Abstract
Trisomy 21, 18, and 13 are the major autosomal aneuploidy disorders in humans. They are mostly derived from chromosome non-disjunction in maternal meiosis, and the extra trisomic chromosome can cause several congenital malformations. Various genes on the trisomic chromosomes are intricately involved in the development of disease, and fundamental treatments have not yet been established. However, chromosome therapy has been developed to correct the extra chromosome in cultured patient cells, and it was recently reported that during reprogramming into iPSCs, fibroblasts from a Down syndrome patient lost the extra chromosome 21 due to a phenomenon called trisomy-biased chromosome loss. To gain preliminary insights into the underlying mechanism of trisomy rescue during the early stages of reprogramming, we reprogrammed skin fibroblasts from patients with trisomy syndromes 21, 18, 13, and 9 to iPSC, and evaluated the genomes of the individual iPSC colonies by molecular cytogenetic techniques. We report the spontaneous correction from trisomy to disomy upon cell reprogramming in at least one cell line examined from each of the trisomy syndromes, and three possible combinations of chromosomes were selected in the isogenic trisomy-rescued iPSC clones. Single nucleotide polymorphism analysis showed that the trisomy-rescued clones exhibited either heterodisomy or segmental uniparental isodisomy, ruling out the possibility that two trisomic chromosomes were lost simultaneously and the remaining one was duplicated, suggesting instead that one trisomic chromosome was lost to generate disomic cells. These results demonstrated that trisomy rescue may be a phenomenon with random loss of the extra chromosome and subsequent selection for disomic iPSCs, which is analogous to the karyotype correction in early preimplantation embryos. Our finding is relevant for elucidating the mechanisms of autonomous karyotype correction and future application in basic and clinical research on aneuploidy disorders.
Highlights
Non-disjunction of chromosomes during cell divisions causes aneuploidy in human embryos
The induced pluripotent stem cells (iPSC) clones at P2 were examined for trisomy rescue by interphase fluorescence in situ hybridization (FISH) and karyotype analysis (Fig 1A)
Interphase FISH revealed that 22 iPSC clones (81%) had disomy 13 while 6 iPSC clones (19%) remained as trisomy 13 (Fig 1B and 1C)
Summary
Non-disjunction of chromosomes during cell divisions causes aneuploidy in human embryos. Aneuploidy can occur for every chromosome, but most of them are rarely compatible with life. Three types of trisomy are live born: trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome). Down syndrome (DS) is the most frequent autosomal trisomy, occurring in approximately 1 in 750 live births. Edwards syndrome occurs in 1 in 6,000–8,000 live births, and its features include intrauterine growth restriction, microcephaly, micrognathia, hypertonia, small pelvis, clenched fists with the second and fifth fingers overlapping, and shortened life expectancy [2]. Patau syndrome is the third most common trisomy, occurring in 1 in 20,000 live births. Its features results from an early developmental defect, leading to midline malformations, including absence of the olfactory nerve and bulb, deafness, holoprosencephaly, and midline cleft lip and palate, which gives a shortened life expectancy [3,4]
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