14 results on '"Meleckyte, Ruta"'
Search Results
2. Common genetic variation drives molecular heterogeneity in human iPSCs
- Author
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Kilpinen, Helena, Goncalves, Angela, Leha, Andreas, Afzal, Vackar, Alasoo, Kaur, Ashford, Sofie, Bala, Sendu, Bensaddek, Dalila, Casale, Francesco Paolo, Culley, Oliver J., Danecek, Petr, Faulconbridge, Adam, Harrison, Peter W., Kathuria, Annie, McCarthy, Davis, McCarthy, Shane A., Meleckyte, Ruta, Memari, Yasin, Moens, Nathalie, Soares, Filipa, Mann, Alice, Streeter, Ian, Agu, Chukwuma A., Alderton, Alex, Nelson, Rachel, Harper, Sarah, Patel, Minal, White, Alistair, Patel, Sharad R., Clarke, Laura, Halai, Reena, Kirton, Christopher M., Kolb-Kokocinski, Anja, Beales, Philip, Birney, Ewan, Danovi, Davide, Lamond, Angus I., Ouwehand, Willem H., Vallier, Ludovic, Watt, Fiona M., Durbin, Richard, Stegle, Oliver, and Gaffney, Daniel J.
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Genetic variation -- Health aspects ,Stem cells -- Genetic aspects -- Health aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
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 546% 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., Author(s): Helena Kilpinen [1]; Angela Goncalves [2]; Andreas Leha [2]; Vackar Afzal [3]; Kaur Alasoo [2]; Sofie Ashford [4]; Sendu Bala [2]; Dalila Bensaddek [3]; Francesco Paolo Casale [1]; Oliver [...]
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- 2017
- Full Text
- View/download PDF
3. Population-scale proteome variation in human induced pluripotent stem cells
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Mirauta, Bogdan Andrei, Seaton, Daniel D, Bensaddek, Dalila, Brenes, Alejandro, Bonder, Marc Jan, Kilpinen, Helena, Agu, Chukwuma A, Alderton, Alex, Danecek, Petr, Denton, Rachel, Durbin, Richard, Gaffney, Daniel J, Goncalves, Angela, Halai, Reena, Harper, Sarah, Kirton, Christopher M, Kolb-Kokocinski, Anja, Leha, Andreas, McCarthy, Shane A, Memari, Yasin, Patel, Minal, Birney, Ewan, Casale, Francesco Paolo, Clarke, Laura, Harrison, Peter W, Streeter, Ian, Denovi, Davide, Stegle, Oliver, Lamond, Angus I, Meleckyte, Ruta, Moens, Natalie, Watt, Fiona M, Ouwehand, Willem H, Beales, Philip, Mirauta, Bogdan Andrei [0000-0002-9733-292X], Bonder, Marc Jan [0000-0002-8431-3180], Kilpinen, Helena [0000-0001-6692-6154], Stegle, Oliver [0000-0002-8818-7193], Lamond, Angus I [0000-0001-6204-6045], Apollo - University of Cambridge Repository, and Helsinki Institute of Life Science HiLIFE
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Male ,Proteomics ,Proteome ,Genome-wide association study ,VARIANTS ,Transcriptome ,0302 clinical medicine ,SCHIZOPHRENIA ,Human proteome project ,genetics ,Disease ,Biology (General) ,Induced pluripotent stem cell ,Child ,GENE-EXPRESSION ,0303 health sciences ,education.field_of_study ,Drug discovery ,General Neuroscience ,General Medicine ,Middle Aged ,Phenotype ,Child, Preschool ,Medicine ,ABUNDANCE ,Female ,Research Article ,Adult ,Adolescent ,Genotype ,QH301-705.5 ,induced pluripotent stem cells ,Science ,Population ,Quantitative Trait Loci ,deleterious variants ,Genomics ,Computational biology ,Quantitative trait locus ,Biology ,General Biochemistry, Genetics and Molecular Biology ,DIFFERENTIAL EXPRESSION ,03 medical and health sciences ,Young Adult ,RESOURCE ,REVEALS ,genomics ,Humans ,human ,RNA, Messenger ,education ,030304 developmental biology ,Aged ,IDENTIFICATION ,General Immunology and Microbiology ,Infant, Newborn ,Genetic Variation ,Infant ,Genetics and Genomics ,QUANTIFICATION ,Genetics, Population ,REGULATORY VARIATION ,3111 Biomedicine ,030217 neurology & neurosurgery - Abstract
Human disease phenotypes are driven primarily by alterations in protein expression and/or function. To date, relatively little is known about the variability of the human proteome in populations and how this relates to variability in mRNA expression and to disease loci. Here, we present the first comprehensive proteomic analysis of human induced pluripotent stem cells (iPSC), a key cell type for disease modelling, analysing 202 iPSC lines derived from 151 donors, with integrated transcriptome and genomic sequence data from the same lines. We characterised the major genetic and non-genetic determinants of proteome variation across iPSC lines and assessed key regulatory mechanisms affecting variation in protein abundance. We identified 654 protein quantitative trait loci (pQTLs) in iPSCs, including disease-linked variants in protein-coding sequences and variants with trans regulatory effects. These include pQTL linked to GWAS variants that cannot be detected at the mRNA level, highlighting the utility of dissecting pQTL at peptide level resolution.
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- 2020
4. Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression
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Cuomo, Anna S. E., Seaton, Daniel D., McCarthy, Davis J., Martinez, Iker, Bonder, Marc Jan, Garcia-Bernardo, Jose, Amatya, Shradha, Madrigal, Pedro, Isaacson, Abigail, Buettner, Florian, Knights, Andrew, Natarajan, Kedar Nath, Vallier, Ludovic, Marioni, John C., Chhatriwala, Mariya, Stegle, Oliver, Agu, Chukwuma A., Alderton, Alex, Danecek, Petr, Denton, Rachel, Durbin, Richard, Gaffney, Daniel J., Goncalves, Angela, Halai, Reena, Harper, Sarah, Kirton, Christopher M., Kolb-Kokocinski, Anja, Leha, Andreas, McCarthy, Shane A., Memari, Yasin, Patel, Minal, Birney, Ewan, Casale, Francesco Paolo, Clarke, Laura, Harrison, Peter W., Kilpinen, Helena, Streeter, Ian, Denovi, Davide, Meleckyte, Ruta, Moens, Natalie, Watt, Fiona M., Ouwehand, Willem H., Lamond, Angus I., Bensaddek, Dalila, Beales, Philip, Seaton, Daniel D. [0000-0002-5222-3893], McCarthy, Davis J. [0000-0002-2218-6833], Madrigal, Pedro [0000-0003-1959-8199], Knights, Andrew [0000-0003-2107-4175], Natarajan, Kedar Nath [0000-0002-9264-1280], Vallier, Ludovic [0000-0002-3848-2602], Marioni, John C. [0000-0001-9092-0852], and Apollo - University of Cambridge Repository
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13/31 ,45/91 ,631/532/2064/2158 ,631/208/729/743 ,45/43 ,article ,631/208/191 ,631/208/205 ,45/100 ,45/15 ,38/91 - Abstract
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.
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- 2020
5. Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs
- Author
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Kilpinen, Helena, Goncalves, Angela, Leha, Andreas, Afzal, Vackar, Alasoo, Kaur, Ashford, Sofie, Bala, Sendu, Bensaddek, Dalila, Casale, Francesco Paolo, Culley, Oliver J., Danecek, Petr, Faulconbridge, Adam, Harrison, Peter W., Kathuria, Annie, McCarthy, Davis, McCarthy, Shane A., Meleckyte, Ruta, Memari, Yasin, Moens, Nathalie, Soares, Filipa, Mann, Alice, Streeter, Ian, Agu, Chukwuma A., Alderton, Alex, Nelson, Rachel, Harper, Sarah, Patel, Minal, White, Alistair, Patel, Sharad R., Clarke, Laura, Halai, Reena, Kirton, Christopher M., Kolb-Kokocinski, Anja, Beales, Philip, Birney, Ewan, Danovi, Davide, Lamond, Angus I., Ouwehand, Willem H., Vallier, Ludovic, Watt, Fiona M., Durbin, Richard, Stegle, Oliver, and Gaffney, Daniel J.
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Helena Kilpinen; Angela Goncalves; Andreas Leha; Vackar Afzal; Kaur Alasoo; Sofie Ashford; Sendu Bala; Dalila Bensaddek; Francesco Paolo Casale; Oliver J. Culley; Petr Danecek; Adam Faulconbridge; Peter W. Harrison; [...]
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- 2017
- Full Text
- View/download PDF
6. Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors
- Author
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Vigilante, Alessandra, Laddach, Anna, Moens, Nathalie, Meleckyte, Ruta, Leha, Andreas, Ghahramani, Arsham, Culley, Oliver J, Kathuria, Annie, Hurling, Chloe, Vickers, Alice, Wiseman, Erika, Tewary, Mukul, Zandstra, Peter W, HipSci Consortium, Durbin, Richard, Fraternali, Franca, Stegle, Oliver, Birney, Ewan, Luscombe, Nicholas M, Danovi, Davide, Watt, Fiona M, Durbin, Richard [0000-0002-9130-1006], and Apollo - University of Cambridge Repository
- Subjects
iPSC ,Induced Pluripotent Stem Cells ,Gene Expression ,cell adhesion ,Cell Differentiation ,Tumour Biology ,Polymorphism, Single Nucleotide ,Cell Line ,Mice ,Phenotype ,Biological Variation, Population ,fibronectin ,stem cells ,SNV ,genetic variation ,high content imaging ,Animals ,Humans ,stem cell niche ,Transcriptome ,Genetics & Genomics ,Computational & Systems Biology ,dimensionality reduction ,Cell Proliferation - Abstract
Large cohorts of human induced pluripotent stem cells (iPSCs) from healthy donors are a potentially powerful tool for investigating the relationship between genetic variants and cellular behavior. Here, we integrate high content imaging of cell shape, proliferation, and other phenotypes with gene expression and DNA sequence datasets from over 100 human iPSC lines. By applying a dimensionality reduction approach, Probabilistic Estimation of Expression Residuals (PEER), we extracted factors that captured the effects of intrinsic (genetic concordance between different cell lines from the same donor) and extrinsic (cell responses to different fibronectin concentrations) conditions. We identify genes that correlate in expression with intrinsic and extrinsic PEER factors and associate outlier cell behavior with genes containing rare deleterious non-synonymous SNVs. Our study, thus, establishes a strategy for examining the genetic basis of inter-individual variability in cell behavior.
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- 2019
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7. Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors
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Vigilante, Alessandra, primary, Laddach, Anna, additional, Moens, Nathalie, additional, Meleckyte, Ruta, additional, Leha, Andreas, additional, Ghahramani, Arsham, additional, Culley, Oliver J., additional, Kathuria, Annie, additional, Hurling, Chloe, additional, Vickers, Alice, additional, Wiseman, Erika, additional, Tewary, Mukul, additional, Zandstra, Peter W., additional, Durbin, Richard, additional, Fraternali, Franca, additional, Stegle, Oliver, additional, Birney, Ewan, additional, Luscombe, Nicholas M., additional, Danovi, Davide, additional, and Watt, Fiona M., additional
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- 2019
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8. Overproduction of reactive oxygen species is the primary pathological event related to neuronal cell death in iPSC derived neurons from patients with familial Parkinson's disease
- Author
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Choi, Minee L, primary, Meleckyte, Ruta, additional, Little, Daniel, additional, Abramov, Andrey Y, additional, Patani, Rickie, additional, and Gandhi, Sonia, additional
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- 2018
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9. A high-content platform to characterise human induced pluripotent stem cell lines
- Author
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Leha, Andreas, Moens, Nathalie, Meleckyte, Ruta, Culley, Oliver J., Gervasio, Mia K., Kerz, Maximilian, Reimer, Andreas, Cain, Stuart A., Streeter, Ian, Folarin, Amos, Stegle, Oliver, Kielty, Cay M., Durbin, Richard, Watt, Fiona M., and Danovi, Davide
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Biochemistry, Genetics and Molecular Biology(all) ,Molecular Biology - Abstract
Induced pluripotent stem cells (iPSCs) provide invaluable opportunities for future cell therapies as well as for studying human development, modelling diseases and discovering therapeutics. In order to realise the potential of iPSCs, it is crucial to comprehensively characterise cells generated from large cohorts of healthy and diseased individuals. The human iPSC initiative (HipSci) is assessing a large panel of cell lines to define cell phenotypes, dissect inter- and intra-line and donor variability and identify its key determinant components. Here we report the establishment of a high-content platform for phenotypic analysis of human iPSC lines. In the described assay, cells are dissociated and seeded as single cells onto 96-well plates coated with fibronectin at three different concentrations. This method allows assessment of cell number, proliferation, morphology and intercellular adhesion. Altogether, our strategy delivers robust quantification of phenotypic diversity within complex cell populations facilitating future identification of the genetic, biological and technical determinants of variance. Approaches such as the one described can be used to benchmark iPSCs from multiple donors and create novel platforms that can readily be tailored for disease modelling and drug discovery.
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- 2016
10. Erratum: Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs
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Kilpinen, Helena, primary, Goncalves, Angela, additional, Leha, Andreas, additional, Afzal, Vackar, additional, Alasoo, Kaur, additional, Ashford, Sofie, additional, Bala, Sendu, additional, Bensaddek, Dalila, additional, Casale, Francesco Paolo, additional, Culley, Oliver J., additional, Danecek, Petr, additional, Faulconbridge, Adam, additional, Harrison, Peter W., additional, Kathuria, Annie, additional, McCarthy, Davis, additional, McCarthy, Shane A., additional, Meleckyte, Ruta, additional, Memari, Yasin, additional, Moens, Nathalie, additional, Soares, Filipa, additional, Mann, Alice, additional, Streeter, Ian, additional, Agu, Chukwuma A., additional, Alderton, Alex, additional, Nelson, Rachel, additional, Harper, Sarah, additional, Patel, Minal, additional, White, Alistair, additional, Patel, Sharad R., additional, Clarke, Laura, additional, Halai, Reena, additional, Kirton, Christopher M., additional, Kolb-Kokocinski, Anja, additional, Beales, Philip, additional, Birney, Ewan, additional, Danovi, Davide, additional, Lamond, Angus I., additional, Ouwehand, Willem H., additional, Vallier, Ludovic, additional, Watt, Fiona M., additional, Durbin, Richard, additional, Stegle, Oliver, additional, and Gaffney, Daniel J., additional
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- 2017
- Full Text
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11. Common genetic variation drives molecular heterogeneity in human IPSCs
- Author
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Kilpinen, Helena, primary, Goncalves, Angela, additional, Leha, Andreas, additional, Afzal, Vackar, additional, Ashford, Sofie, additional, Bala, Sendu, additional, Bensaddek, Dalila, additional, Casale, Francesco Paolo, additional, Culley, Oliver, additional, Danacek, Petr, additional, Faulconbridge, Adam, additional, Harrison, Peter, additional, McCarthy, Davis, additional, McCarthy, Shane A, additional, Meleckyte, Ruta, additional, Memari, Yasin, additional, Moens, Nathalie, additional, Soares, Filipa, additional, Streeter, Ian, additional, Agu, Chukwuma A, additional, Alderton, Alex, additional, Nelson, Rachel, additional, Harper, Sarah, additional, Patel, Minal, additional, Clarke, Laura, additional, Halai, Reena, additional, Kirton, Christopher M, additional, Kolb-Kokocinski, Anja, additional, Beales, Philip, additional, Birney, Ewan, additional, Danovi, Davide, additional, Lamond, Angus I, additional, Ouwehand, Willem H, additional, Vallier, Ludovic, additional, Watt, Fiona M, additional, Durbin, Richard, additional, Stegle, Oliver, additional, and Gaffney, Daniel J, additional
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- 2016
- Full Text
- View/download PDF
12. A high-content platform to characterise human induced pluripotent stem cell lines
- Author
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Leha, Andreas, primary, Moens, Nathalie, additional, Meleckyte, Ruta, additional, Culley, Oliver J., additional, Gervasio, Mia K., additional, Kerz, Maximilian, additional, Reimer, Andreas, additional, Cain, Stuart A., additional, Streeter, Ian, additional, Folarin, Amos, additional, Stegle, Oliver, additional, Kielty, Cay M., additional, Durbin, Richard, additional, Watt, Fiona M., additional, and Danovi, Davide, additional
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- 2016
- Full Text
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13. P-385 - Overproduction of reactive oxygen species is the primary pathological event related to neuronal cell death in iPSC derived neurons from patients with familial Parkinson's disease
- Author
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Choi, Minee L, Meleckyte, Ruta, Little, Daniel, Abramov, Andrey Y, Patani, Rickie, and Gandhi, Sonia
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- 2018
- Full Text
- View/download PDF
14. Common genetic variation drives molecular heterogeneity in human iPSCs
- Author
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Kilpinen, Helena, Goncalves, Angela, Leha, Andreas, Afzal, Vackar, Alasoo, Kaur, Ashford, Sofie, Bala, Sendu, Bensaddek, Dalila, Casale, Francesco Paolo, Culley, Oliver J, Danecek, Petr, Faulconbridge, Adam, Harrison, Peter W, Kathuria, Annie, McCarthy, Davis, McCarthy, Shane A, Meleckyte, Ruta, Memari, Yasin, Moens, Nathalie, Soares, Filipa, Mann, Alice, Streeter, Ian, Agu, Chukwuma A, Alderton, Alex, Nelson, Rachel, Harper, Sarah, Patel, Minal, White, Alistair, Patel, Sharad R, Clarke, Laura, Halai, Reena, Kirton, Christopher M, Kolb-Kokocinski, Anja, Beales, Philip, Birney, Ewan, Danovi, Davide, Lamond, Angus I, Ouwehand, Willem H, Vallier, Ludovic, Watt, Fiona M, Durbin, Richard, Stegle, Oliver, and Gaffney, Daniel J
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Quality Control ,DNA Copy Number Variations ,Genotype ,Induced Pluripotent Stem Cells ,Quantitative Trait Loci ,Genetic Variation ,Cellular Reprogramming ,3. Good health ,Phenotype ,Gene Expression Regulation ,Organ Specificity ,Humans ,Transcriptome ,Cells, Cultured - Abstract
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.
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