As a researcher who had spent several decades studying heredity, Nadeau was aware of myriad factors that could affect Mendel’s ratios. If a fertilized egg ended up with two mutated copies of a recessive gene, the resulting embryo might die early in development. Such embryonic-lethal mutations would alter the ratio of homozygotes to heterozygotes, but it would also reduce the average number of mouse pups in each litter. Yet all of Zechel and Nadeau’s mice had standard litter sizes, and they found no evidence that embryos were dying early after fertilization.

Perhaps, Nadeau reasoned, the problem lay in the sperm, not the egg. He therefore bred male mice with and without the mutation to healthy mutation-free females and found no differences in the males’ fertility — something that would have become obvious if the mutation were affecting sperm formation. Step by step, Nadeau and his team eliminated every possible cause of these wonky ratios of offspring genotypes … except one: that during fertilization, the egg and sperm were genetically biased against the mutant genotype.

Surely, someone else must have already seen this, Nadeau reasoned, so he searched the scientific literature. Although he could find plenty of examples of unexplained offspring ratios, no one had seriously pursued genetically biased fertilization as an answer.

“Everyone just interpreted it as embryonic lethality because we see what we look for and we explain it using what we know,” Nadeau said.

One of those examples Nadeau found was from the lab of the cancer researcher Roseline Godbout at the University of Alberta. Godbout studied the role of a protein called DDX1 in the development of retinoblastoma, a highly heritable childhood cancer. Mice that were missing one functional copy of the DDX1 gene (but with another, fully functional gene as backup) seemed normal and healthy. When Godbout and Devon Germain, now a postdoctoral fellow at the Max F. Perutz Laboratories in Vienna, bred such heterozygote males and females, they found that none of the offspring lacked both copies of DDX1, even though simple Mendelian math would suggest 25 percent of them should. Given the gene’s importance to DNA replication, however, this wasn’t surprising: The homozygotes without DDX1 presumably died after conception. Godbout and Germain also found lower-than-expected numbers of homozygote offspring with two copies of DDX1. A complicated series of mating experiments led the scientists to propose that their results came from a rare mutation that had occurred in the DDX1 gene during their experiments.

Nadeau wasn’t convinced. He wrote to Godbout to ask how her lab had verified that the “knockout” homozygotes without DDX1 genes had died as embryos. They hadn’t. He also asked whether they had considered genetically biased fertilization, wherein the egg preferred to fuse with a sperm of the opposite DDX1 genotype.

“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 egg. Research in Nadeau’s lab has shown that these molecules play an outsized 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.

This article was reprinted on TheAtlantic.com.