Fertile offspring from sterile sex chromosome trisomic mice

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Science  01 Sep 2017:
Vol. 357, Issue 6354, pp. 932-935
DOI: 10.1126/science.aam9046

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Trisomic animals lose third chromosome

Generally, when a third sex chromosome is added to the normal two in mammals (XX for female and XY for male), developmental defects result. Mice that are trisomic for the sex chromosomes are infertile. Hirota et al. demonstrate that reprogramming cells from sterile mice with chromosome trisomies XXY or XYY generates XY stem cells. Sperm generated from these XY stem cells could give rise to healthy, fertile offspring. Reprogramming also promoted loss of the extra chromosome in cells from patients with Klinefelter (XXY) or Down (trisomy 21) syndrome.

Science, this issue p. 932


Having the correct number of chromosomes is vital for normal development and health. Sex chromosome trisomy affects 0.1% of the human population and is associated with infertility. We show that during reprogramming to induced pluripotent stem cells (iPSCs), fibroblasts from sterile trisomic XXY and XYY mice lose the extra sex chromosome through a phenomenon we term trisomy-biased chromosome loss (TCL). Resulting euploid XY iPSCs can be differentiated into the male germ cell lineage and functional sperm that can be used in intracytoplasmic sperm injection to produce chromosomally normal, fertile offspring. Sex chromosome loss is comparatively infrequent during mouse XX and XY iPSC generation. TCL also applies to other chromosomes, generating euploid iPSCs from cells of a Down syndrome mouse model. It can also create euploid iPSCs from human trisomic patient fibroblasts. The findings have relevance to overcoming infertility and other trisomic phenotypes.

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