TY - JOUR

T1 - Chromosome Errors in Human Eggs Shape Natural Fertility over Reproductive Life Span

AU - Gruhn, Jennifer R.

AU - Zielinska, Agata P.

AU - Shukla, Vallari

AU - Blanshard, Robert

AU - Capalbo, Antonio

AU - Cimadomo, Danilo

AU - Nikiforov, Dmitry

AU - Chan, Andrew Chi Ho

AU - Newnham, Louise J.

AU - Vogel, Ivan

AU - Scarica, Catello

AU - Krapchev, Marta

AU - Taylor, Deborah

AU - Kristensen, Stine Gry

AU - Cheng, Junping

AU - Ernst, Erik

AU - Bjørn, Anne Mette Bay

AU - Colmorn, Lotte Berdiin

AU - Blayney, Martyn

AU - Elder, Kay

AU - Liss, Joanna

AU - Hartshorne, Geraldine

AU - Grøndahl, Marie Louise

AU - Rienzi, Laura

AU - Ubaldi, Filippo

AU - McCoy, Rajiv

AU - Lukaszuk, Krzysztof

AU - Andersen, Claus Yding

AU - Schuh, Melina

AU - Hoffmann, Eva R.

PY - 2020

Y1 - 2020

N2 - While it is understood that young females (.13 years to early 20s) and women of advancing maternal age (AMA, mid-30s or older) have reduced fertility rates, the exact mechanisms behind this feature of the fertility curve remain unclear. Because chromosomal errors and aneuploidy cause a significant amount of pregnancy loss and congenital disorders in women of advanced maternal age, meiotic error rates throughout the entire reproductive life span may shape natural fertility. This study of oocytes from females aged 9 to 43 years aimed to determine the mechanism involved in generation of the U-curve of aneuploidy and subsequent natural fertility curve in humans. Two independent patient cohorts were used as sources for oocytes, one including unstimulated girls and women prior to chemotherapy for blood disorders or cancer (cohort 1) and one including women receiving gonadotrophin-stimulation through in vitro fertilization clinics (cohort 2). Maternal age was the only significant factor affecting aneuploidy, with a best-fit model provided by a quadratic equation suggestive of a U-curve of aneuploidy. The rate of chromosome errors was 1.7%to 4.2%, affecting 23.6% to 53.5% of oocytes, suggesting the inverse U-curve of natural fertility is shaped by a similar U-curve of aneuploidy in human oocytes. To test the hypothesis that maternally inherited meiotic errors in preimplantation embryos should also follow a U-curve, a database including 36,768 preimplantation embryo biopsies including genetic testing information was analyzed. A quadratic equation best modeled maternal meiotic errors resulting in a trisomic embryo, and meiotic errors declined significantly with female age in the lower range (18.27.1 years; B = .0.082; 95% confidence interval, .0.157 to 0.059). To understand how the curve of aneuploidy emerges, chromosome segregation at meiosis 1 was inferred, and it was discovered that 3 error types contributed. Meiosis 1 nondisjunction (M1 NDJ) decreased with female age (P < 0.025), precocious separation of sister chromatids or predivision (12, 13) increased linearly with female age (P < 0.001), and reverse segregation (RS) increased between the mid- and AMA groups (P 0.001). When assessed on a chromosomal level, it was observed that chromosome-specific responses to maternal age underlie the U-curve of aneuploidy. Centromeric cohesion remained robust in teenagers, whereas more extensive cohesion loss was correlated with a pronounced increase in RS in AMAs, suggesting cohesion weakening may act as a gmolecular clock h limiting reproductive capacity in AMAs. Correct segregation outcomes are often seen even when chromosomes would be expected to missegregate such as at the second meiotic division in RS. To further analyze this phenomenon, high-resolution imaging of intact metaphase II spindles was conducted, revealing chromatin threads between paired chromatids in 46% of meiosis II eggs. These threads may contribute to chromatid linkage and promote correct chromosomal alignment and segregation throughout both meiosis divisions in aging females with weakened centromeric cohesion. The study results show an increase in precocious separation of sister chromatids and RS derived fromlocalized centromeric and systemic cohesion weakening as women age. Also observed was an increase in M1 NDJ in young females that combined with cohesion weakening processes generates a chromosome-based U-curve of aneuploidy that shapes the distinct natural fertility curve in women.

AB - While it is understood that young females (.13 years to early 20s) and women of advancing maternal age (AMA, mid-30s or older) have reduced fertility rates, the exact mechanisms behind this feature of the fertility curve remain unclear. Because chromosomal errors and aneuploidy cause a significant amount of pregnancy loss and congenital disorders in women of advanced maternal age, meiotic error rates throughout the entire reproductive life span may shape natural fertility. This study of oocytes from females aged 9 to 43 years aimed to determine the mechanism involved in generation of the U-curve of aneuploidy and subsequent natural fertility curve in humans. Two independent patient cohorts were used as sources for oocytes, one including unstimulated girls and women prior to chemotherapy for blood disorders or cancer (cohort 1) and one including women receiving gonadotrophin-stimulation through in vitro fertilization clinics (cohort 2). Maternal age was the only significant factor affecting aneuploidy, with a best-fit model provided by a quadratic equation suggestive of a U-curve of aneuploidy. The rate of chromosome errors was 1.7%to 4.2%, affecting 23.6% to 53.5% of oocytes, suggesting the inverse U-curve of natural fertility is shaped by a similar U-curve of aneuploidy in human oocytes. To test the hypothesis that maternally inherited meiotic errors in preimplantation embryos should also follow a U-curve, a database including 36,768 preimplantation embryo biopsies including genetic testing information was analyzed. A quadratic equation best modeled maternal meiotic errors resulting in a trisomic embryo, and meiotic errors declined significantly with female age in the lower range (18.27.1 years; B = .0.082; 95% confidence interval, .0.157 to 0.059). To understand how the curve of aneuploidy emerges, chromosome segregation at meiosis 1 was inferred, and it was discovered that 3 error types contributed. Meiosis 1 nondisjunction (M1 NDJ) decreased with female age (P < 0.025), precocious separation of sister chromatids or predivision (12, 13) increased linearly with female age (P < 0.001), and reverse segregation (RS) increased between the mid- and AMA groups (P 0.001). When assessed on a chromosomal level, it was observed that chromosome-specific responses to maternal age underlie the U-curve of aneuploidy. Centromeric cohesion remained robust in teenagers, whereas more extensive cohesion loss was correlated with a pronounced increase in RS in AMAs, suggesting cohesion weakening may act as a gmolecular clock h limiting reproductive capacity in AMAs. Correct segregation outcomes are often seen even when chromosomes would be expected to missegregate such as at the second meiotic division in RS. To further analyze this phenomenon, high-resolution imaging of intact metaphase II spindles was conducted, revealing chromatin threads between paired chromatids in 46% of meiosis II eggs. These threads may contribute to chromatid linkage and promote correct chromosomal alignment and segregation throughout both meiosis divisions in aging females with weakened centromeric cohesion. The study results show an increase in precocious separation of sister chromatids and RS derived fromlocalized centromeric and systemic cohesion weakening as women age. Also observed was an increase in M1 NDJ in young females that combined with cohesion weakening processes generates a chromosome-based U-curve of aneuploidy that shapes the distinct natural fertility curve in women.

U2 - 10.1097/OGX.0000000000000817

DO - 10.1097/OGX.0000000000000817

M3 - Comment/debate

AN - SCOPUS:85092408113

VL - 75

SP - 412

EP - 413

JO - Obstetrical & Gynecological Survey

JF - Obstetrical & Gynecological Survey

SN - 0029-7828

IS - 7

ER -