Reproductive Failure

Human conception and pregnancy is both a vulnerable and a robust process. It is vulnerable in that a large proportion of all conceptions are chromosomally abnormal, with the great majority of such pregnancies aborting. It is robust in that more than 99% of the time, a term pregnancy results in a chromosomally normal baby; unbalanced chromosomal abnormalities are seen in less than 1% of newborns. This chapter considers the somewhat surprising vulnerability of the human species to chromosome abnormality, from prior to, at, and following conception. A remarkable fraction of pregnancy loss is due to chromosomal imbalance, and there is an associated maternal age effect. This chapter considers the chromosomal contribution to miscarriage, fetal death in utero, and perinatal death. Recurrent pregnancy loss may have a chromosomal basis, and male and female infertility may relate to abnormality of, in particular, the sex chromosomes. The genetics of hydatidiform mole is reviewed.

Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors

In humans, errors in meiotic chromosome segregation that produce aneuploid gametes increase dramatically as women age, a phenomenon termed the “maternal age effect.” During meiosis, cohesion between sister chromatids keeps recombinant homologs physically attached and premature loss of cohesion can lead to missegregation of homologs during meiosis I. A growing body of evidence suggests that meiotic cohesion deteriorates as oocytes age and contributes to the maternal age effect. One hallmark of aging cells is an increase in oxidative damage caused by reactive oxygen species (ROS). Therefore, increased oxidative damage in older oocytes may be one of the factors that leads to premature loss of cohesion and segregation errors. To test this hypothesis, we used an RNAi strategy to induce oxidative stress in Drosophila oocytes and measured the fidelity of chromosome segregation during meiosis. Knockdown of either the cytoplasmic or mitochondrial ROS scavenger superoxide dismutase (SOD) caused a significant increase in segregation errors, and heterozygosity for an smc1 deletion enhanced this phenotype. FISH analysis indicated that SOD knockdown moderately increased the percentage of oocytes with arm cohesion defects. Consistent with premature loss of arm cohesion and destabilization of chiasmata, the frequency at which recombinant homologs missegregate during meiosis I is significantly greater in SOD knockdown oocytes than in controls. Together these results provide an in vivo demonstration that oxidative stress during meiotic prophase induces chromosome segregation errors and support the model that accelerated loss of cohesion in aging human oocytes is caused, at least in part, by oxidative damage.

Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect

Aneuploidy in human eggs is the leading cause of pregnancy loss and Down’s syndrome. Aneuploid eggs result from chromosome segregation errors when an egg develops from a progenitor cell, called an oocyte. The mechanisms that lead to an increase in aneuploidy with advanced maternal age are largely unclear. Here, we show that many sister kinetochores in human oocytes are separated and do not behave as a single functional unit during the first meiotic division. Having separated sister kinetochores allowed bivalents to rotate by 90 degrees on the spindle and increased the risk of merotelic kinetochore-microtubule attachments. Advanced maternal age led to an increase in sister kinetochore separation, rotated bivalents and merotelic attachments. Chromosome arm cohesion was weakened, and the fraction of bivalents that precociously dissociated into univalents was increased. Together, our data reveal multiple age-related changes in chromosome architecture that could explain why oocyte aneuploidy increases with advanced maternal age.