Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells

Generation of human induced pluripotent stem cells from patient fibroblasts containing ring chromosomes with large deletions reveals that reprogrammed cells lose the abnormal chromosome and duplicate the wild-type homologue through compensatory uniparental disomy, suggesting that cellular reprogramming may hold potential for ‘chromosome therapy’. Renewal through reprogramming Ring chromosomes are structural aberrations that are often associated with birth defects, mental disabilities and growth retardation. Shinya Yamanaka and colleagues derived human induced pluripotent stem (iPS) cells from patient fibroblasts containing ring chromosomes with large deletions, and found that reprogrammed cells lose the abnormal chromosome and duplicate the wild-type homologue through the compensatory uniparental disomy mechanism. Thus, iPS cells have an intrinsic capacity to purge very damaged chromosomes that have ring structures and deletions spanning hundreds of megabases of DNA. The authors propose that cellular reprogramming might serve a very different function to the familiar one, acting as a means of 'chromosome therapy' that reverses combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation 1 , 2 . Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions 2 . Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate 3 , 4 , 5 , 6 , 7 , 8 , 9 . The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) 10 , 11 , 12 from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-deri