Mapping regulatory variants in human induced pluripotent stem cells (hiPSCs)

This study [see attached] illustrates the mind-boggling power of the “human induced pluripotent stem cell (hiPSC) platform.” Authors studied hiPSC-derived sensory neurons from 107 individuals. In addition to identifying thousands of quantitative trait loci (QTL; segments of DNA (the loci) that correlate with variation in a phenotype or quantitative trait) influencing gene expression, chromatin accessibility and RNA splicing –– the work highlights several under-appreciated challenges in the hiPSC field –– particularly those underlying the processes of neurodevelopment. Authors present the first map of regulatory variants in hiPSC-derived neurons, based on differentiating a large cohort of hiPSCs undergoing a sensory neuronal fate (i.e. pluripotent cells that can result in many differentiated types are directionally regulated to form sensory neurons).

Genetic studies have increasingly demonstrated that a combination of rare and common variants underlies many complex diseases. Identifying, and functionally validating, these small and frequently context-dependent (cell-type-specific and/or treatment-dependent) effects is necessary to help untangle how common risk factors interact among diverse cell-types of the human body. On these GEITP pages, we have previously described the Genotype-Tissue Expression (GTEx) Project, which aims to explore the functional roles of common variants by characterizing variation in gene-expression levels across individuals and tissues. The CommonMind Consortium (CMC) is applying similar methodologies –– focused on understanding how genetic variation in the human brain contributes to psychiatric disease. These studies must be accompanied by hiPSC-derived strategies that can generate additional cell-types and/or developmental time-points relevant to disease predisposition that are not readily available in post-mortem data-sets.

Additional advantages of hiPSCbased strategies are that they avoid issues associated with post-mortem RNA decay and lifetime-donor-environmental exposures. Of course, hiPSC-based models are only as valuable as their ability to retain donor-gene-expression signatures. Authors studied 123 differentiations of iPSCs proceeding into a sensory neuronal fate. Using single-cell RNA-sequencing, they found that the number of neuronal versus contaminating cells was influenced by iPSC culture conditions before differentiation. Despite high differentiation-induced variability, authors estimated that recall-by-genotype studies that use iPSC-derived cells –– will require cells from at least 20–80 individuals –– in order to distinguish effects of regulatory variants having moderately large-effect sizes.

Nat Genet Jan 2o18; 50: 54–61 & News’N’Views pp 1–2

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