A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells

PLoS Genet. 2009 Nov;5(11):e1000718. doi: 10.1371/journal.pgen.1000718. Epub 2009 Nov 13.


Normal variation in gene expression due to regulatory polymorphisms is often masked by biological and experimental noise. In addition, some regulatory polymorphisms may become apparent only in specific tissues. We derived human induced pluripotent stem (iPS) cells from adult skin primary fibroblasts and attempted to detect tissue-specific cis-regulatory variants using in vitro cell differentiation. We used padlock probes and high-throughput sequencing for digital RNA allelotyping and measured allele-specific gene expression in primary fibroblasts, lymphoblastoid cells, iPS cells, and their differentiated derivatives. We show that allele-specific expression is both cell type and genotype-dependent, but the majority of detectable allele-specific expression loci remains consistent despite large changes in the cell type or the experimental condition following iPS reprogramming, except on the X-chromosome. We show that our approach to mapping cis-regulatory variants reduces in vitro experimental noise and reveals additional tissue-specific variants using skin-derived human iPS cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • Cluster Analysis
  • Computational Biology / methods*
  • DNA, Complementary
  • Flow Cytometry
  • Gene Expression Regulation / genetics*
  • Human Genome Project
  • Humans
  • Induced Pluripotent Stem Cells*
  • Nucleic Acid Amplification Techniques
  • Organ Specificity*
  • Regulatory Elements, Transcriptional
  • Reproducibility of Results


  • DNA, Complementary