When a woman experiences a miscarriage, the embryo usually has an unusual number of chromosomes in its genome. But under what circumstances does such aneuploidy occur? Researchers have now identified four maternal gene variants that increase the risk of such an abnormality in the number of chromosomes in the embryo and thus of a premature end to the pregnancy. These gene variants are widespread in the population, but contribute little to a woman’s individual risk of miscarriage, as the team reports.
The main reason why a pregnancy ends unintentionally prematurely in women is a so-called aneuploidy. This means that the embryo has more or fewer chromosomes in its genome than usual. Well-known examples of this are Klinefelter and Turner syndrome, in which the newborn has one X chromosome too many or too few. In Down syndrome, chromosome number 21 is present three times, one too many times. In other cases, other chromosomes are affected and the embryo dies before birth. This is not uncommon: it is estimated that every second fertilized egg has a miscarriage, usually due to aneuploidy.
Such an anomaly can occur during meiosis in the course of egg formation in the mother’s body. Aneuplody occurs when the chromosomes divide incorrectly into the daughter cells during cell division, resulting in an egg cell with a defective set of chromosomes. In addition, another factor can increase the risk of aneuploidy: errors in the exchange of DNA sections between chromosomes during egg formation, so-called crossover recombinations. These recombinations not only provide genetic diversity in sexual reproduction, but are also important helpers for spatial chromosome pairing and subsequent segregation, as known from previous studies.
What role do genes play?
It is known that the older the mother is at conception, the higher the risk of aneuplodia in the offspring. A team led by Sara Cariosci from Johns Hopkins University has now investigated whether there are also certain genetic factors that contribute to meiotic or recombinant aneuploidy in the egg and embryo. To do this, they evaluated genetic data from 139,416 embryos that were fertilized in vitro and routinely examined for genetic defects before being inserted into the uterus. Using a computer model, the researchers looked for patterns in this large data set.
The evaluation showed: The researchers found a total of over 3.8 million crossover recombination events in the embryos’ genome. They also found at least one aneuploid chromosome in 30 percent of the embryos examined. In 57,974 cases there was one too many chromosomes (trisomies), in 34,511 cases one too few (monosomies). The most frequently affected were chromosomes 5, 16, 21 and 22. However, these embryos had noticeably fewer recombination events than those with normal chromosome numbers. This confirms that such DNA exchanges are important for proper chromosome segregation during meiosis, the team concludes.
Four gene variants identified
Some embryos stood out from this data set because they had particularly few such crossover events and, at the same time, particularly frequent meiotic aneuploidy. The biomedical scientists found a specific variant of the SMC1B gene in the genome of these embryos. This gene contains the instructions for a protein that helps hold chromosomes together during meiosis, as the team explains. Cariosci and her colleagues found a similar connection in embryos that carried variants of the genes C14orf39, CCNB1IP1 and RNF212 in their DNA. However, these genes are not involved in chromosome division, but in the recombination process of DNA. A mutation in one of these maternal genes is apparently associated with errors in these important processes during egg formation, the researchers conclude. Embryos with such gene variants have a higher risk of miscarriage.
The gain of an additional chromosome during egg formation. The protein SMC1B is part of the ring-like cohesin complex that holds chromosomes together. A variation in the SMC1B gene contributes to the risk of this defective chromosome segregation. © Thom Leach, Amoeba Studios
Statistical analyzes also showed that these risk gene variants are widespread in the population. “The (A) allele of rs2272804, which is associated with lower SMC1B expression and higher aneuploidy risk, is distributed worldwide, with higher frequencies in African populations,” Cariosci and her colleagues write. In a global genetic database, they found this gene variant in 44 percent of all people and 71 percent of Africans. They also found risk alleles of the genes C14orf39, CCNB1IP1 and RNF212 in 39, 42 and 22 percent of the world’s population. This genetic distribution helps to understand why so many pregnancies end prematurely. However, a woman’s individual risk of miscarriage is difficult to predict. Compared to the mother’s age and environmental factors, these gene variants have only a small influence on the risk of aneuploidy, the team emphasizes.
Nevertheless, the study provides important new insights into the genetic factors that influence the risk of pregnancy loss. “This work provides the clearest evidence to date of the molecular pathways that confer variable risk of chromosomal errors in humans,” says senior author Rajiv McCoy of Johns Hopkins University. “These findings deepen our understanding of the earliest stages of human development and open the door to future advances in reproductive genetics and fertility care.” The identified genes are promising targets for future drugs.
Source: Sara Cariosci (Johns Hopkins University) et al.; Nature, doi: 10.1038/s41586-025-09964-2