Globally, the occurrence of pregnancy termination remains a significant concern. It is estimated that approximately 15% of recognized pregnancies conclude in miscarriage, though the actual incidence is likely considerably higher, as numerous gestations cease before they are clinically detected.
A recent investigation has yielded crucial insights into the genetic determinants underpinning aneuploidy, a condition characterized by an aberrant number of chromosomes within a cell, which stands as a primary driver of pregnancy loss.
Miscarriages can be attributed to a multitude of factors, yet chromosomal anomalies represent a prevalent contributor. A substantial proportion, close to half, of all identified miscarriages occurring in the initial or second trimester are associated with fetuses exhibiting either an excess or deficit of chromosomes.
To elucidate the underlying mechanisms of aneuploidy, researchers undertook an extensive analysis of genetic data derived from nearly 140,000 in vitro fertilization (IVF) embryos. This endeavor has brought to light new details concerning how common genetic variations can elevate the susceptibility of certain prospective parents to pregnancy termination.
“This research offers the most compelling evidence to date regarding the molecular pathways responsible for the variable risk of chromosomal errors in humans,” stated senior author Rajiv McCoy, a computational biologist affiliated with Johns Hopkins University.
“These discoveries enhance our comprehension of the incipient phases of human development and pave the way for subsequent advancements in reproductive genetics and fertility treatments,” McCoy added.
The genesis of chromosomal abnormalities predominantly occurs within oocytes, with their incidence exhibiting a positive correlation to the maternal age. Although maternal age is a recognized risk determinant, the researchers emphasize that our understanding of the broader genetic landscape has been constrained by insufficient data.
To address this limitation, scientists necessitate the examination of a vast quantity of genetic information from numerous thousands of embryos prior to any pregnancy loss, complemented by data from their biological progenitors.
“As this characteristic is intrinsically linked to survival and reproductive success, evolutionary pressures permit only genetic variations with subtle impacts to become widespread within the population,” McCoy explained. “Detecting these minor effects requires substantial sample sizes.”
The investigative team leveraged clinical data from pre-implantation genetic assessments of IVF embryos, scrutinizing 139,416 embryos originating from 22,850 pairs of biological parents in pursuit of discernible patterns. They identified 92,485 aneuploid chromosomes across 41,480 distinct embryos.
“The strength of this analysis lies in the immense scale of the datasets,” McCoy remarked. “This afforded us the scope and precision to identify several of the initial, well-characterized associations between a mother’s DNA and her propensity to produce embryos incapable of survival.”
The most pronounced of these associations was observed within genes instrumental in guiding chromosome pairing, recombination, and segregation during the process of meiosis in oocyte lineages.
A specific variant of the gene SMC1B, which provides instructions for synthesizing a protein that aids in maintaining chromosomal integrity during meiosis, was found to be linked to diminished crossover events and an elevated incidence of maternal meiotic aneuploidy, according to the study’s findings.
The analysis also pinpointed connections with several other genes implicated in recombinational crossover processes, including C14orf39, CCNB1IP1, and RNF212.
“This discovery is particularly noteworthy,” McCoy commented, “as the genes identified in our human study are precisely those that experimental biologists have, over many decades, characterized as essential for recombination and chromosomal cohesion in model organisms such as mice and nematodes.”
The initial phase of female meiosis transpires during fetal development, involving chromosome pairing and recombination, before entering a prolonged dormancy until later reactivation for ovulation and fertilization.
Genetic variations may precipitate complications during this interim period, leading to chromosomes that disjoin with undue ease, thereby potentially predisposing to aneuploidy upon the resumption of meiosis.
“Our findings underscore that inherited variations in these meiotic mechanisms contribute to inherent fluctuations in the propensity for aneuploidy and pregnancy loss among individuals,” McCoy concluded.
Despite these revelations, the authors caution that accurate prediction of individual susceptibility to pregnancy loss will likely remain challenging, given the significant influence of factors beyond genetics, such as maternal age and environmental exposures.
Nevertheless, comprehending these genetic determinants holds considerable promise for the development of therapeutic interventions and furnishes a foundational basis for future investigations into both maternal and paternal genetic predispositions associated with pregnancy termination.
