Abstract

Human ring chromosomes are often unstable during mitosis, and daughter cells can be partially or completely aneuploid. We studied the mitotic stability of four ring chromosomes, 8, 13, 18, and 22, in long-term cultures of skin fibroblasts and induced pluripotent stem cells (iPSCs) by GTG karyotyping and aCGH. Ring chromosome loss and secondary aberrations were observed in all fibroblast cultures except for r(18). We found monosomy, fragmentation, and translocation of indexed chromosomes. In iPSCs, aCGH revealed striking differences in mitotic stability both between iPSC lines with different rings and, in some cases, between cell lines with the same ring chromosome. We registered the spontaneous rescue of karyotype 46,XY,r(8) to 46,XY in all six iPSC lines through ring chromosome loss and intact homologue duplication with isoUPD(8)pat occurrence, as proven by SNP genotype distribution analysis. In iPSCs with other ring chromosomes, karyotype correction was not observed. Our results suggest that spontaneous correction of the karyotype with ring chromosomes in iPSCs is not universal and that pluripotency is compatible with a wide range of derivative karyotypes. We conclude that marked variability in the frequency of secondary rearrangements exists in both fibroblast and iPSC cultures, expanding the clinical significance of the constitutional ring chromosome.

Highlights

  • Human ring chromosomes are often unstable during mitosis, and daughter cells can be partially or completely aneuploid

  • Molecular karyotyping of lymphocytes revealed that the ring chromosome originated from a terminal deletion at 8p23.3-p23.1 (7.888 Mb) with a large (27.120 Mb) duplication at 8p23.1-p11.22 (Fig. 1a), which inverted status was confirmed by fluorescence in situ hybridization (FISH) (Fig. 1b)

  • We examined the numerical and microstructural stability of ring chromosomes 8, 13, 18, and 22 in fibroblasts and fibroblast-derived induced pluripotent stem cells (iPSCs)

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Summary

Introduction

Human ring chromosomes are often unstable during mitosis, and daughter cells can be partially or completely aneuploid. We studied the mitotic stability of four ring chromosomes, 8, 13, 18, and 22, in long-term cultures of skin fibroblasts and induced pluripotent stem cells (iPSCs) by GTG karyotyping and aCGH. We conclude that marked variability in the frequency of secondary rearrangements exists in both fibroblast and iPSC cultures, expanding the clinical significance of the constitutional ring chromosome. Other mechanisms include junction of the telomeric or subtelomeric regions without loss of genetic ­material[2,3] and inverted duplication associated with a terminal deletion (inv dup del rearrangements), which may be stabilized through ­circularization[4,5,6,7] Due to their circular structure, ring chromosomes may have problems in mitosis, which depends on sister chromatid exchange (SCE). The complex mitotic behaviour of ring chromosomes can lead to specific patterns of their segregation in different t­ issues[18,19,20]

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