title: Reprogramming LCLs to iPSCs Results in Recovery of Donor-Specific Gene Expression Signature.
abstract: Renewable in vitro cell cultures, such as lymphoblastoid cell lines (LCLs), have facilitated studies that contributed to our understanding of genetic influence on human traits. However, the degree to which cell lines faithfully maintain differences in donor-specific phenotypes is still debated. We have previously reported that standard cell line maintenance practice results in a loss of donor-specific gene expression signatures in LCLs. An alternative to the LCL model is the induced pluripotent stem cell (iPSC) system, which carries the potential to model tissue-specific physiology through the use of differentiation protocols. Still, existing LCL banks represent an important source of starting material for iPSC generation, and it is possible that the disruptions in gene regulation associated with long-term LCL maintenance could persist through the reprogramming process. To address this concern, we studied the effect of reprogramming mature LCL cultures from six unrelated donors to iPSCs on the ensuing gene expression patterns within and between individuals. We show that the reprogramming process results in a recovery of donor-specific gene regulatory signatures, increasing the number of genes with a detectable donor effect by an order of magnitude. The proportion of variation in gene expression statistically attributed to donor increases from 6.9% in LCLs to 24.5% in iPSCs (P < 10-15). Since environmental contributions are unlikely to be a source of individual variation in our system of highly passaged cultured cell lines, our observations suggest that the effect of genotype on gene regulation is more pronounced in iPSCs than in LCLs. Our findings indicate that iPSCs can be a powerful model system for studies of phenotypic variation across individuals in general, and the genetic association with variation in gene regulation in particular. We further conclude that LCLs are an appropriate starting material for iPSC generation.
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Thomas
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Courtney
authors.initials: C
authors.lastname: Kagan
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Pavlovic
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Burnett
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Kristen
authors.initials: K
authors.lastname: Patterson
authors.affiliation: Departments of Genetics and Biology and Howard Hughes Medical Institute, Stanford University, Stanford, California, United States of America.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Pritchard
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Gilad
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D015203:Reproducibility of Results; D059467:Transcriptome