title: 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.
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.
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Findlay
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Lynne-Marie
authors.initials: LM
authors.lastname: Postovit
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D000066449:Human Embryonic Stem Cells; D006801:Humans; D008297:Male; D055457:Nodal Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics; D012727:Sex Characteristics
chemical_list: C526007:NODAL protein, human; D055457:Nodal Protein; D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA
keywords: Alternative splicing; Embryonic stem cells; NODAL; Pluripotency; Sex differences; Single nucleotide polymorphism