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Genetic effects on chromatin accessibility foreshadow gene expression changes in macrophage immune response

View ORCID ProfileKaur Alasoo, Julia Rodrigues, Subhankar Mukhopadhyay, Andrew J. Knights, Alice L. Mann, View ORCID ProfileKousik Kundu, HIPSCI Consortium, Christine Hale, Gordon Dougan, View ORCID ProfileDaniel J. Gaffney
doi: https://doi.org/10.1101/102392
Kaur Alasoo
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
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  • For correspondence: ka8@sanger.ac.uk dg13@sanger.ac.uk
Julia Rodrigues
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
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Subhankar Mukhopadhyay
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
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Andrew J. Knights
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
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Alice L. Mann
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
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Kousik Kundu
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
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  • ORCID record for Kousik Kundu
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
Christine Hale
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
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Gordon Dougan
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
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Daniel J. Gaffney
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
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  • ORCID record for Daniel J. Gaffney
  • For correspondence: ka8@sanger.ac.uk dg13@sanger.ac.uk
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Abstract

Noncoding regulatory variants play an important role in the genetics of complex traits. Although quantitative trait locus (QTL) mapping is a powerful approach to identify these variants, many genetic effects may remain unobserved when cells are sampled in only one of a large number of possible environments. Using a novel induced pluripotent stem cell-derived system, we mapped QTLs regulating chromatin accessibility and gene expression in macrophages in four conditions mimicking the interplay between interferon-gamma response and Salmonella infection. We found that approximately 50% of condition-specific effects on gene expression altered chromatin accessibility prior to stimulation. Furthermore, 6% of the chromatin accessibility QTLs regulated multiple neighbouring regions and these interactions were modulated by stimulation, occasionally producing condition-specific changes in gene expression. Profiling additional states also doubled the number of expression QTLs that could be confidently colocalised with disease associations. Thus, a substantial fraction of disease-associated variants may affect ‘primed’ regulatory elements in naive cells.

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Posted January 26, 2017.
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Genetic effects on chromatin accessibility foreshadow gene expression changes in macrophage immune response
Kaur Alasoo, Julia Rodrigues, Subhankar Mukhopadhyay, Andrew J. Knights, Alice L. Mann, Kousik Kundu, HIPSCI Consortium, Christine Hale, Gordon Dougan, Daniel J. Gaffney
bioRxiv 102392; doi: https://doi.org/10.1101/102392
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Genetic effects on chromatin accessibility foreshadow gene expression changes in macrophage immune response
Kaur Alasoo, Julia Rodrigues, Subhankar Mukhopadhyay, Andrew J. Knights, Alice L. Mann, Kousik Kundu, HIPSCI Consortium, Christine Hale, Gordon Dougan, Daniel J. Gaffney
bioRxiv 102392; doi: https://doi.org/10.1101/102392

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