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1.
Annu Rev Genet ; 57: 341-360, 2023 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-37708421

RESUMO

Many human phenotypes are impossible to recapitulate in model organisms or immortalized human cell lines. Induced pluripotent stem cells (iPSCs) offer a way to study disease mechanisms in a variety of differentiated cell types while circumventing ethical and practical issues associated with finite tissue sources and postmortem states. Here, we discuss the broad utility of iPSCs in genetic medicine and describe how they are being used to study musculoskeletal, pulmonary, neurologic, and cardiac phenotypes. We summarize the particular challenges presented by each organ system and describe how iPSC models are being used to address them. Finally, we discuss emerging iPSC-derived organoid models and the potential value that they can bring to studies of human disease.


Assuntos
Células-Tronco Pluripotentes Induzidas , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Diferenciação Celular/genética , Biologia
2.
PLoS Genet ; 18(3): e1010073, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35263340

RESUMO

The evolution of complex skeletal traits in primates was likely influenced by both genetic and environmental factors. Because skeletal tissues are notoriously challenging to study using functional genomic approaches, they remain poorly characterized even in humans, let alone across multiple species. The challenges involved in obtaining functional genomic data from the skeleton, combined with the difficulty of obtaining such tissues from nonhuman apes, motivated us to consider an alternative in vitro system with which to comparatively study gene regulation in skeletal cell types. Specifically, we differentiated six human (Homo sapiens) and six chimpanzee (Pan troglodytes) induced pluripotent stem cell lines (iPSCs) into mesenchymal stem cells (MSCs) and subsequently into osteogenic cells (bone cells). We validated differentiation using standard methods and collected single-cell RNA sequencing data from over 100,000 cells across multiple samples and replicates at each stage of differentiation. While most genes that we examined display conserved patterns of expression across species, hundreds of genes are differentially expressed (DE) between humans and chimpanzees within and across stages of osteogenic differentiation. Some of these interspecific DE genes show functional enrichments relevant in skeletal tissue trait development. Moreover, topic modeling indicates that interspecific gene programs become more pronounced as cells mature. Overall, we propose that this in vitro model can be used to identify interspecific regulatory differences that may have contributed to skeletal trait differences between species.


Assuntos
Células-Tronco Pluripotentes Induzidas , Osteogênese , Animais , Técnicas de Cultura de Células , Regulação da Expressão Gênica/genética , Osteogênese/genética , Pan troglodytes/genética , Primatas/genética
3.
PLoS Genet ; 18(1): e1009666, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35061661

RESUMO

Dynamic and temporally specific gene regulatory changes may underlie unexplained genetic associations with complex disease. During a dynamic process such as cellular differentiation, the overall cell type composition of a tissue (or an in vitro culture) and the gene regulatory profile of each cell can both experience significant changes over time. To identify these dynamic effects in high resolution, we collected single-cell RNA-sequencing data over a differentiation time course from induced pluripotent stem cells to cardiomyocytes, sampled at 7 unique time points in 19 human cell lines. We employed a flexible approach to map dynamic eQTLs whose effects vary significantly over the course of bifurcating differentiation trajectories, including many whose effects are specific to one of these two lineages. Our study design allowed us to distinguish true dynamic eQTLs affecting a specific cell lineage from expression changes driven by potentially non-genetic differences between cell lines such as cell composition. Additionally, we used the cell type profiles learned from single-cell data to deconvolve and re-analyze data from matched bulk RNA-seq samples. Using this approach, we were able to identify a large number of novel dynamic eQTLs in single cell data while also attributing dynamic effects in bulk to a particular lineage. Overall, we found that using single cell data to uncover dynamic eQTLs can provide new insight into the gene regulatory changes that occur among heterogeneous cell types during cardiomyocyte differentiation.


Assuntos
Perfilação da Expressão Gênica/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Análise de Célula Única/métodos , Técnicas de Cultura de Células , Diferenciação Celular , Linhagem Celular , Linhagem da Célula , Regulação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/química , Miócitos Cardíacos/química , RNA-Seq
4.
Trends Genet ; 37(3): 216-223, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33203573

RESUMO

The notion that topologically associating domains (TADs) are highly conserved across species is prevalent in the field of 3D genomics. However, what exactly is meant by 'highly conserved' and what are the actual comparative data that support this notion? To address these questions, we performed a historical review of the relevant literature and retraced numerous citation chains to reveal the primary data that were used as the basis for the widely accepted conclusion that TADs are highly conserved across evolution. A thorough review of the available evidence suggests the answer may be more complex than what is commonly presented.


Assuntos
Sequência Conservada/genética , Evolução Molecular , Domínios Proteicos/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Genoma Humano/genética , Genômica , Humanos
5.
Trends Genet ; 37(2): 109-124, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32912663

RESUMO

Most disease-associated variants, although located in putatively regulatory regions, do not have detectable effects on gene expression. One explanation could be that we have not examined gene expression in the cell types or conditions that are most relevant for disease. Even large-scale efforts to study gene expression across tissues are limited to human samples obtained opportunistically or postmortem, mostly from adults. In this review we evaluate recent findings and suggest an alternative strategy, drawing on the dynamic and highly context-specific nature of gene regulation. We discuss new technologies that can extend the standard regulatory mapping framework to more diverse, disease-relevant cell types and states.


Assuntos
Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Animais , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Humanos , Sequências Reguladoras de Ácido Nucleico/genética
6.
Genome Res ; 30(4): 611-621, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32312741

RESUMO

Cellular heterogeneity in gene expression is driven by cellular processes, such as cell cycle and cell-type identity, and cellular environment such as spatial location. The cell cycle, in particular, is thought to be a key driver of cell-to-cell heterogeneity in gene expression, even in otherwise homogeneous cell populations. Recent advances in single-cell RNA-sequencing (scRNA-seq) facilitate detailed characterization of gene expression heterogeneity and can thus shed new light on the processes driving heterogeneity. Here, we combined fluorescence imaging with scRNA-seq to measure cell cycle phase and gene expression levels in human induced pluripotent stem cells (iPSCs). By using these data, we developed a novel approach to characterize cell cycle progression. Although standard methods assign cells to discrete cell cycle stages, our method goes beyond this and quantifies cell cycle progression on a continuum. We found that, on average, scRNA-seq data from only five genes predicted a cell's position on the cell cycle continuum to within 14% of the entire cycle and that using more genes did not improve this accuracy. Our data and predictor of cell cycle phase can directly help future studies to account for cell cycle-related heterogeneity in iPSCs. Our results and methods also provide a foundation for future work to characterize the effects of the cell cycle on expression heterogeneity in other cell types.


Assuntos
Ciclo Celular/genética , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de RNA , Análise de Célula Única/métodos , Linhagem Celular , Perfilação da Expressão Gênica , Genes Reporter , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Análise de Sequência de RNA/métodos
7.
Genome Res ; 30(2): 250-262, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31953346

RESUMO

Previously published comparative functional genomic data sets from primates using frozen tissue samples, including many data sets from our own group, were often collected and analyzed using nonoptimal study designs and analysis approaches. In addition, when samples from multiple tissues were studied in a comparative framework, individuals and tissues were confounded. We designed a multitissue comparative study of gene expression and DNA methylation in primates that minimizes confounding effects by using a balanced design with respect to species, tissues, and individuals. We also developed a comparative analysis pipeline that minimizes biases attributable to sequence divergence. Thus, we present the most comprehensive catalog of similarities and differences in gene expression and DNA methylation levels between livers, kidneys, hearts, and lungs, in humans, chimpanzees, and rhesus macaques. We estimate that overall, interspecies and inter-tissue differences in gene expression levels can only modestly be accounted for by corresponding differences in promoter DNA methylation. However, the expression pattern of genes with conserved inter-tissue expression differences can be explained by corresponding interspecies methylation changes more often. Finally, we show that genes whose tissue-specific regulatory patterns are consistent with the action of natural selection are highly connected in both gene regulatory and protein-protein interaction networks.


Assuntos
Metilação de DNA/genética , Expressão Gênica/genética , Genômica , Seleção Genética , Animais , Epigênese Genética , Perfilação da Expressão Gênica , Humanos , Macaca mulatta/genética , Pan troglodytes/genética , Regiões Promotoras Genéticas/genética , Processamento de Proteína Pós-Traducional/genética , Especificidade da Espécie
8.
PLoS Genet ; 15(7): e1008278, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31323043

RESUMO

A growing body of evidence supports the notion that variation in gene regulation plays a crucial role in both speciation and adaptation. However, a comprehensive functional understanding of the mechanisms underlying regulatory evolution remains elusive. In primates, one of the crucial missing pieces of information towards a better understanding of regulatory evolution is a comparative annotation of interactions between distal regulatory elements and promoters. Chromatin conformation capture technologies have enabled genome-wide quantifications of such distal 3D interactions. However, relatively little comparative research in primates has been done using such technologies. To address this gap, we used Hi-C to characterize 3D chromatin interactions in induced pluripotent stem cells (iPSCs) from humans and chimpanzees. We also used RNA-seq to collect gene expression data from the same lines. We generally observed that lower-order, pairwise 3D genomic interactions are conserved in humans and chimpanzees, but higher order genomic structures, such as topologically associating domains (TADs), are not as conserved. Inter-species differences in 3D genomic interactions are often associated with gene expression differences between the species. To provide additional functional context to our observations, we considered previously published chromatin data from human stem cells. We found that inter-species differences in 3D genomic interactions, which are also associated with gene expression differences between the species, are enriched for both active and repressive marks. Overall, our data demonstrate that, as expected, an understanding of 3D genome reorganization is key to explaining regulatory evolution.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Pan troglodytes/genética , Animais , Montagem e Desmontagem da Cromatina , Evolução Molecular , Regulação da Expressão Gênica , Genoma , Humanos , Análise de Sequência de RNA/métodos
9.
PLoS Genet ; 15(4): e1008045, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31002671

RESUMO

Quantification of gene expression levels at the single cell level has revealed that gene expression can vary substantially even across a population of homogeneous cells. However, it is currently unclear what genomic features control variation in gene expression levels, and whether common genetic variants may impact gene expression variation. Here, we take a genome-wide approach to identify expression variance quantitative trait loci (vQTLs). To this end, we generated single cell RNA-seq (scRNA-seq) data from induced pluripotent stem cells (iPSCs) derived from 53 Yoruba individuals. We collected data for a median of 95 cells per individual and a total of 5,447 single cells, and identified 235 mean expression QTLs (eQTLs) at 10% FDR, of which 79% replicate in bulk RNA-seq data from the same individuals. We further identified 5 vQTLs at 10% FDR, but demonstrate that these can also be explained as effects on mean expression. Our study suggests that dispersion QTLs (dQTLs) which could alter the variance of expression independently of the mean can have larger fold changes, but explain less phenotypic variance than eQTLs. We estimate 4,015 individuals as a lower bound to achieve 80% power to detect the strongest dQTLs in iPSCs. These results will guide the design of future studies on understanding the genetic control of gene expression variance.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Locos de Características Quantitativas , População Negra/genética , Linhagem Celular , Simulação por Computador , Perfilação da Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Nigéria , Fenótipo , Análise de Sequência de RNA , Análise de Célula Única
10.
Genome Res ; 28(1): 122-131, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29208628

RESUMO

Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation on gene regulation across different cell types and as models for studies of complex disease. To do so, we established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs); 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across individuals and cell types by measuring gene expression levels, chromatin accessibility, and DNA methylation. Our analysis focused on a comparison of inter-individual regulatory variation across cell types. While most cell-type-specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell-type-specific regulatory QTLs are in shared open chromatin. This observation motivated us to develop a deep neural network to predict open chromatin regions from DNA sequence alone. Using this approach, we were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell-type-specific chromatin accessibility.


Assuntos
Diferenciação Celular , Montagem e Desmontagem da Cromatina , Cromatina/metabolismo , Metilação de DNA , Loci Gênicos , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Linhagem Celular , Cromatina/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia
12.
PLoS Genet ; 12(1): e1005793, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26812582

RESUMO

The advent of induced pluripotent stem cells (iPSCs) revolutionized human genetics by allowing us to generate pluripotent cells from easily accessible somatic tissues. This technology can have immense implications for regenerative medicine, but iPSCs also represent a paradigm shift in the study of complex human phenotypes, including gene regulation and disease. Yet, an unresolved caveat of the iPSC model system is the extent to which reprogrammed iPSCs retain residual phenotypes from their precursor somatic cells. To directly address this issue, we used an effective study design to compare regulatory phenotypes between iPSCs derived from two types of commonly used somatic precursor cells. We find a remarkably small number of differences in DNA methylation and gene expression levels between iPSCs derived from different somatic precursors. Instead, we demonstrate genetic variation is associated with the majority of identifiable variation in DNA methylation and gene expression levels. We show that the cell type of origin only minimally affects gene expression levels and DNA methylation in iPSCs, and that genetic variation is the main driver of regulatory differences between iPSCs of different donors. Our findings suggest that studies using iPSCs should focus on additional individuals rather than clones from the same individual.


Assuntos
Diferenciação Celular/genética , Metilação de DNA/genética , Epigenômica , Células-Tronco Pluripotentes Induzidas , Linhagem da Célula , Fibroblastos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Variação Genética , Humanos
13.
Hum Mol Genet ; 25(10): 2104-2112, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26931462

RESUMO

Genome-wide association studies (GWASs) have become a standard tool for dissecting genetic contributions to disease risk. However, these studies typically require extraordinarily large sample sizes to be adequately powered. Strategies that incorporate functional information alongside genetic associations have proved successful in increasing GWAS power. Following this paradigm, we present the results of 20 different genetic association studies for quantitative traits related to complex diseases, conducted in the Hutterites of South Dakota. To boost the power of these association studies, we collected RNA-sequencing data from lymphoblastoid cell lines for 431 Hutterite individuals. We then used Sherlock, a tool that integrates GWAS and expression quantitative trait locus (eQTL) data, to identify weak GWAS signals that are also supported by eQTL data. Using this approach, we found novel associations with quantitative phenotypes related to cardiovascular disease, including carotid intima-media thickness, left atrial volume index, monocyte count and serum YKL-40 levels.


Assuntos
Doenças Cardiovasculares/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Doenças Cardiovasculares/patologia , Espessura Intima-Media Carotídea , Regulação da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único
14.
Genome Res ; 25(12): 1801-11, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26392366

RESUMO

DNA methylation is an epigenetic mark thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a live pathogenic bacteria is associated with rapid and active demethylation at thousands of loci, independent of cell division. We performed an integrated analysis of data on genome-wide DNA methylation, histone mark patterns, chromatin accessibility, and gene expression, before and after infection. We found that infection-induced demethylation rarely occurs at promoter regions and instead localizes to distal enhancer elements, including those that regulate the activation of key immune transcription factors. Active demethylation is associated with extensive epigenetic remodeling, including the gain of histone activation marks and increased chromatin accessibility, and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that active, rapid changes in DNA methylation in enhancers play a previously unappreciated role in regulating the transcriptional response to infection, even in nonproliferating cells.


Assuntos
Infecções Bacterianas/genética , Metilação de DNA , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Interações Hospedeiro-Patógeno/genética , 5-Metilcitosina/análogos & derivados , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Ilhas de CpG , Citosina/análogos & derivados , Citosina/metabolismo , Células Dendríticas/imunologia , Epigênese Genética , Epigenômica/métodos , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Mycobacterium tuberculosis/imunologia , Fatores de Transcrição/metabolismo , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/metabolismo , Tuberculose/microbiologia
15.
Nat Methods ; 12(11): 1061-3, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26366987

RESUMO

Allele-specific sequencing reads provide a powerful signal for identifying molecular quantitative trait loci (QTLs), but they are challenging to analyze and are prone to technical artifacts. Here we describe WASP, a suite of tools for unbiased allele-specific read mapping and discovery of molecular QTLs. Using simulated reads, RNA-seq reads and chromatin immunoprecipitation sequencing (ChIP-seq) reads, we demonstrate that WASP has a low error rate and is far more powerful than existing QTL-mapping approaches.


Assuntos
Biologia Computacional/métodos , Locos de Características Quantitativas , Análise de Sequência de RNA/métodos , Alelos , Artefatos , Imunoprecipitação da Cromatina , Genoma , Genótipo , Haplótipos , Heterozigoto , Humanos , Funções Verossimilhança , Reprodutibilidade dos Testes , Análise de Sequência de DNA , Software
16.
Nat Rev Genet ; 13(7): 505-16, 2012 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-22705669

RESUMO

The hypothesis that differences in gene regulation have an important role in speciation and adaptation is more than 40 years old. With the advent of new sequencing technologies, we are able to characterize and study gene expression levels and associated regulatory mechanisms in a large number of individuals and species at an unprecedented resolution and scale. We have thus gained new insights into the evolutionary pressures that shape gene expression levels and have developed an appreciation for the relative importance of evolutionary changes in different regulatory genetic and epigenetic mechanisms. The current challenge is to link gene regulatory changes to adaptive evolution of complex phenotypes. Here we mainly focus on comparative studies in primates and how they are complemented by studies in model organisms.


Assuntos
Adaptação Biológica/fisiologia , Evolução Biológica , Epigênese Genética , Regulação da Expressão Gênica/fisiologia , Especiação Genética , Modelos Genéticos , Fisiologia Comparada/métodos , Primatas/genética , Adaptação Biológica/genética , Animais , Regulação da Expressão Gênica/genética , Seleção Genética , Especificidade da Espécie , Fatores de Transcrição/metabolismo
17.
Nature ; 550(7675): 190-191, 2017 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-29022577

Assuntos
Genômica , Humanos
18.
Nature ; 482(7385): 390-4, 2012 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-22307276

RESUMO

The mapping of expression quantitative trait loci (eQTLs) has emerged as an important tool for linking genetic variation to changes in gene regulation. However, it remains difficult to identify the causal variants underlying eQTLs, and little is known about the regulatory mechanisms by which they act. Here we show that genetic variants that modify chromatin accessibility and transcription factor binding are a major mechanism through which genetic variation leads to gene expression differences among humans. We used DNase I sequencing to measure chromatin accessibility in 70 Yoruba lymphoblastoid cell lines, for which genome-wide genotypes and estimates of gene expression levels are also available. We obtained a total of 2.7 billion uniquely mapped DNase I-sequencing (DNase-seq) reads, which allowed us to produce genome-wide maps of chromatin accessibility for each individual. We identified 8,902 locations at which the DNase-seq read depth correlated significantly with genotype at a nearby single nucleotide polymorphism or insertion/deletion (false discovery rate = 10%). We call such variants 'DNase I sensitivity quantitative trait loci' (dsQTLs). We found that dsQTLs are strongly enriched within inferred transcription factor binding sites and are frequently associated with allele-specific changes in transcription factor binding. A substantial fraction (16%) of dsQTLs are also associated with variation in the expression levels of nearby genes (that is, these loci are also classified as eQTLs). Conversely, we estimate that as many as 55% of eQTL single nucleotide polymorphisms are also dsQTLs. Our observations indicate that dsQTLs are highly abundant in the human genome and are likely to be important contributors to phenotypic variation.


Assuntos
Pegada de DNA , Desoxirribonuclease I/metabolismo , Regulação da Expressão Gênica/genética , Variação Genética/genética , Locos de Características Quantitativas/genética , Cromatina/genética , Cromatina/metabolismo , Perfilação da Expressão Gênica , Genoma Humano/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Fatores de Transcrição/metabolismo
19.
PLoS Genet ; 11(1): e1004857, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25569255

RESUMO

It is now well established that noncoding regulatory variants play a central role in the genetics of common diseases and in evolution. However, until recently, we have known little about the mechanisms by which most regulatory variants act. For instance, what types of functional elements in DNA, RNA, or proteins are most often affected by regulatory variants? Which stages of gene regulation are typically altered? How can we predict which variants are most likely to impact regulation in a given cell type? Recent studies, in many cases using quantitative trait loci (QTL)-mapping approaches in cell lines or tissue samples, have provided us with considerable insight into the properties of genetic loci that have regulatory roles. Such studies have uncovered novel biochemical regulatory interactions and led to the identification of previously unrecognized regulatory mechanisms. We have learned that genetic variation is often directly associated with variation in regulatory activities (namely, we can map regulatory QTLs, not just expression QTLs [eQTLs]), and we have taken the first steps towards understanding the causal order of regulatory events (for example, the role of pioneer transcription factors). Yet, in most cases, we still do not know how to interpret overlapping combinations of regulatory interactions, and we are still far from being able to predict how variation in regulatory mechanisms is propagated through a chain of interactions to eventually result in changes in gene expression profiles.


Assuntos
Cromatina/genética , Regulação da Expressão Gênica , Genoma Humano , Locos de Características Quantitativas/genética , Mapeamento Cromossômico , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Fatores de Transcrição/genética
20.
PLoS Genet ; 11(4): e1005111, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25874939

RESUMO

Rhinovirus (RV) is the most prevalent human respiratory virus and is responsible for at least half of all common colds. RV infections may result in a broad spectrum of effects that range from asymptomatic infections to severe lower respiratory illnesses. The basis for inter-individual variation in the response to RV infection is not well understood. In this study, we explored whether host genetic variation is associated with variation in gene expression response to RV infections between individuals. To do so, we obtained genome-wide genotype and gene expression data in uninfected and RV-infected peripheral blood mononuclear cells (PBMCs) from 98 individuals. We mapped local and distant genetic variation that is associated with inter-individual differences in gene expression levels (eQTLs) in both uninfected and RV-infected cells. We focused specifically on response eQTLs (reQTLs), namely, genetic associations with inter-individual variation in gene expression response to RV infection. We identified local reQTLs for 38 genes, including genes with known functions in viral response (UBA7, OAS1, IRF5) and genes that have been associated with immune and RV-related diseases (e.g., ITGA2, MSR1, GSTM3). The putative regulatory regions of genes with reQTLs were enriched for binding sites of virus-activated STAT2, highlighting the role of condition-specific transcription factors in genotype-by-environment interactions. Overall, we suggest that the 38 loci associated with inter-individual variation in gene expression response to RV-infection represent promising candidates for affecting immune and RV-related respiratory diseases.


Assuntos
Resfriado Comum/genética , Loci Gênicos , Variação Genética , Transcriptoma , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Adulto , Resfriado Comum/metabolismo , Feminino , Perfilação da Expressão Gênica , Interação Gene-Ambiente , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Integrina alfa2/genética , Integrina alfa2/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/metabolismo , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo
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