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Allelic series are of candidate therapeutic interest because of the existence of a dose-response relationship between the functionality of a gene and the degree or severity of a phenotype. We define an allelic series as a collection of variants in which increasingly deleterious mutations lead to increasingly large phenotypic effects, and we have developed a gene-based rare-variant association test specifically targeted to identifying genes containing allelic series. Building on the well-known burden test and sequence kernel association test (SKAT), we specify a variety of association models covering different genetic architectures and integrate these into a Coding-Variant Allelic-Series Test (COAST). Through extensive simulations, we confirm that COAST maintains the type I error and improves the power when the pattern of coding-variant effect sizes increases monotonically with mutational severity. We applied COAST to identify allelic-series genes for four circulating-lipid traits and five cell-count traits among 145,735 subjects with available whole-exome sequencing data from the UK Biobank. Compared with optimal SKAT (SKAT-O), COAST identified 29% more Bonferroni-significant associations with circulating-lipid traits, on average, and 82% more with cell-count traits. All of the gene-trait associations identified by COAST have corroborating evidence either from rare-variant associations in the full cohort (Genebass, n = 400,000) or from common-variant associations in the GWAS Catalog. In addition to detecting many gene-trait associations present in Genebass by using only a fraction (36.9%) of the sample, COAST detects associations, such as that between ANGPTL4 and triglycerides, that are absent from Genebass but that have clear common-variant support.
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Variación Genética , Lípidos , Simulación por Computador , Estudios de Asociación Genética , Fenotipo , Estudio de Asociación del Genoma CompletoRESUMEN
Modeling how individuals evolve over time is a fundamental problem in the natural and social sciences. However, existing datasets are often cross-sectional with each individual observed only once, making it impossible to apply traditional time-series methods. Motivated by the study of human aging, we present an interpretable latent-variable model that learns temporal dynamics from cross-sectional data. Our model represents each individual's features over time as a nonlinear function of a low-dimensional, linearly-evolving latent state. We prove that when this nonlinear function is constrained to be order-isomorphic, the model family is identifiable solely from cross-sectional data provided the distribution of time-independent variation is known. On the UK Biobank human health dataset, our model reconstructs the observed data while learning interpretable rates of aging associated with diseases, mortality, and aging risk factors.
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INTRODUCTION: A major goal of neonatal medicine is to identify neonates at highest risk for morbidity and mortality. Previously, we developed PhysiScore (Saria et al., 2010), a novel tool for preterm morbidity risk prediction. We now further define links between overall individual morbidity risk, specific neonatal morbidities, and placental pathologies. METHODS: 102 placentas, including 38 from multiple gestations, were available from the previously defined PhysiScore cohort (gestational age ≤ 34 weeks and birth weight ≤ 2000 g). Placentas were analyzed for gross and histologic variables including maternal malperfusion, amniotic fluid infection sequence, chronic inflammation, and fetal vascular obstruction. Risk as determined by PhysiScore and recorded neonatal morbidities were tested for statistical association with placental findings. RESULTS: In pair-wise correlations, respiratory distress syndrome, bronchopulmonary dysplasia, acute hemodynamic instability, post-hemorrhagic hydrocephalus, culture-positive sepsis, and necrotizing enterocolitis each significantly correlated with at least one placenta histology variable. Amniotic fluid infection sequence (p = 0.039), specifically the fetal inflammatory response (p = 0.017), correlated with higher PhysiScores (greater morbidity) but was not independent of gestational age and birth weight. In multivariate analyses correlating variables with all nine morbidities, gestational age (p < 0.001), placental size <10th percentile (p = 0.031), full thickness perivillous fibrin deposition (p = 0.001), and amniotic fluid infection sequence (umbilical arteritis, p = 0.031; ≥2 chorionic plate vessels with vasculitis, p = 0.0125), each were significant associations. DISCUSSION: Amniotic fluid infection sequence plays a significant role in neonatal morbidity. Less neonatal morbidity was observed in older and heavier infants and those with small placental size and full thickness perivillous fibrin deposition. The combined assessment of placental gross and histologic findings together with physiologic risk evaluation may allow more precise prediction of neonatal morbidity risk soon after delivery.
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Enfermedades del Prematuro/epidemiología , Recien Nacido Prematuro , Trabajo de Parto Prematuro/patología , Enfermedades Placentarias/epidemiología , Placenta/patología , Líquido Amniótico/microbiología , Femenino , Humanos , Recién Nacido , Masculino , Morbilidad , Embarazo , Índice de Severidad de la EnfermedadRESUMEN
We consider the problem of parameter estimation and energy minimization for a region-based semantic segmentation model. The model divides the pixels of an image into non-overlapping connected regions, each of which is to a semantic class. In the context of energy minimization, the main problem we face is the large number of putative pixel-to-region assignments. We address this problem by designing an accurate linear programming based approach for selecting the best set of regions from a large dictionary. The dictionary is constructed by merging and intersecting segments obtained from multiple bottom-up over-segmentations. The linear program is solved efficiently using dual decomposition. In the context of parameter estimation, the main problem we face is the lack of fully supervised data. We address this issue by developing a principled framework for parameter estimation using diverse data. More precisely, we propose a latent structural support vector machine formulation, where the latent variables model any missing information in the human annotation. Of particular interest to us are three types of annotations: (i) images segmented using generic foreground or background classes; (ii) images with bounding boxes specified for objects; and (iii) images labeled to indicate the presence of a class. Using large, publicly available datasets we show that our methods are able to significantly improve the accuracy of the region-based model.
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To understand the regulation of tissue-specific gene expression, the GTEx Consortium generated RNA-seq expression data for more than thirty distinct human tissues. This data provides an opportunity for deriving shared and tissue specific gene regulatory networks on the basis of co-expression between genes. However, a small number of samples are available for a majority of the tissues, and therefore statistical inference of networks in this setting is highly underpowered. To address this problem, we infer tissue-specific gene co-expression networks for 35 tissues in the GTEx dataset using a novel algorithm, GNAT, that uses a hierarchy of tissues to share data between related tissues. We show that this transfer learning approach increases the accuracy with which networks are learned. Analysis of these networks reveals that tissue-specific transcription factors are hubs that preferentially connect to genes with tissue specific functions. Additionally, we observe that genes with tissue-specific functions lie at the peripheries of our networks. We identify numerous modules enriched for Gene Ontology functions, and show that modules conserved across tissues are especially likely to have functions common to all tissues, while modules that are upregulated in a particular tissue are often instrumental to tissue-specific function. Finally, we provide a web tool, available at mostafavilab.stat.ubc.ca/GNAT, which allows exploration of gene function and regulation in a tissue-specific manner.
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Algoritmos , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Modelos Genéticos , Secuencia de Bases , Humanos , Especificidad de Órganos/genéticaRESUMEN
Ribosome profiling data report on the distribution of translating ribosomes, at steady-state, with codon-level resolution. We present a robust method to extract codon translation rates and protein synthesis rates from these data, and identify causal features associated with elongation and translation efficiency in physiological conditions in yeast. We show that neither elongation rate nor translational efficiency is improved by experimental manipulation of the abundance or body sequence of the rare AGG tRNA. Deletion of three of the four copies of the heavily used ACA tRNA shows a modest efficiency decrease that could be explained by other rate-reducing signals at gene start. This suggests that correlation between codon bias and efficiency arises as selection for codons to utilize translation machinery efficiently in highly translated genes. We also show a correlation between efficiency and RNA structure calculated both computationally and from recent structure probing data, as well as the Kozak initiation motif, which may comprise a mechanism to regulate initiation.
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Codón/genética , ARN Mensajero/genética , Elongación de la Transcripción Genética , Proliferación Celular/genética , Eliminación de Gen , Modelos Genéticos , ARN de Hongos/genética , ARN de Transferencia/genética , Saccharomyces cerevisiae/genéticaRESUMEN
To determine the breadth and underpinning of changes in immunocyte gene expression due to genetic variation in mice, we performed, as part of the Immunological Genome Project, gene expression profiling for CD4(+) T cells and neutrophils purified from 39 inbred strains of the Mouse Phenome Database. Considering both cell types, a large number of transcripts showed significant variation across the inbred strains, with 22% of the transcriptome varying by 2-fold or more. These included 119 loci with apparent complete loss of function, where the corresponding transcript was not expressed in some of the strains, representing a useful resource of "natural knockouts." We identified 1222 cis-expression quantitative trait loci (cis-eQTL) that control some of this variation. Most (60%) cis-eQTLs were shared between T cells and neutrophils, but a significant portion uniquely impacted one of the cell types, suggesting cell type-specific regulatory mechanisms. Using a conditional regression algorithm, we predicted regulatory interactions between transcription factors and potential targets, and we demonstrated that these predictions overlap with regulatory interactions inferred from transcriptional changes during immunocyte differentiation. Finally, comparison of these and parallel data from CD4(+) T cells of healthy humans demonstrated intriguing similarities in variability of a gene's expression: the most variable genes tended to be the same in both species, and there was an overlap in genes subject to strong cis-acting genetic variants. We speculate that this "conservation of variation" reflects a differential constraint on intraspecies variation in expression levels of different genes, either through lower pressure for some genes, or by favoring variability for others.
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Regulación de la Expresión Génica , Variación Genética , Inmunidad/genética , Ratones Endogámicos/genética , Ratones Endogámicos/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Mapeo Cromosómico , Análisis por Conglomerados , Biología Computacional , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Genotipo , Humanos , Ratones , Neutrófilos/inmunología , Neutrófilos/metabolismo , Sitios de Carácter Cuantitativo , Reproducibilidad de los Resultados , TranscriptomaRESUMEN
B cells produce a diverse antibody repertoire by undergoing gene rearrangements. Pathogen exposure induces the clonal expansion of B cells expressing antibodies that can bind the infectious agent. To assess human B cell responses to trivalent seasonal influenza and monovalent pandemic H1N1 vaccination, we sequenced gene rearrangements encoding the immunoglobulin heavy chain, a major determinant of epitope recognition. The magnitude of B cell clonal expansions correlates with an individual's secreted antibody response to the vaccine, and the expanded clones are enriched with those expressing influenza-specific monoclonal antibodies. Additionally, B cell responses to pandemic influenza H1N1 vaccination and infection in different people show a prominent family of convergent antibody heavy chain gene rearrangements specific to influenza antigens. These results indicate that microbes can induce specific signatures of immunoglobulin gene rearrangements and that pathogen exposure can potentially be assessed from B cell repertoires.
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Anticuerpos Antivirales/genética , Anticuerpos Antivirales/inmunología , Reordenamiento Génico de Linfocito B , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Formación de Anticuerpos , Humanos , Vacunas contra la Influenza/administración & dosificaciónRESUMEN
To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4(+) T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
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Enfermedades Autoinmunes/genética , Autoinmunidad/genética , Linfocitos T CD4-Positivos/inmunología , Predisposición Genética a la Enfermedad/genética , Monocitos/inmunología , Enfermedades Neurodegenerativas/genética , Inmunidad Adaptativa/genética , Alelos , Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/genética , Enfermedades Autoinmunes/etnología , Etnicidad/genética , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo , Humanos , Inmunidad Innata/genética , Esclerosis Múltiple/etnología , Esclerosis Múltiple/genética , Enfermedades Neurodegenerativas/etnología , Enfermedad de Parkinson/etnología , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Fiebre Reumática/etnología , Fiebre Reumática/genética , TranscriptomaRESUMEN
The adaptive immune system confers protection by generating a diverse repertoire of antibody receptors that are rapidly expanded and contracted in response to specific targets. Next-generation DNA sequencing now provides the opportunity to survey this complex and vast repertoire. In the present work, we describe a set of tools for the analysis of antibody repertoires and their application to elucidating the dynamics of the response to viral vaccination in human volunteers. By analyzing data from 38 separate blood samples across 2 y, we found that the use of the germ-line library of V and J segments is conserved between individuals over time. Surprisingly, there appeared to be no correlation between the use level of a particular VJ combination and degree of expansion. We found the antibody RNA repertoire in each volunteer to be highly dynamic, with each individual displaying qualitatively different response dynamics. By using combinatorial phage display, we screened selected VH genes paired with their corresponding VL library for affinity against the vaccine antigens. Altogether, this work presents an additional set of tools for profiling the human antibody repertoire and demonstrates characterization of the fast repertoire dynamics through time in multiple individuals responding to an immune challenge.
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Anticuerpos/inmunología , Inmunidad/inmunología , Vacunas Virales/inmunología , Células Clonales , Vectores Genéticos , Voluntarios Sanos , Humanos , Región Variable de Inmunoglobulina/genética , Masculino , Mutación/genética , Reproducibilidad de los Resultados , Factores de Tiempo , Recombinación V(D)J/genética , VacunaciónRESUMEN
Elderly humans show decreased humoral immunity to pathogens and vaccines, yet the effects of aging on B cells are not fully known. Chronic viral infection by CMV is implicated as a driver of clonal T cell proliferations in some aging humans, but whether CMV or EBV infection contributes to alterations in the B cell repertoire with age is unclear. We have used high-throughput DNA sequencing of IGH gene rearrangements to study the BCR repertoires over two successive years in 27 individuals ranging in age from 20 to 89 y. Some features of the B cell repertoire remain stable with age, but elderly subjects show increased numbers of B cells with long CDR3 regions, a trend toward accumulation of more highly mutated IgM and IgG Ig genes, and persistent clonal B cell populations in the blood. Seropositivity for CMV or EBV infection alters B cell repertoires, regardless of the individual's age: EBV infection correlates with the presence of persistent clonal B cell expansions, whereas CMV infection correlates with the proportion of highly mutated Ab genes. These findings isolate effects of aging from those of chronic viral infection on B cell repertoires and provide a baseline for understanding human B cell responses to vaccination or infectious stimuli.
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Envejecimiento/inmunología , Linfocitos B/inmunología , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/inmunología , Linfocitos B/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Citomegalovirus/genética , Infecciones por Citomegalovirus/virología , Infecciones por Virus de Epstein-Barr/virología , Genes de Inmunoglobulinas/genética , Genes de Inmunoglobulinas/inmunología , Herpesvirus Humano 4/genética , Humanos , Persona de Mediana Edad , Mutación/genética , Mutación/inmunología , Adulto JovenRESUMEN
Understanding the consequences of regulatory variation in the human genome remains a major challenge, with important implications for understanding gene regulation and interpreting the many disease-risk variants that fall outside of protein-coding regions. Here, we provide a direct window into the regulatory consequences of genetic variation by sequencing RNA from 922 genotyped individuals. We present a comprehensive description of the distribution of regulatory variation--by the specific expression phenotypes altered, the properties of affected genes, and the genomic characteristics of regulatory variants. We detect variants influencing expression of over ten thousand genes, and through the enhanced resolution offered by RNA-sequencing, for the first time we identify thousands of variants associated with specific phenotypes including splicing and allelic expression. Evaluating the effects of both long-range intra-chromosomal and trans (cross-chromosomal) regulation, we observe modularity in the regulatory network, with three-dimensional chromosomal configuration playing a particular role in regulatory modules within each chromosome. We also observe a significant depletion of regulatory variants affecting central and critical genes, along with a trend of reduced effect sizes as variant frequency increases, providing evidence that purifying selection and buffering have limited the deleterious impact of regulatory variation on the cell. Further, generalizing beyond observed variants, we have analyzed the genomic properties of variants associated with expression and splicing and developed a Bayesian model to predict regulatory consequences of genetic variants, applicable to the interpretation of individual genomes and disease studies. Together, these results represent a critical step toward characterizing the complete landscape of human regulatory variation.
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Variación Genética , Sitios de Carácter Cuantitativo , Análisis de Secuencia de ARN , Transcriptoma , Teorema de Bayes , Cromosomas Humanos , Genoma Humano , Genotipo , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple , Secuencias Reguladoras de Ácido RibonucleicoRESUMEN
Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121-134 and found a positive correlation between the level of somatic hypermutation (SHM) and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121-134 but were still capable of neutralizing roughly 40-80% of PGT121-134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121-134. Such antibodies with lower levels of SHM may be more amenable to elicitation through vaccination while still providing noteworthy coverage. Binding characterization indicated a preference of inferred intermediates for native Env binding over monomeric gp120, suggesting that the PGT121-134 lineage may have been selected for binding to native Env at some point during maturation. Analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. Finally, patterns of neutralization of inferred bnAb intermediates suggest hypotheses as to how SHM may lead to potent and broad HIV neutralization and provide important clues for immunogen design.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/inmunología , Anticuerpos Neutralizantes/genética , Femenino , Anticuerpos Anti-VIH/genética , Proteína gp120 de Envoltorio del VIH/genética , VIH-1/genética , Humanos , Masculino , Polisacáridos/genética , Polisacáridos/inmunologíaRESUMEN
Transcriptomic assays that measure expression levels are widely used to study the manifestation of environmental or genetic variations in cellular processes. RNA-sequencing in particular has the potential to considerably improve such understanding because of its capacity to assay the entire transcriptome, including novel transcriptional events. However, as with earlier expression assays, analysis of RNA-sequencing data requires carefully accounting for factors that may introduce systematic, confounding variability in the expression measurements, resulting in spurious correlations. Here, we consider the problem of modeling and removing the effects of known and hidden confounding factors from RNA-sequencing data. We describe a unified residual framework that encapsulates existing approaches, and using this framework, present a novel method, HCP (Hidden Covariates with Prior). HCP uses a more informed assumption about the confounding factors, and performs as well or better than existing approaches while having a much lower computational cost. Our experiments demonstrate that accounting for known and hidden factors with appropriate models improves the quality of RNA-sequencing data in two very different tasks: detecting genetic variations that are associated with nearby expression variations (cis-eQTLs), and constructing accurate co-expression networks.
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Secuencia de Bases/genética , Modelos Genéticos , Análisis de Secuencia de ARN/métodos , Transcriptoma/genética , Biología Computacional/métodos , Proyectos de Investigación , Análisis de Secuencia de ARN/normasRESUMEN
Dengue is the most prevalent mosquito-borne viral disease in humans, and the lack of early prognostics, vaccines, and therapeutics contributes to immense disease burden. To identify patterns that could be used for sequence-based monitoring of the antibody response to dengue, we examined antibody heavy-chain gene rearrangements in longitudinal peripheral blood samples from 60 dengue patients. Comparing signatures between acute dengue, postrecovery, and healthy samples, we found increased expansion of B cell clones in acute dengue patients, with higher overall clonality in secondary infection. Additionally, we observed consistent antibody sequence features in acute dengue in the highly variable major antigen-binding determinant, complementarity-determining region 3 (CDR3), with specific CDR3 sequences highly enriched in acute samples compared to postrecovery, healthy, or non-dengue samples. Dengue thus provides a striking example of a human viral infection where convergent immune signatures can be identified in multiple individuals. Such signatures could facilitate surveillance of immunological memory in communities.
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Anticuerpos Antivirales/sangre , Virus del Dengue/inmunología , Dengue/inmunología , Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Regiones Determinantes de Complementariedad/inmunología , Humanos , Memoria InmunológicaRESUMEN
The differentiation of αßT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes. In contrast, transit through the CD4(+)CD8(+) stage involved a global shutdown of housekeeping genes that is rare among cells of the immune system and correlated tightly with expression of the transcription factor c-Myc. Selection driven by major histocompatibility complex (MHC) molecules promoted a large-scale transcriptional reactivation. We identified distinct signatures that marked cells destined for positive selection versus apoptotic deletion. Differences in the expression of unexpectedly few genes accompanied commitment to the CD4(+) or CD8(+) lineage, a similarity that carried through to peripheral T cells and their activation, demonstrated by mass cytometry phosphoproteomics. The transcripts newly identified as encoding candidate mediators of key transitions help define the 'known unknowns' of thymocyte differentiation.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos de Diferenciación de Linfocitos T/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/genética , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Proliferación Celular , Células Cultivadas , Análisis por Conglomerados , Citometría de Flujo , Antígenos de Histocompatibilidad/genética , Antígenos de Histocompatibilidad/inmunología , Antígenos de Histocompatibilidad/metabolismo , Lectinas Tipo C/inmunología , Lectinas Tipo C/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosforilación/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Timocitos/citología , Timocitos/inmunología , Timocitos/metabolismo , Transcriptoma/genética , Transcriptoma/inmunologíaRESUMEN
Despite the importance of the immune system in many diseases, there are currently no objective benchmarks of immunological health. In an effort to identifying such markers, we used influenza vaccination in 30 young (20-30 years) and 59 older subjects (60 to >89 years) as models for strong and weak immune responses, respectively, and assayed their serological responses to influenza strains as well as a wide variety of other parameters, including gene expression, antibodies to hemagglutinin peptides, serum cytokines, cell subset phenotypes and in vitro cytokine stimulation. Using machine learning, we identified nine variables that predict the antibody response with 84% accuracy. Two of these variables are involved in apoptosis, which positively associated with the response to vaccination and was confirmed to be a contributor to vaccine responsiveness in mice. The identification of these biomarkers provides new insights into what immune features may be most important for immune health.
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Anticuerpos Antivirales/inmunología , Citocinas/inmunología , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Vacunación , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Antivirales/sangre , Apoptosis , Inteligencia Artificial , Biomarcadores/sangre , Citocinas/sangre , Femenino , Humanos , Inmunidad Humoral/efectos de los fármacos , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/inmunología , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/sangre , Gripe Humana/inmunología , Masculino , Ratones , Persona de Mediana Edad , Pronóstico , Vacunas de SubunidadRESUMEN
The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages. Using Ontogenet, we found differentiation stage-specific regulators of mouse hematopoiesis and identified many known hematopoietic regulators and 175 previously unknown candidate regulators, as well as their target genes and the cell types in which they act. Among the previously unknown regulators, we emphasize the role of ETV5 in the differentiation of γδ T cells. As the transcriptional programs of human and mouse cells are highly conserved, it is likely that many lessons learned from the mouse model apply to humans.
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Algoritmos , Regulación de la Expresión Génica/inmunología , Sistema Inmunológico/metabolismo , Transcripción Genética/inmunología , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/inmunología , Humanos , Sistema Inmunológico/citología , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transactivadores/genética , Transactivadores/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Transcriptoma/genética , Transcriptoma/inmunologíaRESUMEN
Much of the knowledge about cell differentiation and function in the immune system has come from studies in mice, but the relevance to human immunology, diseases, and therapy has been challenged, perhaps more from anecdotal than comprehensive evidence. To this end, we compare two large compendia of transcriptional profiles of human and mouse immune cell types. Global transcription profiles are conserved between corresponding cell lineages. The expression patterns of most orthologous genes are conserved, particularly for lineage-specific genes. However, several hundred genes show clearly divergent expression across the examined cell lineages, and among them, 169 genes did so even with highly stringent criteria. Finally, regulatory mechanisms--reflected by regulators' differential expression or enriched cis-elements--are conserved between the species but to a lower degree, suggesting that distinct regulation may underlie some of the conserved transcriptional responses.
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Perfilación de la Expresión Génica , Sistema Inmunológico/metabolismo , Transcripción Genética , Animales , Humanos , Activación de Linfocitos , Ratones , Linfocitos T/inmunologíaRESUMEN
Measuring complete gene expression profiles for a large number of experiments is costly. We propose an approach in which a small subset of probes is selected based on a preliminary set of full expression profiles. In subsequent experiments, only the subset is measured, and the missing values are inputed. We developed several algorithms to simultaneously select probes and input missing values, and we demonstrate that these 'probe selection for imputation' (PSI) algorithms can successfully reconstruct missing gene expression values in a wide variety of applications, as evaluated using multiple metrics of biological importance. We analyze the performance of PSI methods under varying conditions, provide guidelines for choosing the optimal method based on the experimental setting, and indicate how to estimate imputation accuracy. Finally, we apply our approach to a large-scale study of immune system variation.