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The Fudan University team published a review of infertility genetics in Science


On April 13, 2023, the journal Science launched a special issue of human reproduction for the first time, and Professor Wang Lei and Sang Qing of the Institute of Biomedical Sciences of Fudan University were invited to publish a review paper entitled “Understanding the genetics of human infertility”. Infertility has become a major disease affecting human health, and the incidence of infertility is increasing year by year. This review paper focuses on human gamete quality, focusing on the factors found in recent years that affect human gamete quality, especially genetic factors. The paper is presented from four perspectives: gamete production, gamete quality, related potential treatment options, and future prospects and challenges.

Human sperm and eggs combine to form a fertilized egg, initiating embryonic development, after which pregnancy is established. The production of normal numbers, morphology, and functional gametes is a prerequisite for successful fertility. Genetic studies of diseases affecting gamete production have been carried out in depth, while genetic studies affecting the quality of gametes themselves have only been carried out in recent years. The review first introduced the genetic study of gamete production abnormalities caused by disorders of the hypothalamic-pituitary-gonadal axis (HPG axis), including hypogonadotropic hypofunction, hypergonadotropic hypofunction (Kirschner syndrome, Turner syndrome, premature ovarian failure), and polycystic ovary syndrome. Then, the disease-causing genes that affect sperm self-motility, morphology and development, as well as egg maturation, fertilization and embryonic development, are summarized. Sperm abnormalities involve relatively many disease-causing genes due to their easy phenotype observation and early history of genetic research (Figure 1). With the continuous application of assisted reproductive technology, the phenotype of abnormal development of eggs, fertilization and early embryos has been continuously discovered (Figure 2), which has promoted genetic research in this direction, and more than 20 disease-causing genes have been identified in recent years, showing the important role of genetic factors in egg quality.

Fig. 1 Different types of sperm dysplasia and pathogenic genes

Fig. 2 Different types of eggs, fertilization and embryonic developmental abnormalities and pathogenic genes

Elucidating the factors that affect gamete quality is a key step in understanding the mechanisms of infertility and treating the disease. In recent years, the treatment of infertility has included new drug development, intestinal flora, personalized intervention for specific genes, gene editing, etc., and the review paper introduces the research progress in this regard. Compared with other complex diseases, the history of genetic research on gamete quality is relatively short, and there is still much room for improvement in the understanding of the corresponding pathological mechanisms. This also contributes to the limitations of the current molecular diagnosis of clinical diseases. In addition, the limited understanding of pathological mechanisms and the ethical constraints of gametes objectively hinder the development and application of corresponding treatments. At the same time, there will still be many challenges in infertility research, such as: how to more effectively obtain reproductive system disease tissue, how to improve the molecular diagnosis rate of diseases, how to translate laboratory treatments more effectively into the clinic, and so on.

However, there are opportunities in the challenges, and in the context of multi-omics and multidisciplinary interdisciplinary research, a large number of genes, proteins, and metabolites related to reproductive regulation will be discovered; Different inheritance patterns, mutation types, pathogenic mechanisms will be revealed; Infertility cohorts for refined phenotypic assessment will be established; Research on gene editing and organoid models will continue to be deepened. These studies are bound to advance the understanding of the mechanisms of human infertility, improve the rate of clinical diagnosis of diseases, and ultimately achieve personalized medicine.

Sang Qing and Wang Lei, Institute of Biomedical Sciences, Fudan University, respectively, were the first authors and corresponding authors of the review paper, and Professor Pierre Ray of the Université Grenoble Alpes in France participated in the writing of the progress of sperm genetics research.  

Original link: https://doi.org/10.1126/science.adf776
 
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