A group based at the German Cancer Research Center and the European Molecular Biology Laboratory (both Heidelberg, Germany), with international collaboration, have determined that induced pluripotent stem cells (iPSCs) can be used to identify genetic variations linked to rare diseases.

The results of the paper, published in Nature Genetics, present iPSCs as a potential tool for the analysis of genetic variants on cell differentiation and function.

In order to understand the mechanisms behind the genetic diseases that variations such as single nucleotide polymorphisms can sometimes cause, significant efforts have been made to determine in which tissues the variations can be linked to changes in gene activity. These tests are generally performed in blood cells or tissue biopsies.

“Pluripotent stem cells, however, might be better suited for this purpose in many cases, as they are undifferentiated and therefore reflect the ancestral state of all cells,” explained Oliver Stegle (German Cancer Research Center). “Stem cells could be particularly relevant when searching for the cause of diseases that occur early in development.”

In this study, the research group analyzed sequence and transcriptome data from the iPSCs of approximately 1000 donors. They assessed associations between individual genetic variants and altered expression patterns in the cells.

Of all the genes active in the iPSCs, 67% were found to exhibit differential expression patterns depending on genetic variants. For over 4000 of these associations, the genetic variants could be linked to specific diseases such as coronary heart disease and hereditary cancers.

“We were surprised to find such a large number of disease-associated genetic variants that are already visible in the expression pattern at the earliest time point of cell differentiation, represented by the iPSCs,” commented first author of the study, Marc Jan Bonder (European Molecular Biology Laboratory).

Further, the research group analyzed the iPSCs of 65 individuals with a range of rare diseases for whom the genetic cause of their disease had been previously identified. Transcriptome analysis of the iPSCs reliably directed the researcher to the causative genes.

“Such screenings were previously impossible because there were simply no sufficiently large reference collections of iPSC transcriptomes,” continued Bonder.

The group are continuing to investigate the potential of iPSC transcriptome analysis to assess the impact of genetics variations on cellular differentiation.

Link: https://www.regmednet.com/analysis-of-ipscs-allows-identification-of-disease-associated-genetic-variations/