Abstract
BackgroundHuman aneuploidy is the leading cause of early pregnancy loss, mental retardation, and multiple congenital anomalies. Due to the high mortality associated with aneuploidy, the pathophysiological mechanisms of aneuploidy syndrome remain largely unknown. Previous studies focused mostly on whether dosage compensation occurs, and the next generation transcriptomics sequencing technology RNA-seq is expected to eventually uncover the mechanisms of gene expression regulation and the related pathological phenotypes in human aneuploidy.ResultsUsing next generation transcriptomics sequencing technology RNA-seq, we profiled the transcriptomes of four human aneuploid induced pluripotent stem cell (iPSC) lines generated from monosomy × (Turner syndrome), trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome), and partial trisomy 11:22 (Emanuel syndrome) as well as two umbilical cord matrix iPSC lines as euploid controls to examine how phenotypic abnormalities develop with aberrant karyotype. A total of 466 M (50-bp) reads were obtained from the six iPSC lines, and over 13,000 mRNAs were identified by gene annotation. Global analysis of gene expression profiles and functional analysis of differentially expressed (DE) genes were implemented. Over 5000 DE genes are determined between aneuploidy and euploid iPSCs respectively while 9 KEGG pathways are overlapped enriched in four aneuploidy samples.ConclusionsOur results demonstrate that the extra or missing chromosome has extensive effects on the whole transcriptome. Functional analysis of differentially expressed genes reveals that the genes most affected in aneuploid individuals are related to central nervous system development and tumorigenesis.
Highlights
Human aneuploidy is the leading cause of early pregnancy loss, mental retardation, and multiple congenital anomalies
Several aneuploid human embryonic stem cell (ESC) lines have been established as models for studying human aneuploidy syndromes [12,13,14,15], which has expanded the scope of aneuploidy research, leading to investigations of other syndromes caused by the gain or loss of a chromosome
41-47% of reads from the four aneuploid induced pluripotent stem cell (iPSC) lines were uniquely mapped onto the reference genome, compared to only 24% and 33% reads uniquely mapped in euploid controls
Summary
Human aneuploidy is the leading cause of early pregnancy loss, mental retardation, and multiple congenital anomalies. Human aneuploidy was first discovered in 1959 by Lejeune and colleagues through monosomy X, known as Turner syndrome [1] This is the leading cause of early pregnancy loss, mental retardation, and multiple congenital anomalies [2]. Several aneuploid human embryonic stem cell (ESC) lines have been established as models for studying human aneuploidy syndromes [12,13,14,15], which has expanded the scope of aneuploidy research, leading to investigations of other syndromes caused by the gain or loss of a chromosome. Due to the outstanding performance of the RNA-seq method, analyzing the gene expression profiles of these aneuploid iPSCs will provide a great way to understand the pathological mechanisms of human aneuploidy
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