Sperm-Delivered Small RNAs Act as Genetic "Instruction Manual" for Embryo Development

Globally, approximately one in six couples face infertility issues, with about one-third of these cases having no known cause. Although in vitro fertilization (IVF) has become a significant solution, the success rate remains around 30%, with embryo quality being a major limiting factor. Traditional views often attribute fertility problems more to women, but recent research has found that small RNA (sRNA) molecules carried by sperm are subtly influencing the ultimate fate of the embryo.

Recently, a study published in Nature Communications titled "Small RNA in sperm–Paternal contributions to human embryo development" by scientists from Linköping University in Sweden and other institutions confirmed that sperm also provides a sophisticated "developmental instruction manual"-a class of regulatory molecules called small RNAs. This study included 69 couples undergoing IVF treatment and analyzed 70 treatment cycles. By sequencing small RNAs from remaining sperm samples, the study for the first time clearly established a strong correlation between different types of small RNAs in sperm and key IVF outcomes. These findings may offer new hope for improving infertility treatment.

Professor Anita Öst, one of the researchers, explained that in addition to carrying DNA, sperm also contain various molecules that help initiate and regulate embryonic development. This means that the male's role in conception is far more important than we previously understood.

Through systematic analysis, researchers discovered several classes of small RNAs in sperm with clear predictive value. Mitochondrial small RNAs (mitosRNAs) and Y-RNAs were associated with sperm concentration. Specifically, MT-TS1-Ser1, derived from a mitochondrial tRNA gene, showed a significant positive correlation with high sperm concentration, with an area under the curve (AUC) of 0.891 for distinguishing between high and low sperm concentrations. RNY4, from the Y-RNA family, was associated with low sperm concentration, with an AUC of 0.845. Both have strong clinical predictive value. A ​​group of small RNAs from the same genomic locus, potentially annotated as either piRNA or tsRNA, influenced fertilization success rates. Although the current data requires further validation with larger sample sizes, it suggests a potential regulatory role of this locus in sperm fertilization capacity.

Closely related to the rate of high-quality embryos were two types of small RNAs with opposing functions-microRNAs (miRNAs) showed a positive correlation with high-quality embryos, while ribosomal RNA-derived fragments (rsRNAs) showed a negative correlation. Among these, hsa-let-7g, miR-30d, and miR-320b/a were the most crucial miRNAs, with their predicted targets mostly related to embryogenesis and cell proliferation. Hsa-let-7g alone had an AUC of 0.812 for distinguishing between high and low-quality embryos. RsRNAs derived from 28S ribosomal RNA showed a negative correlation with high-quality embryos, with an AUC of 0.792. Most excitingly, these key microRNAs predicted embryo quality with an accuracy exceeding 80%, providing a novel non-invasive assessment tool for IVF treatment.

Figure 1. Sperm sRNA differs between samples of high and low rates of high-quality embryos. (Isacson S, et al., 2025)

The researchers pointed out that detecting these small RNAs from sperm samples could, in principle, predict the quality of embryos formed a few days later, much like reading the "instruction manual" for embryonic development in advance. The 2006 Nobel Prize in Physiology or Medicine was awarded to the scientists who first discovered microRNAs in nematodes, and they subsequently confirmed that these small molecules are essential for embryonic development.

What is surprising about this study is that the key regulatory microRNAs in human sperm (such as the let-7 family) belong to the same family as those discovered in nematodes. From worms to humans, these molecules have consistently played a protective role in the earliest stages of life, demonstrating a high degree of evolutionary conservation. Furthermore, the study also found that some transfer RNA-derived fragments (tsRNAs) are related to fetal growth and development. Although no definitive conclusions have been reached due to the small sample size (only two cases of infants born small for gestational age), it lays the groundwork for future exploration of the long-term impact of paternal small RNAs on offspring development.

Reference

Isacson S, et al. Small RNA in sperm–Paternal contributions to human embryo development. Nature Communications, 2025, 16(1): 6571.