“We really thought it was just a weird pattern of inheritance,” Germain recalled. “We hadn’t thought about nonrandom fertilization.”
Later, on a whim, Germain decided to review all the raw data from his experiments. As he looked over the results, he remembered Godbout’s questions that had been prompted by Nadeau’s email. The more he looked at the data, the more that genetically biased fertilization looked like “the most plausible explanation,” he said.
Frustrated at how few scientists had seriously considered genetically biased fertilization as an explanation for their results, Nadeau wrote up his hypothesis in “Can Gametes Woo?,” an article published in October in Genetics. His goal, he said, was to spur more research into this area and determine if and how egg-and-sperm interactions can alter fertilization.
“We’ve been blinded by our preconceptions. It’s a different way to think about fertilization with very different implications about the process of fertilization,” Nadeau says.
Other scientists, such as Manier at George Washington University, say that Nadeau’s hypothesis is intriguing and even plausible, but they point out that no one has any evidence about how it could happen. Nadeau agrees and points to two possibilities.
The first involves the metabolism of B vitamins such as folic acid, which form important signaling molecules on sperm and eggs. Research in Nadeau’s lab has shown that these molecules play an outsize role in fertilization, and he believes abnormalities in certain signaling genes may alter how much sperm and egg attract each other.
A competing hypothesis builds on the fact that sperm are often present in the female reproductive tract before the final set of cell divisions that produce the egg. Signals from the sperm could influence these cell divisions and bias the identity of the cell that becomes the egg.
Whatever the mechanism might be, this work challenges the standard view of female physiology as passive during fertilization. “Females were seen as passive objects with no choice, but females are going to have a vested interest in the outcome of fertilization,” said Renee Firman, an evolutionary biologist at the University of Western Australia. “We still have a long way to go to understand this process, but I don’t think we still really appreciate how common this is and how often it happens.”
Finding data to support or refute this hypothesis could be challenging, Manier said. It will depend on showing that genes within the sperm affect their surface molecules, and that the egg can sense these differences. Such results will require detailed biochemical studies of individual sperm cells and sequencing information about their genome.
Nadeau is prepared for skeptics—he’s encountered many at conferences when he presents the results of his mouse studies and his hypothesis for what’s going on. Critics often approach him after the talk and begin asking him questions. Whether they walk away convinced is unclear, but Nadeau feels they are much less certain that biased fertilization doesn’t happen. To Harmit Malik, a geneticist and virologist at the Fred Hutchinson Cancer Research Center, the situation is the ultimate Sherlock Holmesian solution.
“If you’ve eliminated the impossible, then what remains, however unlikely, must be the truth,” he quipped.