Quantitative genetic analysis deciphers the impact of cis and trans regulation on cell-to-cell variability in protein expression levels

Autoři: Michael D. Morgan aff001;  Etienne Patin aff003;  Bernd Jagla aff004;  Milena Hasan aff004;  Lluís Quintana-Murci aff003;  John C. Marioni aff001
Působiště autorů: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom aff001;  Cancer Research UK–Cambridge Institute, Robinson Way, Cambridge, United Kingdom aff002;  Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR2000, Paris, France aff003;  Cytometry and Biomarkers UTechS, Institut Pasteur, Paris, France aff004;  Hub Bioinformatique et Biostatisque, Départment de Biologie Computationalle—USR 3756 CNRS, Institut Pasteur, Paris, France aff005;  Human Genomics and Evolution, Collège de France, Paris, France aff006;  EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom aff007
Vyšlo v časopise: Quantitative genetic analysis deciphers the impact of cis and trans regulation on cell-to-cell variability in protein expression levels. PLoS Genet 16(3): e32767. doi:10.1371/journal.pgen.1008686
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008686


Identifying the factors that shape protein expression variability in complex multi-cellular organisms has primarily focused on promoter architecture and regulation of single-cell expression in cis. However, this targeted approach has to date been unable to identify major regulators of cell-to-cell gene expression variability in humans. To address this, we have combined single-cell protein expression measurements in the human immune system using flow cytometry with a quantitative genetics analysis. For the majority of proteins whose variability in expression has a heritable component, we find that genetic variants act in trans, with notably fewer variants acting in cis. Furthermore, we highlight using Mendelian Randomization that these variability-Quantitative Trait Loci might be driven by the cis regulation of upstream genes. This indicates that natural selection may balance the impact of gene regulation in cis with downstream impacts on expression variability in trans.

Klíčová slova:

Flow cytometry – Gene expression – Gene regulation – Genetic polymorphism – Human genetics – Immune system proteins – Phenotypes – Protein expression


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