RESUMEN
Epigenomics regulates gene expression and is as important as genomics in precision personal health, as it is heavily influenced by environment and lifestyle. We profiled whole-genome DNA methylation and the corresponding transcriptome of peripheral blood mononuclear cells collected from a human volunteer over a period of 36 months, generating 28 methylome and 57 transcriptome datasets. We found that DNA methylomic changes are associated with infrequent glucose level alteration, whereas the transcriptome underwent dynamic changes during events such as viral infections. Most DNA meta-methylome changes occurred 80-90 days before clinically detectable glucose elevation. Analysis of the deep personal methylome dataset revealed an unprecedented number of allelic differentially methylated regions that remain stable longitudinally and are preferentially associated with allele-specific gene regulation. Our results revealed that changes in different types of 'omics' data associate with different physiological aspects of this individual: DNA methylation with chronic conditions and transcriptome with acute events.
Asunto(s)
Metilación de ADN/genética , Epigenómica , Glucosa/metabolismo , Transcriptoma/genética , Alelos , Islas de CpG/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Genoma Humano/genética , Glucosa/genética , Humanos , Leucocitos Mononucleares/metabolismo , VoluntariosRESUMEN
The health of an individual depends upon their DNA as well as upon environmental factors (environome or exposome). It is expected that although the genome is the blueprint of an individual, its analysis with that of the other omes such as the DNA methylome, the transcriptome, proteome, and metabolome will further provide a dynamic assessment of the physiology and health state of an individual. This review will help to categorize the current progress of omics analyses and how omics integration can be used for medical research. We believe that integrative personal omics profiling (iPOP) is a stepping stone to a new road to personalized health care and may improve disease risk assessment, accuracy of diagnosis, disease monitoring, targeted treatments, and understanding the biological processes of disease states for their prevention.
Asunto(s)
Biología Computacional/métodos , Medicina de Precisión/métodos , Animales , ADN/genética , Humanos , Neoplasias/genética , Proteoma/genética , ARN/genéticaRESUMEN
Gene expression differs among individuals and populations and is thought to be a major determinant of phenotypic variation. Although variation and genetic loci responsible for RNA expression levels have been analysed extensively in human populations, our knowledge is limited regarding the differences in human protein abundance and the genetic basis for this difference. Variation in messenger RNA expression is not a perfect surrogate for protein expression because the latter is influenced by an array of post-transcriptional regulatory mechanisms, and, empirically, the correlation between protein and mRNA levels is generally modest. Here we used isobaric tag-based quantitative mass spectrometry to determine relative protein levels of 5,953 genes in lymphoblastoid cell lines from 95 diverse individuals genotyped in the HapMap Project. We found that protein levels are heritable molecular phenotypes that exhibit considerable variation between individuals, populations and sexes. Levels of specific sets of proteins involved in the same biological process covary among individuals, indicating that these processes are tightly regulated at the protein level. We identified cis-pQTLs (protein quantitative trait loci), including variants not detected by previous transcriptome studies. This study demonstrates the feasibility of high-throughput human proteome quantification that, when integrated with DNA variation and transcriptome information, adds a new dimension to the characterization of gene expression regulation.
Asunto(s)
Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Fenotipo , Biosíntesis de Proteínas , Proteoma/análisis , Proteoma/genética , Línea Celular , Etnicidad/genética , Femenino , Variación Genética , Genotipo , Proyecto Mapa de Haplotipos , Humanos , Masculino , Espectrometría de Masas , Proteoma/biosíntesis , Proteómica , Sitios de Carácter Cuantitativo , ARN Mensajero/análisis , ARN Mensajero/genética , TranscriptomaRESUMEN
Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.
Asunto(s)
Genoma Humano , Genómica , Medicina de Precisión , Diabetes Mellitus Tipo 2/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Metabolómica , Persona de Mediana Edad , Mutación , Proteómica , Virus Sincitiales Respiratorios/aislamiento & purificación , Rhinovirus/aislamiento & purificaciónRESUMEN
Plant mitochondrial group II introns do not all possess hallmark ribozymic features such as the bulged adenosine involved in lariat formation. To gain insight into their splicing pathways, we have examined the physical form of excised introns in germinating wheat embryos. Using RT-PCR and cRT-PCR, we observed conventional lariats consistent with a two-step transesterification pathway for introns such as nad2 intron 4, but this was not the case for the cox2 intron or nad1 intron 2. For cox2, we detected full-length linear introns, which possess non-encoded 3'terminaladenosines, as well as heterogeneous circular introns, which lack 3' nucleotide stretches. These observations are consistent with hydrolytic splicing followed by polyadenylation as well as an in vivo circularization pathway, respectively. The presence of both linear and circular species in vivo is supported by RNase H analysis. Furthermore, the nad1 intron 2, which lacks a bulged nucleotide at the branchpoint position, comprised a mixed population of precisely full-length molecules and circular ones which also include a short, discrete block of non-encoded nucleotides. The presence of these various linear and circular forms of excised intron molecules in plant mitochondria points to multiple novel group II splicing mechanisms in vivo.
Asunto(s)
Intrones , Empalme del ARN , ARN de Planta/química , ARN/química , Triticum/genética , Secuencia de Bases , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , ARN/metabolismo , ARN Mitocondrial , ARN de Planta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleasa H , Triticum/metabolismoRESUMEN
We examined RNA profiles of wheat mitochondrial genes during the developmental period when seeds leave dormancy, germinate and develop into seedlings. Mitochondrial RNAs isolated from 0 h to 6 days post-imbibition were subjected to Northern analysis, using coding-specific and intron-specific probes. Stable, edited mRNAs were observed in dormant seeds and precursor RNAs were subsequently detected early in embryo germination. The respiratory chain genes (nad7, cox1, cox2, atp6) showed mRNA profiles which paralleled those of the ribosomal RNAs, whereas ribosomal protein genes (rps2, rps3, rps7) had proportionately lower steady-state mRNA levels in later stages of seedling development. The relative levels of precursors compared with the respective mRNAs shifted down during development, consistent with transcription outpacing RNA processing in the early stages but co-ordination being more effective several days after imbibition. In the case of multiply split genes containing group II introns, complex patterns of splicing intermediates were observed, suggesting a lack of strict polarity of intron removal, although splicing efficiency appears to differ among introns. Excised intron RNAs typically are relatively more abundant in embryos than seedlings. These observations are consistent with a transient imbalance of RNA-processing machinery at the onset of seed germination, which is a period of rapid mitochondrial biogenesis.