Evidence that Weakened Centromere Cohesion Is a Leading Cause of Age-Related Aneuploidy in Oocytes

Abstract

Summary Aneuploidy arising early in development is the leading genetic cause of birth defects and developmental disabilities in humans. Most errors in chromosome number originate from the egg, and maternal age is well established as the key risk factor. Although the importance of this problem for reproductive health is widely recognized, the underlying molecular basis for age-related aneuploidy in female meiosis is unknown. Here we show that weakened chromosome cohesion is a leading cause of aneuploidy in oocytes in a natural aging mouse model. We find that sister kinetochores are farther apart at both Metaphase I and II, indicating reduced centromere cohesion. Moreover, levels of the meiotic cohesin protein REC8 are severely reduced on chromosomes in oocytes from old mice. To test whether cohesion defects lead to the observed aneuploidies, we monitored chromosome segregation dynamics at Anaphase I in live oocytes and counted chromosomes in the resulting Metaphase II eggs. About 90% of age-related aneuploidies are best explained by weakened centromere cohesion. Together, these results demonstrate that the maternal age-associated increase in aneuploidy is often due to a failure to effectively replace cohesin proteins that are lost from chromosomes during aging.

DNA damage response during mouse oocyte maturation

“…An interesting question for future investigation is whether the increased level of DSBs in GV-stage oocytes from both older human females or mice 17 contributes to the higher incidence of aneuploidy associated with age; loss of cohesion is the primary source. 34 H2AX is phosphorylated during DDR in interphase cells and forms typical gH2AX foci. 6 However, during mitosis gH2AX does not form foci but rather spreads over the condensed chromosomes and H2AX phosphorylation increases in PIKKs (ATM, DNA-PKcs)-dependent manner even in the absence of exogenous DNA damage.…”

Retrieval and in vitro maturation of human oocytes from ovaries removed during surgery for endometrial carcinoma: a novel strategy for human oocyte research

“…A common aging-related problem during the maturation of human oocytes is poor sister chromatid cohesion during meiosis I and meiosis II [14]. In aged mouse oocytes, there are lower levels of cohesion proteins such as Rec8 and shugoshins, which control meiotic chromosome segregation [2,8]. On the other hand, there are no reports to date about changes in cohesion proteins associated with aging of human oocytes.…”

A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

“…Oocyte aneuploidy frequently arises at the resumption of meiosis-I and is embryonically lethal in most cases (Munne et al 2004). Aneuploidy incidence rates increase with age in humans and mice, with evidence suggesting age-related degradation of cohesin proteins in the oocyte nucleus is involved (Chiang et al 2010, Lister et al 2010, Kuliev et al 2011, Duncan et al 2012. Oocyte mitochondrial counts also decline in older females, leading to reduced embryo viability (Wai et al 2010, Kushnir et al 2012, Fragouli et al 2015.…”