Cookie Settings

We use cookies to optimize our website. These include cookies that are necessary for the operation of the site, as well as those that are only used for anonymous statistic. You can decide for yourself which categories you want to allow. Further information can be found in our data privacy protection .

Essential

These cookies are necessary to run the core functionalities of this website and cannot be disabled.

Name Webedition CMS
Purpose This cookie is required by the CMS (Content Management System) Webedition for the system to function correctly. Typically, this cookie is deleted when the browser is closed.
Name econda
Purpose Session cookie emos_jcsid for the web analysis software econda. This runs in the “anonymized measurement” mode. There is no personal reference. As soon as the user leaves the site, tracking is ended and all data in the browser are automatically deleted.
Statistics

These cookies help us understand how visitors interact with our website by collecting and analyzing information anonymously. Depending on the tool, one or more cookies are set by the provider.

Name econda
Purpose Statistics
External media

Content from external media platforms is blocked by default. If cookies from external media are accepted, access to this content no longer requires manual consent.

Name YouTube
Purpose Show YouTube content
Name Twitter
Purpose activate Twitter Feeds

Induced pluripotent stem cells reveal causes of disease

No. 14 | 04/03/2021 | by Koh

Induced pluripotent stem cells (iPSC) are suitable for discovering the genes that underly complex and also rare genetic diseases. Scientists from the German Cancer Research Center (DKFZ) and the European Molecular Biology Laboratory (EMBL), together with international partners, have studied genotype-phenotype relationships in iPSCs using data from approximately one thousand donors.

Using single-cell analyses, researchers from DKFZ and EMBL systematically searched for correlations between individual genetic variants in induced pluripotent stem cells to discover genes that underlie complex and rare genetic diseases.
© Tobias Wüstefeld / EMBL

Tens of thousands of tiny genetic variations (SNPs, single nucleotide polymorphisms) have been identified in the human genome that are associated with specific diseases. Many of these genetic variants are not located in the protein-coding regions of genes, but affect regulatory sections. Therefore, scientists are trying to find out if and in which tissues these variants can be linked to changes in the activity of specific genes.

Typically, such analyses are performed in blood cells or tissue biopsies, depending on the type of disease. "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," says Oliver Stegle, division head at the German Cancer Research Center and group leader at EMBL. "Stem cells could be particularly relevant when searching for the cause of diseases that occur early in development." Pluripotent stem cells can be generated in the culture dish from normal body cells obtained from a blood sample, for example. They are referred to as "induced pluripotent stem cells," or iPSCs for short, since they are not naturally occurring stem cells.

Together with scientists from Stanford University and additional international cooperation partners, Oliver Stegle's team has compiled sequence and transcriptome data on iPSCs from around 1000 donors. The researchers systematically examined these data to identify correlations between individual genetic variants and altered expression patterns in stem cells. The results have now been published in the journal Nature Genetics.

For more than 67 percent of all genes active in iPSCs, the researchers found differential expression patterns depending on genetic variants. Many of these associations are novel and have not been described in somatic cell types before. For over 4000 of these associations, the genetic variants responsible for the altered expression patterns could be linked to specific diseases. These included, for example, variants associated with coronary heart disease, lipid metabolism disorders or hereditary cancers.

Stegle and colleagues also investigated whether iPS are suitable for identifying the causative genes of rare genetic diseases. They used iPSC lines from 65 patients who suffered from various rare diseases, whose causal gene defects were already known through previous analyses. In the transcriptome data of these iPSC lines, the scientists searched for particularly conspicuous "outliers" in the expression pattern. These analyses reliably led to the trace of the genetic basis of the disease. "Such screenings were previously impossible because there were simply no sufficiently large reference collections of iPS transcriptomes," explained Marc Jan Bonder, first author of the study.

"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". Until now, the relevance of iPSCs for such biomedical analyses has been significantly underestimated.

In a companion paper, published in the same issue of Nature Genetics, Stegle and colleagues from EMBL-EBI and the Wellcome Trust Sanger Institute used more than 200 iPSC lines to investigate how genetic variants affect differentiation into neuronal cells.

The scientists performed RNA single-cell sequencing at different time points of neuronal cell differentiation. This allowed them to analyze how genetic variants affect expression patterns in different cellular states, including different neuronal cell types. "The study demonstrates the power of combining single-cell sequencing with iPSC technologies to dissect the effect of genetic variants in cell types that would otherwise be inaccessible," Stegle explains.

Bonder, M.J. Smail, C., Gloudemans, M.J., Frésard, L., Jakubosky, D., D'Antonio, M., Li, X., Ferraro, N.M., Carcamo-Orive, I., Mirauta, B., Seaton, D.D., Cai, N., Kilpinen, H., Vakili, D., Horta, D., Wheeler, M.T., Zhao, C., Zastrow, D.B., Bonner, D.E., HipSci Consortium, iPSCORE Consortium, GENESiPS Consortium, PhLiPS Consortium, Undiagnosed Diseases Network, Knowles, J.W., Smith, E.N., Frazer, K.A., Montgomery, S.B., Stegle, O.: Identification of rare and common disease variants using population-scale transcriptomics of pluripotent cells.
Nature Genetics 2021, DOI: https://dx.doi.org/10.1038/s41588-021-00800-7

Jerber, J., Seaton, D.D., Cuomo, A.S.E., Kumasaka, N., Haldane, J., Steer, J., Patel, M., Pearce, D., Andersson, M., Bonder, M.J., Mountjoy, E., Ghoussaini, M., Lancaster, M.A., HipSci Consortium, Marioni, J.C., Merkle, F.T., Gaffney, D.J., Stegle, O: Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation
Nature Genetics 2021, DOI: https://dx.doi.org/10.1038/s41588-021-00801-6

With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany’s largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.

To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:

  • National Center for Tumor Diseases (NCT, 6 sites)
  • German Cancer Consortium (DKTK, 8 sites)
  • Hopp Children's Cancer Center (KiTZ) Heidelberg
  • Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ
  • DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
  • National Cancer Prevention Center (jointly with German Cancer Aid)
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

RSS-Feed

Subscribe to our RSS-Feed.

to top
powered by webEdition CMS