Because natural selection is likely to act on multiple genes underlying a given phenotypic trait, we study here the potential effect of ongoing and past selection on the genetic diversity of human biological pathways. We first show that genes included in gene sets are generally under stronger selective constraints than other genes and that their evolutionary response is correlated. We then introduce a new procedure to detect selection at the pathway level based on a decomposition of the classical McDonald–Kreitman test extended to multiple genes. This new test, called 2DNS, detects outlier gene sets and takes into account past demographic...

  12. Genetic Heterogeneity in Algerian Human Populations

    Bekada, Asmahan; Arauna, Laura R.; Deba, Tahria; Calafell, Francesc; Benhamamouch, Soraya; Comas, David
    The demographic history of human populations in North Africa has been characterized by complex processes of admixture and isolation that have modeled its current gene pool. Diverse genetic ancestral components with different origins (autochthonous, European, Middle Eastern, and sub-Saharan) and genetic heterogeneity in the region have been described. In this complex genetic landscape, Algeria, the largest country in Africa, has been poorly covered, with most of the studies using a single Algerian sample. In order to evaluate the genetic heterogeneity of Algeria, Y-chromosome, mtDNA and autosomal genome-wide makers have been analyzed in several Berber- and Arab-speaking groups. Our results show...

  13. IPSCs, a promising tool to restore muscle atrophy

    Pareja-Galeano, Helios; Sanchis-Gomar, Fabian; Emanuele, Enzo; Gallardo, M. Esther; Lucia, Alejandro
    Induced pluripotent stem cells (iPSCs) are a promising tool for regenerative medicine in chronic conditions associated with muscle atrophy since iPSCs are easier to obtain, pose less ethical limitations and can better capture human genetic diversity compared with human embryonic stem cells. We highlight the potentiality of iPSCs for treating muscle-affecting conditions for which no effective cure is yet available, notably aging sarcopenia and inherited neurometabolic conditions.

  14. Aurora a drives early signalling and vesicle dynamics during T-cell activation

    Blas-Rus, Noelia; Alarcón, Balbino; Sánchez-Madrid, Francisco
    Aurora A is a serine/threonine kinase that contributes to the progression of mitosis by inducing microtubule nucleation. Here we have identified an unexpected role for Aurora A kinase in antigen-driven T-cell activation. We find that Aurora A is phosphorylated at the immunological synapse (IS) during TCR-driven cell contact. Inhibition of Aurora A with pharmacological agents or genetic deletion in human or mouse T cells severely disrupts the dynamics of microtubules and CD3¿-bearing vesicles at the IS. The absence of Aurora A activity also impairs the activation of early signalling molecules downstream of the TCR and the expression of IL-2, CD25...

  15. Cochlear homocysteine metabolism at the crossroad of nutrition and sensorineural hearing loss

    Partearroyo, Teresa; Vallecillo, Néstor; Pajares, María A.; Varela-Moreiras, Gregorio; Varela-Nieto, Isabel
    Hearing loss (HL) is one of the most common causes of disability, affecting 360 million people according to the World Health Organization (WHO). HL is most frequently of sensorineural origin, being caused by the irreversible loss of hair cells and/or spiralmganglion neurons. The etiology of sensorineural HL (SNHL) is multifactorial, with genetic and environmental factors such as noise, ototoxic substances and aging playing a role. The nutritional status is central in aging disability, but the interplay between nutrition and SNHL has only recently gained attention. Dietary supplementation could therefore constitute the first step for the prevention and potential repair of...

  16. 1H NMR metabolomic study of auxotrophic starvation in yeast using Multivariate Curve Resolution-Alternating Least Squares for Pathway Analysis

    Puig-Castellví, Francesc; Alfonso, Ignacio; Piña, Benjamin; Tauler, Romà
    Disruption of specific metabolic pathways constitutes the mode of action of many known toxicants and it is responsible for the adverse phenotypes associated to human genetic defects. Conversely, many industrial applications rely on metabolic alterations of diverse microorganisms, whereas many therapeutic drugs aim to selectively disrupt pathogens' metabolism. In this work we analyzed metabolic changes induced by auxotrophic starvation conditions in yeast in a non-targeted approach, using one-dimensional proton Nuclear Magnetic Resonance spectroscopy (1H NMR) and chemometric analyses. Analysis of the raw spectral datasets showed specific changes linked to the different stages during unrestricted yeast growth, as well as specific...

  17. Distribution and genetic diversity of the human polyomaviruses JC and BK in surface water and sewage treatment plant during 2009 in Porto Alegre, Southern Brazil

    Comerlato,J.; Souza-Campos,F.; Souza-Arantes,T.; Roos-Kulmann,M. I.; Trindade-Oliveira,M.; Rosado-Spilki,F.; Guedes-Frazzon,A. P.; Roehe,P. M.; Franco,A. C.
    Abstract The human polyomaviruses JC and BK (JCPyV and BKPyV) are ubiquitous, species-specific viruses that belong to the family Polyomaviridae. These viruses are known to be excreted in human urine, and they are potential indicators of human wastewater contamination. In order to assess the distribution of both JCPyV and BKPyV in urban water samples collected from a sewage treatment plant (STP) and from a canalized water stream of Porto Alegre, Brazil, two nested-PCR assays were optimized and applied to the samples collected. The amplicons obtained were submitted to sequencing, and the sequences were analyzed with sequences of human polyomaviruses previously...

  18. O aborto como direito e o aborto como crime: o retrocesso neoconservador

    Machado,Lia Zanotta
    Resumo Este artigo analisa o confronto político entre as argumentações feministas e as fundamentalistas sobre o aborto, no Brasil dos anos dois mil. Está em jogo a disputa por concepções de vida. As feministas defendem a distinção entre “vida vivida” e “vida abstrata”. A noção fundamentalista exclusiva de “vida abstrata” advinda de argumentos religiosos sustenta os direitos absolutos do concepto desde a fecundação. O aborto deveria ser crime (porque pecado) em qualquer circunstância (sem quaisquer permissivos legais). A análise dos depoimentos de deputados e religiosos fundamentalistas revela o confronto com a laicidade do Estado. Capturam e distorcem os discursos jurídico...

  19. Corpos comensuráveis: produção de modelos animais nas ciências biomédicas

    Souza,Iara Maria de Almeida
    Resumo: A utilização de modelo animal, em especial camundongos e ratos, é uma prática consolidada nas pesquisas biomédicas, que visam, usualmente, caracterizar processos biológicos ou testar tratamentos, medicamentos em animais não humanos antes de verificar se os resultados se aplicam aos humanos. Tal uso de animais se assenta na proximidade genética entre humanos e roedores, portanto, na suposição de que os processos biológicos de humanos e animais são similares. Os corpos dos animais são tratados como substitutos ou representativos dos humanos, mas isso não significa dizer que são apenas representações cognitivas, eles são também encarnações de ações e práticas que...

  20. Genetic Methods and Studies of Human Growth and Development Across the Allelic Spectrum

    Guo, Michael
    Genetics is an incredibly powerful tool for interrogating human biology, as it allows us to identify genes influencing biological processes and diseases in a hypothesis-free manner and in the context of the human body. The discovery of these genes can also have diagnostic and prognostic value for patients. The study of human genetics can be applied along the allelic spectrum, from rare variants in Mendelian disorders to common variants in polygenic traits and diseases. Here, I perform genetic studies along the allelic spectrum to uncover underlying biological and disease mechanisms for human growth and development. First, I demonstrated that exome...

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