With our discovery of sperm RNAs and establishing their presence in both mouse and man (1), we faced a strong headwind but stayed the course toward understanding their complexity and function. We were cognizant that zygotic genome activation proceeds at a much faster rate in mice than in men. With approximately 50% of the infertile couples presenting with a male factor component, our studies are directed to address whether sperm RNAs provide a means to understand infertility as a disease and how it may impact other aspects of the father's life course that reaches his child. We carried out the first microarray study (2) for any male reproductive tissue and subsequently demonstrated human paternal RNAs delivery to the oocyte upon fertilization (3). Continuing these studies, we showed that teratozoospermia was likely to result from a defective proteasome proteolytic pathway involved in many diseases. We provided a comprehensive account of the sperm RNAs (4), with the first whole-cell description of sperm sncRNAs (< 100 nt) and RNAs (>100 nt) using novel approaches to RNA-Seq (5). A series of paternally delivered RNAs with some possibly essential to maintaining one of the two cells in a pluripotent state was identified (6). Moving forward, we showed that during epididymal transport the maturing sperm could exchange RNAs with their environment through exosomes (7). We have now extended the repertoire of the ejaculate to include the microbiome providing the ability to detect any symbiotic or foreign passengers (8). In collaboration with national and international clinics and agencies, we continue to develop sperm RNAs as a measure of male fertility status to ease the burden on women (9) and more equally distribute the responsibility for the birth of a healthy child between the couple. Sperm RNAs within the infertile male now serve as markers of disease, often unbeknownst to the father that may besiege the next generation (10). Understanding their impact provides a pathway for maximizing a healthy lifecourse of each generation.
1. Wykes, S. M., Miller, D. and Krawetz, S.A. (2000) Mammalian spermatozoal mRNAs: tools for functional analysis of male gametes. Journal of Submicroscopic Cytology and Pathology 32:77-81. PMID: 10877105
2. Ostermeier, G.C., Dix, D.J., Miller, D., Khatri, P. and Krawetz, S.A. (2002) Spermatozoal RNA profiles of normal fertile men. The Lancet. 360:773-777. PMID: 12241836
3. Ostermeier, G.C., Miller, D., Huntriss, J.D., Diamond, M.P. and Krawetz, S.A. (2004) Delivering spermatozoan RNA to the oocyte. Nature 429:154. PMID: 15141202
4. Platts, A.E., Dix, D. J., Chemes, H.E., Thompson, K.E., Goodrich, R., Rockett, J. C., Rawe, V.Y., Quintana, S., Diamond, M.P., Strader, L.F. and Krawetz, S.A. (2007) Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs. Human Molecular Genetics. 16:763-773. PMID: 17327269
5. Krawetz, S.A., Kruger, A., Lalancette, C., Tagett, R., Anton, E., Draghici, S. and Diamond, M. (2011) A survey of small RNAs in human sperm. Human Reproduction. 26:3401-3412 PMID: 21989093
6. Sendler, E., Johnson, G.D., Mao, S., Goodrich, R.J., Diamond, M.P., Hauser, R., and Krawetz, S.A. (2013)Stability, Delivery and Functions of Human Sperm RNAs at Fertilization. Nucleic Acids Research 41:4104-4117. PMID: 23471003
7. Johnson, G.D., Mackie, P., Jodar, M., Moskovtsev, S. and Krawetz, S.A. (2015) Chromatin and extracellular vesicle associated sperm RNAs. Nucleic Acids Research. 43:6847-6859 PMID: 26071953
8. Swanson, G.M., Moskovtsev, S., Librach, C., Pilsner, J.R. Ph., Goodrich, R. and Krawetz, S.A. (2020) What human sperm RNA-Seq tells us about the microbiome. Journal of Assisted Reproduction and Genetics 37:359-368. PMID: 31902104.
9. Jodar, M., Sendler, E., Moskovtsev, S. Librach, C., Goodrich, R., Swanson, S., Hauser, R., Diamond, M.and Krawetz, S.A. (2015) Absence of sperm RNA elements correlates with idiopathic male infertility. Science Translational Medicine. 7(295):295re6. PMID: 26157032
10. Burl, R.B., Clough, S., Sendler, E., Estill, M and Krawetz, S.A. (2018) Sperm RNA elements as markers of health. Systems Biology in Reproductive Medicine. 64:25-38. PMID: 29199464