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Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes

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Science  05 Jun 2015:
Vol. 348, Issue 6239, pp. 1143-1147
DOI: 10.1126/science.aaa9529

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Earliest stages of human development revealed

Most of our knowledge about meiosis in mammalian oocytes stems from studies of mouse oocytes. However, chromosome segregation in mouse oocytes is much more reliable than in human oocytes. Working with the clinic that first pioneered IVF, Holubcové et al. studied freshly harvested human oocytes. They used high-resolution fluorescence microscopy to watch more than 100 human oocytes as they went through each step of meiosis.

Science, this issue p. 1143

Abstract

Aneuploidy in human eggs is the leading cause of pregnancy loss and several genetic disorders such as Down syndrome. Most aneuploidy results from chromosome segregation errors during the meiotic divisions of an oocyte, the egg’s progenitor cell. The basis for particularly error-prone chromosome segregation in human oocytes is not known. We analyzed meiosis in more than 100 live human oocytes and identified an error-prone chromosome-mediated spindle assembly mechanism as a major contributor to chromosome segregation defects. Human oocytes assembled a meiotic spindle independently of either centrosomes or other microtubule organizing centers. Instead, spindle assembly was mediated by chromosomes and the small guanosine triphosphatase Ran in a process requiring ~16 hours. This unusually long spindle assembly period was marked by intrinsic spindle instability and abnormal kinetochore-microtubule attachments, which favor chromosome segregation errors and provide a possible explanation for high rates of aneuploidy in human eggs.

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