Increasing The Genetic Admixture of Available Lines of Human Pluripotent Stem Cells

Abstract

Human pluripotent stem cells (hPSCs) may significantly improve drug development pipeline, serving as an in vitro system for the identification of novel leads, and for testing drug toxicity. Furthermore, these cells may be used to address the issue of differential drug response, a phenomenon greatly influenced by genetic factors. This application depends on the availability of hPSC lines from populations with diverse ancestries. So far, it has been reported that most lines of hPSCs derived worldwide are of European or East Asian ancestries. We have established 23 lines of hPSCs from Brazilian individuals, and we report the analysis of their genomic ancestry. We show that embryo-derived PSCs are mostly of European descent, while induced PSCs derived from participants of a national-wide Brazilian cohort study present high levels of admixed European, African and Native American genomic ancestry. Additionally, we use high density SNP data and estimate local ancestries, particularly those of CYP genes loci. Such information will be of key importance when interpreting variation among cell lines with respect to cellular phenotypes of interest. The availability of genetically admixed lines of hPSCs will be of relevance when setting up future in vitro studies of drug response.Human pluripotent stem cells (hPSCs) are an ideal cell source for the development of cell based assays for drug response. In addition to their extensive proliferation and genetic stability in culture, these human cells can give rise to primary cell types relevant for drug response, including cardiomyocytes, hepatocytes and neurons 1 . Individual differences in drug response can result from the effects of age, sex, disease, ancestry, or drug interactions, but genetic factors play a major role in influencing adverse drug reactions and ineffective therapy 2 . Thus, a collection of genetically diverse lines of hPSCs is required for a broader study of differential drug response in vitro 3 .To date, most lines of hPSCs available are of European or Eastern Asian ancestry 4 , although one hiPSC line from a Native American, and one from an African (Yoruba) have been reported 5 . More recently, one hiPSC line of African American and of Hispanic Latino ancestry each have been described, although the authors do not show the genetic evidence of those ethnicities 6 .The Brazilian population results from 500 years of admixture among the original Native Americans, Europeans (mostly Portuguese), and sub-Saharan Africans, most of which were brought to the country as slaves 7 . Different analyses of genomic ancestry in Brazil have shown that, on average, the urban population has 60% contribution from European, 25% from African, and 15% from Native American populations, although these proportions vary according to the Brazilian geographic region analyzed [7][8][9][10][11] . Therefore, from the genetic point of view the Brazilian population is significantly distinct from the ancestral populations, containing novel genotypes and haplotypes that may impact various phenotyp...

Long-term single-cell passaging of human iPSC fully supports pluripotency and high-efficient trilineage differentiation capacity

“…Human erythroblasts and skin fibroblast were reprogrammed for hiPSC generation. Erythroblasts were genetically modified using an episomal vector system previously described in the literature 16 , 17 with slight modifications. Briefly, mononuclear cells (MNCs) were isolated from 10 mL of peripheral blood by Ficoll gradient.…”

Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes

“…iPSC models are also limited in the availability of non-European lines. A few recent studies have recognized this and focused on creating diverse human pluripotent cell lines (6)(7)(8)(9). Nonetheless, availability of iPSC lines and data derived from these cells have not kept pace with iPSC technologies.…”

Genetic Ancestry Analysis Reveals Misclassification of Commonly Used Cancer Cell Lines

“…Also, SNPs identified in European populations do not completely capture the genetic variation contributing to a phenotype in other racial groups (28). More disturbingly, entire demographics are ignored in key mechanistic studies hindered by the restraints monoethnic cellular models afford (29,30). This is problematic as underrepresented racial/ethnic groups, who are more likely to suffer disproportionate disease incidence and mortality, remain also underrepresented in biospecimens available for research (31)(32)(33)(34).…”