RESUMEN
Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.
Asunto(s)
Variación Genética/genética , Células Madre Pluripotentes Inducidas/metabolismo , Células Cultivadas , Reprogramación Celular/genética , Variaciones en el Número de Copia de ADN/genética , Regulación de la Expresión Génica/genética , Genotipo , Humanos , Especificidad de Órganos , Fenotipo , Control de Calidad , Sitios de Carácter Cuantitativo/genética , Transcriptoma/genéticaRESUMEN
This corrects the article DOI: 10.1038/nature22403.
RESUMEN
We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.
Asunto(s)
Regulación de la Expresión Génica/genética , Variación Genética/genética , Genoma/genética , Ratones Endogámicos/genética , Ratones/genética , Fenotipo , Alelos , Animales , Animales de Laboratorio/genética , Genómica , Ratones/clasificación , Ratones Endogámicos C57BL/genética , Filogenia , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Natural variation within species reveals aspects of genome evolution and function. The fission yeast Schizosaccharomyces pombe is an important model for eukaryotic biology, but researchers typically use one standard laboratory strain. To extend the usefulness of this model, we surveyed the genomic and phenotypic variation in 161 natural isolates. We sequenced the genomes of all strains, finding moderate genetic diversity (π = 3 × 10(-3) substitutions/site) and weak global population structure. We estimate that dispersal of S. pombe began during human antiquity (â¼340 BCE), and ancestors of these strains reached the Americas at â¼1623 CE. We quantified 74 traits, finding substantial heritable phenotypic diversity. We conducted 223 genome-wide association studies, with 89 traits showing at least one association. The most significant variant for each trait explained 22% of the phenotypic variance on average, with indels having larger effects than SNPs. This analysis represents a rich resource to examine genotype-phenotype relationships in a tractable model.