Molecular and functional variation in iPSC-derived sensory neurons

Schwartzentruber, Jeremy; Foskolou, Stefanie; Kilpinen, Helena; Rodrigues, Julia; Alasoo, Kaur; Knights, Andrew; Patel, Minal; Gonçalves, Ângela; Ferreira, Rita; Benn, Caroline; Wilbrey, Anna; Bictash, Magda; Impey, Emma; Cao, Lishuang; Laínez, Sergio; Loucif, Alexandre; Whiting, Paul J.; Gutteridge, Alex; Gaffney, Daniel J.

doi:10.1038/s41588-017-0005-8

Cited by 191 publications

(176 citation statements)

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“…Critically, recent technological developments have begun to facilitate such studies in vitro. In particular, the generation of population-scale collections of human induced pluripotent stem cells (iPSCs) 1,2 has allowed for assessing regulatory genetic variants in pluripotent 1,2 as well as in differentiated cells [3][4][5] . In addition, the rapid developments in single-cell RNA-seq now allow for assessing the molecular impact of genetic variability in a continuous manner across early human development.…”

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confidence: 99%

Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression

et al. 2020

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Recent developments in stem cell biology have enabled the study of cell fate decisions in early human development that are impossible to study in vivo. However, understanding how development varies across individuals and, in particular, the influence of common genetic variants during this process has not been characterised. Here, we exploit human iPS cell lines from 125 donors, a pooled experimental design, and single-cell RNA-sequencing to study population variation of endoderm differentiation. We identify molecular markers that are predictive of differentiation efficiency of individual lines, and utilise heterogeneity in the genetic background across individuals to map hundreds of expression quantitative trait loci that influence expression dynamically during differentiation and across cellular contexts.There are amendments to this paper

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confidence: 99%

Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression

et al. 2020

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“…Understanding the mechanisms through which genetic variations act in the human population is of great relevance to characterising risk factors and susceptibility to disease. There is growing interest in the potential for studying disease mechanisms using disease relevant tissues that are derived from panels of iPSCs 30–33 . Our study provides important information for advancing such studies on the genetic regulation of protein expression and disease-relevant phenotypes in iPSC-derived model systems.…”

Section: Discussionmentioning

confidence: 99%

Population-scale proteome variation in human induced pluripotent stem cells

Mirauta

Seaton

Bensaddek

et al. 2018

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29Realising the potential of human induced pluripotent stem cell (iPSC) technology for drug 30 discovery, disease modelling and cell therapy requires an understanding of variability across 31 iPSC lines. While previous studies have characterized iPS cell lines genetically and 32 transcriptionally, little is known about the variability of the iPSC proteome. Here, we present 33 the first comprehensive proteomic iPSC dataset, analysing 202 iPSC lines derived from 151 34 donors. We characterise the major genetic determinants affecting proteome and transcriptome 35 variation across iPSC lines and identify key regulatory mechanisms affecting variation in 36 protein abundance. Our data identified >700 human iPSC protein quantitative trait loci 37 (pQTLs). We mapped trans regulatory effects, identifying an important role for protein-protein 38 interactions. We discovered that pQTLs show increased enrichment in disease-linked GWAS 39 variants, compared with RNA-based eQTLs. 40 41 42 Induced pluripotent stem cells (iPSC) hold enormous promise for advancing basic research 43 and biomedicine. By enabling the in vitro reconstitution of development and cell differentiation, 44 iPS cells allow the investigation of mechanisms underlying development and the aetiology of 45 many forms of genetic disease. To realize this potential, it is essential to characterize how 46 genetic and non-genetic effects in human iPSCs influence molecular and cellular phenotypes. 47 48 Recently, the establishment of population reference panels of normal human iPSC lines 1-3 49 have provided valuable resources for functional experiments in different genetic backgrounds.50 Additionally, these data have yielded detailed characterizations of the iPS transcriptome, 51 identifying thousands of cis expression Quantitative Trait Loci (eQTL) 1,4,5 , including at disease-52 relevant loci. While these RNA-based analyses are informative for studying mechanisms 53 affecting gene regulation at the transcriptional level, most cellular phenotypes involve 54 mechanisms acting downstream, at the protein level. Evidence in other contexts, including in 55 lymphoblast cell lines and in cancer, point to substantial differences in the genetic regulation 56 of protein and RNA traits, identifying protein QTL 6-9 and assessing the extent of buffering of 57 genetic effects between layers 10,11 . However, existing protein datasets have been limited by 58 scale (i.e. number of samples) or resolution (i.e. number of proteins, availability of RNA data).59 Importantly, no population-scale proteome datasets have been generated from human 60 pluripotent cells. 61 62 Here, we report on the first comprehensive, population-scale, combined proteomics and gene 63 expression analysis in human iPSC lines. Our data comprise matched quantitative proteomic 64 (TMT Mass Spectrometry) and transcriptomic (RNA-seq) profiles of 202 iPSC lines, derived 65 from 151 donors that are part of the HipSci project 1 . We identify both genetic and non-genetic 66 effects causing variability in protein expressi...

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“…QTL studies have yielded large advances in mapping the genotype-phenotype connections, with eQTL studies likely being the most common means of assembling regulatory networks linked to genotype. However, these studies often rely on whole tissue ('The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans ', 2015) or sorted cell profiling where the multi-cellularity context is absent (Heng and Painter, 2008;Dimas et al, 2009;Link et al, 2018;Schwartzentruber et al, 2018). Most recently, profiling single cell gene expression and genotype of multiple cell-types has become a viable option (van der Wijst et al, 2018), yet due to prohibitive costs and high level of noise, generating networks and associating their variation to genotypic variants remains difficult.…”

Section: Introductionmentioning

confidence: 99%

Architecture of a multi-cellular polygenic network governing immune homeostasis

Dubovik

Starosvetsky

LeRoy

et al. 2018

Preprint

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Variation in immune cellular homeostasis exists between individuals, is heritable and due to genes and environment. Environmental influences increase with age, masking genetic determinants and barring human adult studies from informing on the origin of baseline variability.To identify genetic factors affecting individuals' immune profile in early life we profiled the bone marrow of 55 genetically diverse Collaborative Cross mouse strains, using high resolution masscytometry. We identified 1,662 genes associated with 11 well defined cell subsets, 862 of which validated in an independent cohort. These genes were strongly enriched for basic housekeeping functions of proliferation and death, predicted cellular abundance and showed a higher mutation rate across multiple human cancers. Thus, akin to mRNA or protein species abundance, cellular variation is determined by genetic variants of production and turnover genes. Given these affect baseline homeostasis, reaching an at-risk immune state would differ for individuals, set by the genetic determinants we identified here.

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Molecular and functional variation in iPSC-derived sensory neurons

Cited by 191 publications

References 48 publications

Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression

Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression

Population-scale proteome variation in human induced pluripotent stem cells

Architecture of a multi-cellular polygenic network governing immune homeostasis

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