a little drop of poison

'Poisonous' sperm may offer clues to a common medical problem

"Imagine a marathon, in which all participants get poisoned drinking water, but some runners also take an antidote."

The father of genetics, Gregor Mendel, presumed all sperm have an equal opportunity in the race for fertilization. In a marathon sprint to the egg, so his theory goes, all sperm have the same chance to reach their target before any other sperm.

But Mendel underestimated his subject. Not all sperm are equal — in the United States, male fertility problems account for a third of conception issues, but despite the prevalence, many of these issues are unexplained. In a new study in mice, researchers show how sperm which carry a specific gene variation not swim faster, but also “poison” their peers.

What's new — The new findings, published this week in the journal PLOS Genetics, suggest genetic variation in the gene which encodes for the protein RAC1 may have a deadly affect on sperm's chances of survival. The study also links this kind of variation to ramped up activity in a protein affecting sperm movement, enabling them to swim more efficiently.

The research zooms in on a genetic variation called a t-haplotype variation in RAC1. If sperm carry this variation, then they have a 99 percent rate of success in fertilizing the egg, according to the results.

Mouse sperm can be “normal,” in that they don't carry the variation, or the individual sperm may be mixed, with some carrying different variations, the researchers behind the new study say.

Sperm with the t-haplotype are not only better swimmers than their peers, the results show. They also effectively “poison” those that don’t have it, stopping these competing sperm dead in their tracks (literally).

Competition among spermatozoa is fierce. These sperm all carry the same genetic variant, causing them to swim atypically.Alexandra Amaral MPI

To fully understand this idea, we need to zoom out. Bernhard Herrmann, Director at the Max Planck Institute for Molecular Genetics and of the Institute of Medical Genetics at Charité – Universitätsmedizin Berlin, uses a more familiar scene to explain:

“The trick is that the t-haplotype ‘poisons’ all sperm, but at the same time produces an antidote, which acts only in t-sperm and protects them,” Herrmann said in a statement.

“Imagine a marathon, in which all participants get poisoned drinking water, but some runners also take an antidote,” he says.

Why it matters — In the race for fertilization, these genetic factors all play a part in the role of sperm success as they fight to reach the egg.

Alexandra Amaral is a researcher at the Max Planck Institute for Molecular Genetics and first author of the study. She tells Inverse every variation can be crucial for sperm success.

Essentially, if sperm carry an evolutionary advantageous gene variant, then that sperm may be better poised for success.

“sperm cells are ruthless competitors”

Digging into the details — Curiously, t-sperm appear to only have this advantage over “normal” sperm if the two are mixed together. By themselves, the t-sperm aren't so fabulous at the survival-of-the-fittest game.

T-haplotypes “turn on” the RAC1 protein. But how much of the protein is expressed needs to be in a delicate balance for it to help the sperm — not too much, and not too little, Amaral says.

“We found out that the level of this protein… can be more or less active,” she says. Essentially, the protein acts like “a lightbulb switch that can be turned on or off” in the t-haplotype sperm, she explains.

“The level of protein that is on has to be quite well regulated. If it is too much, sperm don't move well. And if it’s too low, it also doesn’t move well,” she says.

If the RAC1 level is not balanced, Amaral says the sperm “move a little bit, but they’re kind of in circles.”

This is why mice with sperm which carry only t-haplotypes are sterile — the RAC1 level is too high for them to move well. In fact, Amaral says, “the motility” of these sperm is “really bad.” If the sperm carry no t-haplotype variation, then they naturally perform the best, she says.

"Our data highlight the fact that sperm cells are ruthless competitors," Herrmann says.

What's next — This study is preliminary, and it is also in mice. Polina Lishko is a cell biologist at the University of California in Berkeley, and is not affiliated with this study. She notes it is not exactly clear from these results how the disruption happens, so more work is needed to discover the mechanism behind the peculiar effects.

Also, sperm are “different among all species” — meaning what’s true in mice's sperm may not necessarily translate exactly into humans, or other mammals, she says.

There is some evidence to suggest the affects seen here may be carried in other species, however. The protein has also been studied in bull sperm, and if RAC1 is limited, it affects sperm movement in much the same way as in mice, Amaral says.

These results indicate what might happen if the same limitations were applied to human sperm, she says. But it is too early to say anything definitive, for now.

“Bull sperm are more similar to human sperm than the mice sperm, so we believe that this probably is also the case for human sperm,” Amaral says.

Amaral and her colleagues hope to find out. They are now looking at the RAC1 protein in human sperm with the hopes of discovering whether it may be linked to male infertility in our own species.

Abstract: Mammalian spermatozoa employ calcium (Ca2+) and cyclic adenosine monophosphate (cAMP) signaling in generating flagellar beat. However, how sperm direct their movement towards the egg cells has remained elusive. Here we show that the Rho small G protein RAC1 plays an important role in controlling progressive motility, in particular average path velocity and linearity. Upon RAC1 inhibition of wild type sperm with the drug NSC23766, progressive movement is impaired. Moreover, sperm from mice homozygous for the genetically variant t-haplotype region (tw5/tw32), which are sterile, show strongly enhanced RAC1 activity in comparison to wild type (+/+) controls, and quickly become immotile in vitro. Sperm from heterozygous (t/+) males, on the other hand, display intermediate RAC1 activity, impaired progressive motility and transmission ratio distortion (TRD) in favor of t-sperm. We show that t/+-derived sperm consist of two subpopulations, highly progressive and less progressive. The majority of highly progressive sperm carry the t-haplotype, while most less progressive sperm contain the wild type (+) chromosome. Dosage-controlled RAC1 inhibition in t/+ sperm by NSC23766 rescues progressive movement of (+)-sperm in vitro, directly demonstrating that impairment of progressive motility in the latter is caused by enhanced RAC1 activity. The combined data show that RAC1 plays a pivotal role in controlling progressive motility in sperm, and that inappropriate, enhanced or reduced RAC1 activity interferes with sperm progressive movement. Differential RAC1 activity within a sperm population impairs the competitiveness of sperm cells expressing suboptimal RAC1 activity and thus their fertilization success, as demonstrated by t/+-derived sperm. In conjunction with t-haplotype triggered TRD, we propose that Rho GTPase signaling is essential for directing sperm towards the egg cells.
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