A recent study by Johns Hopkins University published in Nature has identified specific maternal genetic variants that explain the high rate of embryo inviability and pregnancy loss due to aneuploidy. Although the finding sheds light on the molecular causes of infertility through the large-scale analysis of 139,000 embryos created through in vitro fertilization (IVF), the research raises a serious bioethical debate: the embryos were used and destroyed without the usual regulatory protection, as they were not considered “human participants” by the University’s institutional review board (IRB).
The most critical period of human embryonic development begins 14 days after fertilization. Following implantation of the embryo in the blastocyst state (composed of around 100 cells), the primary germ layers begin to form and most of the genes in the genome are activated, so that cell differentiation and organ and tissue organization can take place in the new being.
The fact is that only about 30% of embryos produced by IVF and implanted in the uterus successfully pass this stage, a rate comparable to that of those conceived naturally. Many embryos are expelled or their development collapses for no known reason. In a previous article, we reported on efforts to learn more about the causes of this great loss of embryonic viability through the creation of synthetic embryos, embryoids, or embryo models, in an attempt to circumvent the technical, ethical, and legal restrictions on studies on the development of human embryos from 14 days onwards.
During the early stages of human embryonic development, a large proportion of viability is therefore lost. Research into its causes is not permitted, which in turn hinders progress in the investigation of this important factor in human infertility. Since it is well established that all embryonic development is genetically regulated in space and time, genetic factors must explain the high loss of viability. Nonetheless, regardless of the explanation, the analysis must consider the influence of genes in the formation of the gametes that combine to create each new being.
Human gametogenesis
Before discussing a study that analyzes the causes of embryonic inviability, it is worth recalling some fundamental aspects about the formation of gametes, the creation of the zygote, and the early stages of embryonic development.
Female gametogenesis, or “oogenesis”, takes place in the germline tissue from very early stages of embryonic-fetal development. Once this tissue is formed, the germ cells begin female meiosis to generate the eggs, arresting the process in meiotic prophase I, in a state known as “dictyotene”. They remain in this state for years, until sexual maturity is reached. At puberty, meiosis resumes from the point where it had arrested and the eggs are produced asynchronously, one per menstrual cycle.[1]
In contrast, male gametogenesis or “spermatogenesis” takes place in the male germline tissue in adulthood, beginning at sexual maturity, without temporary interruption of meiosis of the spermatogonial stem cells.
It is important to remember that, during meiosis, the 23 pairs of chromosomes (23 maternal and 23 paternal) pair up longitudinally to form 23 bivalents. Once their chromatids—the lateral elements of each chromosome—are aligned, breakages and reciprocal exchanges between homologous paternal and maternal regions occur. This process is called “crossing-over” and gives rise to genetic recombination, which is the main source of non-mutational variation in sexually reproducing species. The points of exchange between chromatids, which can be observed microscopically, are called “chiasmata”.
Following this genetic exchange, the 46 chromosomes are aligned and separated into two sets of 23, which are passed to each daughter cell during the first meiotic division. The second meiotic division involves a further division of these cells, so that each of the four resulting cells contains a set of 23 chromatids. Another difference between female and male gametogenesis is that, in the former, only one of the four resulting cells matures into an egg, while in males, all four cells give rise to functional sperm.
The search for genes causing embryonic inviability
Recently, researchers from Johns Hopkins University in New York (USA) published a paper in Nature that seeks to unravel the causes of high embryonic inviability and pregnancy loss in human reproduction, based on genetic regulation during meiosis.[2] In the study, specific genetic variations in maternal genes were identified as a cause of embryos presenting chromosomal abnormalities incompatible with life.
New evidence was also provided that supports previous knowledge: the leading cause of inviability in embryonic-fetal development is aneuploidy, i.e., alterations in the number of chromosomes—either an extra or missing chromosome—that combine in the gametes. It is estimated that only about half of human conceptions survive to birth, mainly due to the abundance of inviable aneuploidies in the early stages of gestation.[4] The imbalance in the number of chromosomes leads to genetic instability that, in many cases, is incompatible with life. This is not always the case, however, since there are situations in which the presence of one chromosome more or one less is tolerated, albeit with phenotypic consequences. Examples include trisomy 21, which causes Down syndrome (2n = 47); monosomy of the sex chromosomes, responsible for Turner syndrome (2n = 45:22’’ + X0); and trisomy of the sex chromosomes, causing Klinefelter syndrome (2n = 47:22’’ + XXY).
We also know that many chromosomal abnormalities are passed down through the female line and that their frequency increases with maternal age. The study discussed herein provides new evidence in this regard and also demonstrates the influence of a genetic component that determines embryonic viability or inviability. To address this factor, the researchers conducted a large-scale analysis of common and rare genetic combinations in 139,000 IVF-derived embryos from 23,000 couples, using a combined study of embryonic DNA—similar to preimplantation genetic diagnosis (PGD)—and parental DNA.
Comparative analysis of the data was carried out using computing tools, enabling the identification of associations between maternal DNA variants and embryos that failed to complete their developmental cycle, in which major genes and molecular markers like single nucleotide polymorphisms (SNPs) were involved.
Among the major genes implicated, a variant of the SMC1B gene was detected; this encodes a family of proteins necessary for cohesion of the chromatids of the maternal and paternal chromosomes and DNA recombination during meiosis and mitosis. This gene is involved in the maintenance of homologous chromosome pairs during female meiosis through structures that keep them together. The deterioration of these structures increases over time, which, as mentioned, in the case of female gametogenesis, is several decades. This would explain the increase in the frequency of aneuploidies, their particular incidence through the maternal line, and their relationship with the mother’s age. The longer the time spent in prophase of meiosis I, the greater the likelihood of deterioration of the molecular machinery responsible for keeping the chromosome pairs together.
Statistical analysis also revealed that the number of crossovers was lower in aneuploid versus euploid embryos, which is consistent with the fundamental role of these structures in chromosome pairing and correct segregation.
The SMC1B gene is located on human chromosome 22 and had already been identified in mice and other species. [3] According to researcher Rajiv McCoy, co-author of the paper, “the genes that emerged from our study in humans are exactly the ones that experimental biologists have detailed over decades as critical for recombination and chromosome cohesion in model organisms like mice and worms”.
The statistical analysis, which compared the parental genotypes with the viable and inviable embryonic ones, also implicated another genetic factor located on human chromosome 14: the C14orf39 gene, responsible for a meiotic protein that localizes to the central element of the “synaptonemal complex”. This is a structure that is needed for the precise pairing of homologous chromosomes during prophase and for their proper segregation at the end of meiosis I.
These findings highlight the dual role of recombination: on the one hand, in the generation of genetic diversity and, on the other, in ensuring the fidelity of chromosome distribution in meiosis.
The authors also conducted a genome-wide association study (GWAS) considering maternal meiotic aneuploidies affecting any chromosome. They identified, among others, two significant associations at the genomic level: SNP rs9351349, located within an intergenic region of chromosome 6; and SNP rs6006737, located on chromosome 22, whose incidence in the samples analyzed was associated with lower rates of female recombination.
The findings of this study suggest that there are variants of certain genes or genomic regions that affect meiotic stability and, consequently, a balanced constitution of the chromosome number in the offspring. Therefore, the authors pose the evolutionary paradox of the high incidence of aneuploidy in human reproduction. Given the severity of its effects, one would expect that natural selection would have eliminated the allelic combinations responsible for this instability over the course of generations. However, the authors speculate on the reasons for this paradox, which is 
Finally, it should be noted that one of the most positive aspects of finding genes involved in any phenotypic manifestation—and in this case, in the incidence of aneuploidies as a cause of embryonic inviability—is the possibility of seeking solutions through drugs that act on the molecular mechanisms responsible for these alterations.
Bioethical assessment
The research discussed herein did not meet the requirements to be considered research with human participants since, as stated in the paper, “[it] does not obtain information or biospecimens through intervention or interaction with a human participant”; therefore, it did not require federally regulated approval according to the Johns Hopkins University Homewood IRB.
However, as explained, it involved 139,000 human embryos, obtained through IVF from 23,000 couples.
The vast majority of these embryos are surplus embryos from assisted reproduction techniques, i.e., embryos that were not implanted, which were either cryopreserved or discarded due to having some type of abnormality.
The study does not report on the fate of these embryos, although in most cases they are destroyed.
The Johns Hopkins University IRB considers that the more than 130,000 human embryos used and discarded—destroyed—in the study are not “human participants”, and do not require regulatory intervention by the aforementioned committee.
The human nature of the embryo today constitutes scientific evidence that is undisputed by experts. However, the human embryo continues to be acted upon as if it were not, as if it were a pre-embryo, an obsolete and outdated concept proposed in the 1980s.
Research aimed at identifying genetic causes that could help treat cases of infertility by detecting chromosomal abnormalities in conceived embryos is considered, a priori, a legitimate objective.
Nevertheless, the methods to be used in this type of research must also be evaluated bioethically, in order to determine whether the entire process is ethically legitimate.
Sacrificing more than 130,000 human embryos after their genetic diagnosis in an attempt to establish a correlation with the information obtained from the parental genome can never be considered a licit and bioethically acceptable means to justify research of this nature.
For the same paper to talk about human embryos and then justify not requiring ethical validation because it does not include human participants is unacceptable for an institution like Johns Hopkins University, as well as for a journal like Nature, which should also uphold the ethics of the research it publishes.
On previous occasions we have stressed the need to include strict ethical criteria when experimenting with human embryos, whose dignity must be respected in all circumstances.
Nicolás Jouve
Professor Emeritus of Genetics at the University of Alcalá
Member of the Bioethics Observatory of the Catholic University of Valencia
Julio Tudela
Bioethics Observatory – Institute of Life Sciences
Catholic University of Valencia
References
[1] Bata OY, Kono T. Maternal primary imprinting is established at a specific time for each gene throughout oocyte growth. J. Biol. Chem. 277 (2002): 5285–5289.
[2] Carioscia, S.A., Biddanda, A., Starostik, M.R. et al. Common variation in meiosis genes shapes human recombination and aneuploidy. Nature (2026). https://doi.org/10.1038/s41586-025-09964-2
[3] Hodges CA, Revenkova E, Jessberger R, Hassold TJ, Hunt PA. SMC1-beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nat. Genet. 37 (2005): 1351–1355.
[4] McCoy RC, Summers MC, McCollin A, et al. Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos. Genome Med. 15 (2023): 77.
