Brief Report: Common Genetic Variation in Chromosome 10 q22.1 Shows a Strong Sex Bias in Human Embryonic Stem Cell Lines and Directly Controls the Novel Alternative Splicing of Human NODAL which is Associated with XIST Expression in Female Cell Lines. (28th December 2015)

• Record Type: Journal Article
• Authors: Findlay, Scott D.; Postovit, Lynne‐Marie
• Is Part Of: Stem cells. Volume 34:Number 3(2016:Mar.)
• Page Start: 791
• Page End: 796
• Publication Date: 2015-12-28
• Subjects: Single nucleotide polymorphism -- Embryonic stem cells -- NODAL -- Alternative splicing -- Sex differences -- Pluripotency; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2258
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: The potential use of pluripotent stem cells for personalized regenerative medicine necessitates an improved understanding of how germ‐line genetic variation may affect pluripotency. Given previous reports of a female bias in established human embryonic stem cell (hESC) lines, sex‐specific differences must also be considered. Herein we describe, for the first time, how genetic polymorphisms may affect the establishment of widely used hESC lines. We demonstrate that the minor allele of the human single nucleotide polymorphism (SNP) rs2231947 found within the NODAL gene locus is under‐represented in male but not female hESC lines. We also show that this SNP is highly functional in hESC lines. The SNP rs2231947 directly controls the alternative splicing of a novel NODAL transcript isoform. Thus we demonstrate that genetic variation drastically affects the expression of a gene that plays a major role in the regulation of pluripotency and cell fate. Our work helps detail how genetic heterogeneity is manifested in hESC biology and highlights the need to identify how specific genetic variants can explain important differences between pluripotent cell line models both within and between species. Stem Cells 2016;34:791–796 Abstract : The minor allele (T) for SNP rs2231947 is found at normal frequencies in female human embryonic stem cell lines where it causes the alternative splicing of NODAL. In male human embryonic stem cell lines, this SNP allele is largely absent. Constitutive NODAL exons are shown in orange. The alternatively spliced NODAL exon is shown in blue. Straight lines represent introns. Diagonal lines connect splice sites.