Chromosome errors in human eggs shape natural fertility over reproductive life span

Abstract

Chromosome errors, or aneuploidy, affect an exceptionally high number of human conceptions, causing pregnancy loss and congenital disorders. Here, we have followed chromosome segregation in human oocytes from females aged 9 to 43 years and report that aneuploidy follows a U-curve. Specific segregation error types show different age dependencies, providing a quantitative explanation for the U-curve. Whole-chromosome nondisjunction events are preferentially associated with increased aneuploidy in young girls, whereas centromeric and more extensive cohesion loss limit fertility as women age. Our findings suggest that chromosomal errors originating in oocytes determine the curve of natural fertility in humans.

The First Mitotic Division of the Human Embryo is Highly Error-prone

“…2c). Because errors from a mitotic origin are reported to be independent of maternal age (McCoy, 2017), we next tested whether the frequency of lagging chromosomes or multipolar spindles at the first mitotic division were associated with older patients (>36 years) vs. younger patients (<35 years), as 35 years seems to be the age at which meiotic errors increase exponentially (Gruhn et al, 2019). The incidence of either multipolar spindles or lagging chromosomes appeared to be age-independent ( Fig.…”

“…The failure of homologous chromosomes or sister chromatids to segregate equally during female meiosis leads to deviations in chromosome number (Hassold and Hunt, 2001). Meiotic aneuploidies in human oocytes follow a U-shaped curve, with aneuploidy rates increasing exponentially with maternal age from about 35 years old (Gruhn et al, 2019). Studies of aneuploidy characteristics identify the precocious separation of sister chromatids and reverse segregation (two sister chromatids segregate) during meiosis I as errors which increase with maternal age.…”

“…Studies of aneuploidy characteristics identify the precocious separation of sister chromatids and reverse segregation (two sister chromatids segregate) during meiosis I as errors which increase with maternal age. These errors are thought to be caused by a weakening in the cohesin complex, persistence of chromatid threads which hold sisters together and/or the geometry of kinetochore attachment (Gruhn et al, 2019;Patel et al, 2015;Zielinska et al, 2015). However, over 50% of blastocysts have blastomeres with different chromosome compositions (Chavez et al, 2012;McCoy, 2017).…”

Initial spindle positioning at the oocyte center protects against incorrect kinetochore-microtubule attachment and aneuploidy in mice

“…The leading genetic cause of infertility is aneuploidy and can be characterized as errors within chromosomal segregation (Jacobs, et al, 1959, Lejeune, et al, 1959. Fertility and aneuploidy demonstrate an inversely correlated relationship throughout the lifetime of a female, with the highest incidence of aneuploidy occurring at the lowest rate of fertility (Gruhn, et al, 2019). Aneuploidy often causes failure to fertilize, miscarriage, spontaneous abortion, congenital defects in vivo (ex: down syndrome), and is the leading contributor to in vitro fertilization failure (Angell, et al, 1986, Byrne, et al, 1985, Gruhn, Zielinska, Shukla, Blanshard, Capalbo, Cimadomo, Nikiforov, Chan, Newnham, Vogel, Scarica, Krapchev, Taylor, Kristensen, Cheng, Ernst, Bjorn, Colmorn, Blayney, Elder, Liss, Hartshorne, Grondahl, Rienzi, Ubaldi, McCoy, Lukaszuk, Andersen, Schuh and Hoffmann, 2019, Hassold and Hunt, 2001.…”

Pregnancy loss: more a matter of chromosomes or maternal discretion?

“…It seems that the dance of meiotic chromosomes is susceptible to missteps at both ends of our reproductive lifespan (not just advanced maternal age). Apparently, distinct mechanisms modulate the interactions of our 23 homologous chromosome pairs with spindle components along the pathway to becoming balanced haploid contributions to newly formed zygotes [4]. With respect to congenital malformations, it is interesting to note that years ago, the tendency to see the so-called U-shape curve prior to and after our peak times of fecundity did not go unnoticed [5].…”