Abstract
Based on studies in mice and humans, cohesin loss from chromosomes during the period of protracted meiotic arrest appears to play a major role in chromosome segregation errors during female meiosis. In mice, mutations in meiosis-specific cohesin genes cause meiotic disturbances and infertility. However, the more clinically relevant situation, heterozygosity for mutations in these genes, has not been evaluated. We report here evidence from the mouse that partial loss of gene function for either Smc1b or Rec8 causes perturbations in the formation of the synaptonemal complex (SC) and affects both synapsis and recombination between homologs during meiotic prophase. Importantly, these defects increase the frequency of chromosomally abnormal eggs in the adult female. These findings have important implications for humans: they suggest that women who carry mutations or variants that affect cohesin function have an elevated risk of aneuploid pregnancies and may even be at increased risk of transmitting structural chromosome abnormalities.
Highlights
In humans, the likelihood of an aneuploid conception is extremely high due to errors in chromosome segregation that occur during the meiotic divisions
We tested the hypothesis that partial loss of gene function for either of two meiosis-specific cohesins, Smc1b or Rec8, might adversely affect synapsis or recombination between homologs during meiotic prophase
Reduced gene function led to an increase the frequency of chromosomally abnormal eggs in the adult female, suggesting that, in humans, women carrying cohesin mutations may be at an increased risk of chromosomally abnormal pregnancies
Summary
The likelihood of an aneuploid conception is extremely high due to errors in chromosome segregation that occur during the meiotic divisions (reviewed in: [1,2,3,4]). Studies from several different laboratories have provided direct evidence that perturbations in cohesin proteins affect the orderly segregation of homologs at meiosis I (MI) and of sister chromatids at the second meiotic division (MII) [5,6,7,8] and deterioration of cohesion has been postulated to be a major mechanism of human age-related aneuploidy [7,9,10]. Different combinations of core component proteins create a variety of cohesin complexes in vertebrate meiocytes [15,16], but the particular functions of individual complexes remain poorly understood
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