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1.
Cell ; 167(5): 1369-1384.e19, 2016 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-27863249

RESUMEN

Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here, we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases.


Asunto(s)
Células Sanguíneas/citología , Enfermedad/genética , Regiones Promotoras Genéticas , Linaje de la Célula , Separación Celular , Cromatina , Elementos de Facilitación Genéticos , Epigenómica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hematopoyesis , Humanos , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo
2.
Cell ; 167(5): 1398-1414.e24, 2016 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-27863251

RESUMEN

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.


Asunto(s)
Epigenómica , Enfermedades del Sistema Inmune/genética , Monocitos/metabolismo , Neutrófilos/metabolismo , Linfocitos T/metabolismo , Transcripción Genética , Adulto , Anciano , Empalme Alternativo , Femenino , Predisposición Genética a la Enfermedad , Células Madre Hematopoyéticas/metabolismo , Código de Histonas , Humanos , Masculino , Persona de Mediana Edad , Sitios de Carácter Cuantitativo , Adulto Joven
3.
Cell ; 167(5): 1415-1429.e19, 2016 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-27863252

RESUMEN

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.


Asunto(s)
Variación Genética , Estudio de Asociación del Genoma Completo , Células Madre Hematopoyéticas/metabolismo , Enfermedades del Sistema Inmune/genética , Alelos , Diferenciación Celular , Predisposición Genética a la Enfermedad , Células Madre Hematopoyéticas/patología , Humanos , Enfermedades del Sistema Inmune/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Población Blanca/genética
4.
Cell ; 143(3): 367-78, 2010 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-21029860

RESUMEN

ATRX is an X-linked gene of the SWI/SNF family, mutations in which cause syndromal mental retardation and downregulation of α-globin expression. Here we show that ATRX binds to tandem repeat (TR) sequences in both telomeres and euchromatin. Genes associated with these TRs can be dysregulated when ATRX is mutated, and the change in expression is determined by the size of the TR, producing skewed allelic expression. This reveals the characteristics of the affected genes, explains the variable phenotypes seen with identical ATRX mutations, and illustrates a new mechanism underlying variable penetrance. Many of the TRs are G rich and predicted to form non-B DNA structures (including G-quadruplex) in vivo. We show that ATRX binds G-quadruplex structures in vitro, suggesting a mechanism by which ATRX may play a role in various nuclear processes and how this is perturbed when ATRX is mutated.


Asunto(s)
ADN Helicasas/metabolismo , Proteínas Nucleares/metabolismo , Animales , Células Cultivadas , Inmunoprecipitación de Cromatina , Cromosomas de los Mamíferos/metabolismo , Islas de CpG , ADN Helicasas/genética , ADN Ribosómico/metabolismo , G-Cuádruplex , Expresión Génica , Estudio de Asociación del Genoma Completo , Histonas/metabolismo , Humanos , Ratones , Repeticiones de Minisatélite , Mutación , Proteínas Nucleares/genética , Telómero/metabolismo , Proteína Nuclear Ligada al Cromosoma X
5.
Nucleic Acids Res ; 45(D1): D635-D642, 2017 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-27899575

RESUMEN

Ensembl (www.ensembl.org) is a database and genome browser for enabling research on vertebrate genomes. We import, analyse, curate and integrate a diverse collection of large-scale reference data to create a more comprehensive view of genome biology than would be possible from any individual dataset. Our extensive data resources include evidence-based gene and regulatory region annotation, genome variation and gene trees. An accompanying suite of tools, infrastructure and programmatic access methods ensure uniform data analysis and distribution for all supported species. Together, these provide a comprehensive solution for large-scale and targeted genomics applications alike. Among many other developments over the past year, we have improved our resources for gene regulation and comparative genomics, and added CRISPR/Cas9 target sites. We released new browser functionality and tools, including improved filtering and prioritization of genome variation, Manhattan plot visualization for linkage disequilibrium and eQTL data, and an ontology search for phenotypes, traits and disease. We have also enhanced data discovery and access with a track hub registry and a selection of new REST end points. All Ensembl data are freely released to the scientific community and our source code is available via the open source Apache 2.0 license.


Asunto(s)
Biología Computacional/métodos , Bases de Datos Genéticas , Genómica/métodos , Motor de Búsqueda , Programas Informáticos , Navegador Web , Animales , Minería de Datos , Evolución Molecular , Regulación de la Expresión Génica , Variación Genética , Genoma Humano , Humanos , Anotación de Secuencia Molecular , Especificidad de la Especie , Vertebrados
6.
Nucleic Acids Res ; 44(D1): D710-6, 2016 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-26687719

RESUMEN

The Ensembl project (http://www.ensembl.org) is a system for genome annotation, analysis, storage and dissemination designed to facilitate the access of genomic annotation from chordates and key model organisms. It provides access to data from 87 species across our main and early access Pre! websites. This year we introduced three newly annotated species and released numerous updates across our supported species with a concentration on data for the latest genome assemblies of human, mouse, zebrafish and rat. We also provided two data updates for the previous human assembly, GRCh37, through a dedicated website (http://grch37.ensembl.org). Our tools, in particular the VEP, have been improved significantly through integration of additional third party data. REST is now capable of larger-scale analysis and our regulatory data BioMart can deliver faster results. The website is now capable of displaying long-range interactions such as those found in cis-regulated datasets. Finally we have launched a website optimized for mobile devices providing views of genes, variants and phenotypes. Our data is made available without restriction and all code is available from our GitHub organization site (http://github.com/Ensembl) under an Apache 2.0 license.


Asunto(s)
Bases de Datos Genéticas , Genómica , Anotación de Secuencia Molecular , Animales , Genes , Variación Genética , Humanos , Internet , Ratones , Proteínas/genética , Ratas , Secuencias Reguladoras de Ácidos Nucleicos , Programas Informáticos
7.
Nucleic Acids Res ; 43(Database issue): D662-9, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25352552

RESUMEN

Ensembl (http://www.ensembl.org) is a genomic interpretation system providing the most up-to-date annotations, querying tools and access methods for chordates and key model organisms. This year we released updated annotation (gene models, comparative genomics, regulatory regions and variation) on the new human assembly, GRCh38, although we continue to support researchers using the GRCh37.p13 assembly through a dedicated site (http://grch37.ensembl.org). Our Regulatory Build has been revamped to identify regulatory regions of interest and to efficiently highlight their activity across disparate epigenetic data sets. A number of new interfaces allow users to perform large-scale comparisons of their data against our annotations. The REST server (http://rest.ensembl.org), which allows programs written in any language to query our databases, has moved to a full service alongside our upgraded website tools. Our online Variant Effect Predictor tool has been updated to process more variants and calculate summary statistics. Lastly, the WiggleTools package enables users to summarize large collections of data sets and view them as single tracks in Ensembl. The Ensembl code base itself is more accessible: it is now hosted on our GitHub organization page (https://github.com/Ensembl) under an Apache 2.0 open source license.


Asunto(s)
Bases de Datos de Ácidos Nucleicos , Genómica , Animales , Epigénesis Genética , Variación Genética , Genoma Humano , Humanos , Internet , Ratones , Anotación de Secuencia Molecular , Secuencias Reguladoras de Ácidos Nucleicos , Programas Informáticos
8.
Nucleic Acids Res ; 42(Database issue): D749-55, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24316576

RESUMEN

Ensembl (http://www.ensembl.org) creates tools and data resources to facilitate genomic analysis in chordate species with an emphasis on human, major vertebrate model organisms and farm animals. Over the past year we have increased the number of species that we support to 77 and expanded our genome browser with a new scrollable overview and improved variation and phenotype views. We also report updates to our core datasets and improvements to our gene homology relationships from the addition of new species. Our REST service has been extended with additional support for comparative genomics and ontology information. Finally, we provide updated information about our methods for data access and resources for user training.


Asunto(s)
Bases de Datos Genéticas , Genómica , Animales , Cordados/genética , Variación Genética , Humanos , Internet , Ratones , Anotación de Secuencia Molecular , Fenotipo , Ratas
9.
Nat Genet ; 39(5): 666-72, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17435758

RESUMEN

Characterizing the relationships between genomic and phenotypic variation is essential to understanding disease etiology. Information-dense data sets derived from pathophysiological, proteomic and transcriptomic profiling have been applied to map quantitative trait loci (QTLs). Metabolic traits, already used in QTL studies in plants, are essential phenotypes in mammalian genetics to define disease biomarkers. Using a complex mammalian system, here we show chromosomal mapping of untargeted plasma metabolic fingerprints derived from NMR spectroscopic analysis in a cross between diabetic and control rats. We propose candidate metabolites for the most significant QTLs. Metabolite profiling in congenic strains provided evidence of QTL replication. Linkage to a gut microbial metabolite (benzoate) can be explained by deletion of a uridine diphosphate glucuronosyltransferase. Mapping metabotypic QTLs provides a practical approach to understanding genome-phenotype relationships in mammals and may uncover deeper biological complexity, as extended genome (microbiome) perturbations that affect disease processes through transgenomic effects may influence QTL detection.


Asunto(s)
Diabetes Mellitus/genética , Ligamiento Genético , Genoma/genética , Metabolismo/genética , Fenotipo , Sitios de Carácter Cuantitativo , Animales , Secuencia de Bases , Benzoatos/química , Biomarcadores/análisis , Glucuronosiltransferasa/genética , Escala de Lod , Datos de Secuencia Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Ratas , Análisis de Secuencia de ADN
10.
Bioinformatics ; 30(7): 1008-9, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24363377

RESUMEN

MOTIVATION: Using high-throughput sequencing, researchers are now generating hundreds of whole-genome assays to measure various features such as transcription factor binding, histone marks, DNA methylation or RNA transcription. Displaying so much data generally leads to a confusing accumulation of plots. We describe here a multithreaded library that computes statistics on large numbers of datasets (Wiggle, BigWig, Bed, BigBed and BAM), generating statistical summaries within minutes with limited memory requirements, whether on the whole genome or on selected regions. AVAILABILITY AND IMPLEMENTATION: The code is freely available under Apache 2.0 license at www.github.com/Ensembl/Wiggletools


Asunto(s)
Genoma , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Biblioteca Genómica , Internet , Programas Informáticos
11.
Nucleic Acids Res ; 41(2): 827-41, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23221638

RESUMEN

The ENCODE Project has generated a wealth of experimental information mapping diverse chromatin properties in several human cell lines. Although each such data track is independently informative toward the annotation of regulatory elements, their interrelations contain much richer information for the systematic annotation of regulatory elements. To uncover these interrelations and to generate an interpretable summary of the massive datasets of the ENCODE Project, we apply unsupervised learning methodologies, converting dozens of chromatin datasets into discrete annotation maps of regulatory regions and other chromatin elements across the human genome. These methods rediscover and summarize diverse aspects of chromatin architecture, elucidate the interplay between chromatin activity and RNA transcription, and reveal that a large proportion of the genome lies in a quiescent state, even across multiple cell types. The resulting annotation of non-coding regulatory elements correlate strongly with mammalian evolutionary constraint, and provide an unbiased approach for evaluating metrics of evolutionary constraint in human. Lastly, we use the regulatory annotations to revisit previously uncharacterized disease-associated loci, resulting in focused, testable hypotheses through the lens of the chromatin landscape.


Asunto(s)
Cromatina/química , Genoma Humano , Anotación de Secuencia Molecular , Elementos Reguladores de la Transcripción , Elementos de Facilitación Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Elementos Aisladores , Regiones Promotoras Genéticas , Proteínas/genética , Regiones Terminadoras Genéticas , Transcripción Genética
12.
Nucleic Acids Res ; 41(Database issue): D56-63, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23193274

RESUMEN

The Encyclopedia of DNA Elements (ENCODE), http://encodeproject.org, has completed its fifth year of scientific collaboration to create a comprehensive catalog of functional elements in the human genome, and its third year of investigations in the mouse genome. Since the last report in this journal, the ENCODE human data repertoire has grown by 898 new experiments (totaling 2886), accompanied by a major integrative analysis. In the mouse genome, results from 404 new experiments became available this year, increasing the total to 583, collected during the course of the project. The University of California, Santa Cruz, makes this data available on the public Genome Browser http://genome.ucsc.edu for visual browsing and data mining. Download of raw and processed data files are all supported. The ENCODE portal provides specialized tools and information about the ENCODE data sets.


Asunto(s)
Bases de Datos Genéticas , Genoma Humano , Genómica , Animales , Humanos , Internet , Ratones , Programas Informáticos
13.
Nucleic Acids Res ; 41(Database issue): D48-55, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23203987

RESUMEN

The Ensembl project (http://www.ensembl.org) provides genome information for sequenced chordate genomes with a particular focus on human, mouse, zebrafish and rat. Our resources include evidenced-based gene sets for all supported species; large-scale whole genome multiple species alignments across vertebrates and clade-specific alignments for eutherian mammals, primates, birds and fish; variation data resources for 17 species and regulation annotations based on ENCODE and other data sets. Ensembl data are accessible through the genome browser at http://www.ensembl.org and through other tools and programmatic interfaces.


Asunto(s)
Bases de Datos Genéticas , Genómica , Animales , Regulación de la Expresión Génica , Variación Genética , Humanos , Internet , Ratones , Anotación de Secuencia Molecular , Ratas , Programas Informáticos , Pez Cebra/genética
14.
Nucleic Acids Res ; 40(Database issue): D84-90, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22086963

RESUMEN

The Ensembl project (http://www.ensembl.org) provides genome resources for chordate genomes with a particular focus on human genome data as well as data for key model organisms such as mouse, rat and zebrafish. Five additional species were added in the last year including gibbon (Nomascus leucogenys) and Tasmanian devil (Sarcophilus harrisii) bringing the total number of supported species to 61 as of Ensembl release 64 (September 2011). Of these, 55 species appear on the main Ensembl website and six species are provided on the Ensembl preview site (Pre!Ensembl; http://pre.ensembl.org) with preliminary support. The past year has also seen improvements across the project.


Asunto(s)
Bases de Datos Genéticas , Genómica , Animales , Regulación de la Expresión Génica , Variación Genética , Humanos , Ratones , Anotación de Secuencia Molecular , Ratas
15.
Nucleic Acids Res ; 39(Database issue): D800-6, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21045057

RESUMEN

The Ensembl project (http://www.ensembl.org) seeks to enable genomic science by providing high quality, integrated annotation on chordate and selected eukaryotic genomes within a consistent and accessible infrastructure. All supported species include comprehensive, evidence-based gene annotations and a selected set of genomes includes additional data focused on variation, comparative, evolutionary, functional and regulatory annotation. The most advanced resources are provided for key species including human, mouse, rat and zebrafish reflecting the popularity and importance of these species in biomedical research. As of Ensembl release 59 (August 2010), 56 species are supported of which 5 have been added in the past year. Since our previous report, we have substantially improved the presentation and integration of both data of disease relevance and the regulatory state of different cell types.


Asunto(s)
Bases de Datos Genéticas , Genómica , Animales , Variación Genética , Humanos , Ratones , Anotación de Secuencia Molecular , Ratas , Secuencias Reguladoras de Ácidos Nucleicos , Programas Informáticos , Pez Cebra/genética
16.
Nucleic Acids Res ; 38(Database issue): D557-62, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19906699

RESUMEN

Ensembl (http://www.ensembl.org) integrates genomic information for a comprehensive set of chordate genomes with a particular focus on resources for human, mouse, rat, zebrafish and other high-value sequenced genomes. We provide complete gene annotations for all supported species in addition to specific resources that target genome variation, function and evolution. Ensembl data is accessible in a variety of formats including via our genome browser, API and BioMart. This year marks the tenth anniversary of Ensembl and in that time the project has grown with advances in genome technology. As of release 56 (September 2009), Ensembl supports 51 species including marmoset, pig, zebra finch, lizard, gorilla and wallaby, which were added in the past year. Major additions and improvements to Ensembl since our previous report include the incorporation of the human GRCh37 assembly, enhanced visualisation and data-mining options for the Ensembl regulatory features and continued development of our software infrastructure.


Asunto(s)
Biología Computacional/métodos , Bases de Datos Genéticas , Bases de Datos de Ácidos Nucleicos , Acceso a la Información , Animales , Biología Computacional/tendencias , Bases de Datos de Proteínas , Variación Genética , Genómica/métodos , Humanos , Almacenamiento y Recuperación de la Información/métodos , Internet , Estructura Terciaria de Proteína , Programas Informáticos , Especificidad de la Especie
17.
Mamm Genome ; 21(9-10): 499-508, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20878524

RESUMEN

Insulin resistance and altered endocrine pancreas function are central pathophysiological features of type 2 diabetes mellitus (T2DM). The Goto-Kakizaki (GK) rat is a model of spontaneous T2DM characterised by reduced beta cell mass and genetically determined glucose intolerance and altered insulin secretion. To identify genetic determinants of endocrine pancreas histopathology, we carried out quantitative trait locus (QTL) mapping of histological phenotypes (beta cell mass -BCM and insulin-positive cell area -IPCA) and plasma concentration of hormones and growth factors in a F2 cohort derived from GK and normoglycemic Brown Norway rats. Although IPCA and BCM in the duodenal region of the pancreas were highly positively correlated (P < 10(-6)), and similarly in the splenic region, both measures were poorly correlated when comparing duodenal and splenic phenotypes. Strongest evidence of linkage to pancreas morphological traits was obtained between BCM and chromosome 10 (LOD 3.2). Evidence of significant linkage (LOD 4.2) to plasma corticosterone was detected in a region of chromosome 1 distal to other QTLs previously identified in the GK. Male-specific genetic effects were detected, including linkages (LOD > 4) to growth hormome (GH) on chromosome 6 and prolactin on chromosome 17. These data suggest independent genetic control of the structure and function of ontologically different regions of the endocrine pancreas. Novel QTLs for corticosterone, prolactin and GH may contribute to diabetes in the GK. The QTLs that we have identified in this, and previous genetic studies collectively underline the complex and multiple mechanisms involved in diabetes in the GK strain.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/patología , Sitios de Carácter Cuantitativo , Animales , Glucemia , Mapeo Cromosómico , Corticosterona/sangre , Cruzamientos Genéticos , Modelos Animales de Enfermedad , Femenino , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Hormona del Crecimiento/sangre , Hormona del Crecimiento/genética , Insulina/sangre , Insulina/genética , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/ultraestructura , Masculino , Páncreas/patología , Fenotipo , Prolactina/sangre , Prolactina/genética , Ratas , Ratas Endogámicas BN
18.
BMC Genomics ; 10: 63, 2009 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-19196459

RESUMEN

BACKGROUND: Microarray technologies are widely used to quantify the abundance of transcripts corresponding to thousands of genes. To maximise the robustness of transcriptome results, we have tested the performance and reproducibility of rat and mouse gene expression data obtained with Affymetrix, Illumina and Operon platforms. RESULTS: We present a thorough analysis of the degree of reproducibility provided by analysing the transcriptomic profile of the same animals of several experimental groups under different popular microarray technologies in different tissues. Concordant results from inter- and intra-platform comparisons were maximised by testing many popular computational methods for generating fold changes and significances and by only considering oligonucleotides giving high expression levels. The choice of Affymetrix signal extraction technique was shown to have the greatest effect on the concordance across platforms. In both species, when choosing optimal methods, the agreement between data generated on the Affymetrix and Illumina was excellent; this was verified using qRT-PCR on a selection of genes present on all platforms. CONCLUSION: This study provides an extensive assessment of analytical methods best suited for processing data from different microarray technologies and can assist integration of technologically different gene expression datasets in biological systems.


Asunto(s)
Diabetes Mellitus Experimental/genética , Perfilación de la Expresión Génica/métodos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Endogámicas BN , Ratas Endogámicas WKY , Reproducibilidad de los Resultados
19.
Sci Rep ; 9(1): 3656, 2019 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-30842494

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. To disentangle etiological relationships between these conditions and identify genetically-determined metabolites involved in NAFLD processes, we mapped 1H nuclear magnetic resonance (NMR) metabolomic and disease-related phenotypes in a mouse F2 cross derived from strains showing resistance (BALB/c) and increased susceptibility (129S6) to these diseases. Quantitative trait locus (QTL) analysis based on single nucleotide polymorphism (SNP) genotypes identified diet responsive QTLs in F2 mice fed control or high fat diet (HFD). In HFD fed F2 mice we mapped on chromosome 18 a QTL regulating liver micro- and macrovesicular steatosis and inflammation, independently from glucose intolerance and adiposity, which was linked to chromosome 4. Linkage analysis of liver metabolomic profiling data identified a QTL for octopamine, which co-localised with the QTL for liver histopathology in the cross. Functional relationship between these two QTLs was validated in vivo in mice chronically treated with octopamine, which exhibited reduction in liver histopathology and metabolic benefits, underlining its role as a mechanistic biomarker of fatty liver with potential therapeutic applications.


Asunto(s)
Cromosomas de los Mamíferos/genética , Metabolómica/métodos , Enfermedad del Hígado Graso no Alcohólico/genética , Octopamina/administración & dosificación , Polimorfismo de Nucleótido Simple , Animales , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones Endogámicos BALB C , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Octopamina/farmacología , Espectroscopía de Protones por Resonancia Magnética , Sitios de Carácter Cuantitativo , Biología de Sistemas , Resultado del Tratamiento
20.
G3 (Bethesda) ; 6(11): 3671-3683, 2016 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-27646706

RESUMEN

To test the impact of genetic heterogeneity on cis- and trans-mediated mechanisms of gene expression regulation, we profiled the transcriptome of adipose tissue in 20 inbred congenic strains derived from diabetic Goto-Kakizaki (GK) rats and Brown-Norway (BN) controls, which contain well-defined blocks (1-183 Mb) of genetic polymorphisms, and in 123 genetically heterogeneous rats of an (GK × BN)F2 offspring. Within each congenic we identified 73-1351 differentially expressed genes (DEGs), only 7.7% of which mapped within the congenic blocks, and which may be regulated in cis The remainder localized outside the blocks, and therefore must be regulated in trans Most trans-regulated genes exhibited approximately twofold expression changes, consistent with monoallelic expression. Altered biological pathways were replicated between congenic strains sharing blocks of genetic polymorphisms, but polymorphisms at different loci also had redundant effects on transcription of common distant genes and pathways. We mapped 2735 expression quantitative trait loci (eQTL) in the F2 cross, including 26% predominantly cis-regulated genes, which validated DEGs in congenic strains. A hotspot of >300 eQTL in a 10 cM region of chromosome 1 was enriched in DEGs in a congenic strain. However, many DEGs among GK, BN and congenic strains did not replicate as eQTL in F2 hybrids, demonstrating distinct mechanisms of gene expression when alleles segregate in an outbred population or are fixed homozygous across the entire genome or in short genomic regions. Our analysis provides conceptual advances in our understanding of the complex architecture of genome expression and pathway regulation, and suggests a prominent impact of epistasis and monoallelic expression on gene transcription.

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