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1000
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Abstract/Summary
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Aneuploidy seriously compromises female fertility and increases incidence of birth defects. Rates of aneuploidy in
human eggs from even young women are significantly higher than those in other mammals. However, intrinsic
genetic factors underlying this high incidence of aneuploidy in human eggs remain largely unknown. Here, we found
that ectopic expression of human TUBB8 in mouse oocytes increases rates of aneuploidy by causing
kinetochore–microtubule (K–MT) attachment defects. Stretched bivalents in mouse oocytes expressing TUBB8 are
under less tension, resulting in continuous phosphorylation status of HEC1 by AURKB/C at late metaphase I that
impairs the established correct K–MT attachments. This reduced tension in stretched bivalents likely correlates with
decreased recruitment of KIF11 on meiotic spindles. We also found that ectopic expression of TUBB8 without its
C-terminal tail decreases aneuploidy rates by reducing erroneous K–MT attachments. Importantly, variants in the
C-terminal tail of TUBB8 were identified in patients with recurrent miscarriages. Ectopic expression of an identified
TUBB8 variant in mouse oocytes also compromises K–MT attachments and increases aneuploidy rates. In conclusion,
our study provides novel understanding for physiological mechanisms of aneuploidy in human eggs as well as for
pathophysiological mechanisms involved in recurrent miscarriages.
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