New Insights on Male-Factor Infertility

Sperm play a critical role in the creation of new life, delivering essentially half of the genetic material required.

Researchers at the University of Michigan are now delving into the molecular-level details of sperm formation, with a particular focus on how abnormalities in this process might lead to male-factor infertility.

Unlike other cells in the body, sperm possess a unique characteristic: their genetic material is packed with proteins called protamines.

The significance of this protamine-based packaging system of sperm cells raises an intriguing question: why do sperm use protamines to package DNA instead of histones, which are employed by all other cell types?

Most mammals have multiple types of protamines and these need to be maintained in well-defined ratio, and deviations in this ratio have been associated with infertility.

Conventional wisdom has it that protamines are particularly efficient at tightly packaging DNA into dense structures called chromatin because they are rich in arginine, a positively charged amino acid that strongly binds to the negatively charged DNA.

However, recent studies have shown that protamines also have non-arginine amino acids that are species specific and have unexpected post-translational modifications that chemically change proteins after they are made.

Furthermore, what was intriguing was the presence of post-translational modifications on protamines, despite the fact that sperm are not transcriptionally active.

“The fact that protamines have all of these different modifications on them suggests that these modifications must have some function in chromatin packaging,” said Moritz, co-first author on the paper.

Using mice, they analyzed a modified lysine residue specific to a mouse protamine and present in mature mouse sperm. Substituting lysine with an alanine amino acid resulted in abnormally shaped sperm, impaired embryonic development, and reduced fertility.

What’s more surprising was that replacing the lysine with a positively charged arginine did not correct the defective sperm packaging, meaning the interactions go beyond the charge of the molecule.

Male-factor infertility often lacks a clear cause, which highlights the importance of studying these modifications.

The team hopes to next examine the mechanisms of sperm cell packaging in greater detail in the hopes of recreating the process completely in vitro.


Lindsay Moritz, Samantha B. Schon, Mashiat Rabbani, Yi Sheng, Ritvija Agrawal, Juniper Glass-Klaiber, Caleb Sultan, Jeannie M. Camarillo, Jourdan Clements, Michael R. Baldwin, Adam G. Diehl, Alan P. Boyle, Patrick J. O’Brien, Kaushik Ragunathan, Yueh-Chiang Hu, Neil L. Kelleher, Jayakrishnan Nandakumar, Jun Z. Li, Kyle E. Orwig, Sy Redding, Saher Sue Hammoud. Sperm chromatin structure and reproductive fitness are altered by substitution of a single amino acid in mouse protamine 1. Nature Structural & Molecular Biology, 2023; DOI: 10.1038/s41594-023-01033-4

Michigan Medicine – University of Michigan. “Modifications to amino acids in sperm could be behind infertility: Researchers dive into the molecular-level details of sperm formation.” ScienceDaily. ScienceDaily, 31 July 2023. <>.

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Photo by Drew Hays