Choosy Eggs May Pick Sperm for Their Genes, Defying Mendel’s Law

The first genetic rule states that gametes unite at random, however tests suggest that occasionally eggs actively choose sperm for their genetic advantages.

Millions of sperm compete in a winner-take-all sprint toward the egg that is waiting at the finish line during fertilization. Due to missing or malformed tails and other flaws, many sperm never even reach the starting line. Others run out of energy before finishing the exhausting voyage through the female reproductive canal, or they become entangled in gummy fluid that is designed to snag all but the fastest swimmers. The ultimate victor would be selected by one last race to the finish line for the subset of a subset of spermatozoa that reach their trophy. The egg waited quietly till the Michael Phelps of gametes eventually came; the sperm's precise identification was random. Or so researchers believed.

This conventional wisdom is being contested by Joe Nadeau, chief scientist of the Pacific Northwest Research Institute. In theory, random fertilization should result in kids with precise gene ratios, however Nadeau has discovered two instances from only his own lab that show fertilization can be anything but random: It is substantially more likely for some gamete gene pairs than for others. He had to come to the obvious conclusion that fertilization wasn't at all random after ruling out all other possibilities.

Nadeau described it as "the gamete equivalent of picking a mate."

His idea that the egg could seduce sperm with certain genes and that sperm could do the same for the egg is part of a growing biological understanding that the egg is not the passive, servile cell that scientists have long believed it to be. Instead, scientists now consider the egg to be a comparable and active participant in reproduction, adding levels of evolutionary control and selection to one of the most critical life processes.

According to Mollie Manier, an evolutionary biologist at George Washington University, "Female reproductive anatomy is more obscure and difficult to investigate, yet there is an increasing acknowledgment of the female involvement in conception."

Cellular-level sexual selection

The concept of sexual selection predates Charles Darwin by several hundred years. He cited the flashy tail of the peacock and the enormous antlers of the elk as examples of features that developed to assist men advertise their attractiveness as mates to females in On the Origin of Species. For the following century, biologists concentrated on every facet of sexual selection that took place in the circumstances preceding copulation. After mating, the female had already made her decision, and the sperm swimming toward the egg constituted the sole rivalry.

According to Emily Martin, an anthropologist at New York University, this male-oriented perception of female reproductive biology as mainly compliant was widespread. Martin made this claim in a 1991 study. The egg is perceived as being big and unactive. It 'transports' itself passively along the fallopian tube rather than moving or traveling. Sperm, on the other hand, are tiny, "streamlined," and always active, she said.

But starting in the 1970s, science started to disprove that myth. The Smithsonian Tropical Research Institute's behavioral ecologist William Eberhard has studied all the ways in which females may influence which males fertilize their eggs even after mating. It's a large list, and researchers are still unsure if they have covered everything. These discoveries weren't all made too late because of sexism. Games of hide-and-seek with sperm within the female reproductive canal are considerably harder to notice than two walruses sparring with their tusks.

"Sexual selection begins as soon as you have eggs and sperm. Eggs and seminal fluid are capable of amazing things, according to evolutionary scientist Andrea Pilastro of the University of Padova in Italy.

Females of animals whose fertilization takes place externally frequently cover their eggs in a viscous, protein-rich fluid called ovarian fluid. The University of East Anglia in England's Matthew Gage conducted experiments in 2013 that demonstrated this fluid carries chemical cues to aid in attracting the right kind of sperm. When salmon and trout eggs were exposed to combinations of sperm from both species, the eggs' own species fertilized 70% of the time, which is substantially more often than would be predicted by chance.

"The sperm exhibited distinct behaviors in various ovarian secretions. In their own fluid, they actually swam more straight, according to Gage.

The techniques used by internal fertilizers are what Eberhard called "cryptic female choice." Some female reproductive tubes are labyrinthine, with dead ends and false beginnings that can obstruct sperm except for the strongest. Biologists believe that a large majority of animals, including many species of reptiles, fish, birds, and amphibians, copulate with more than one male. Some females may store sperm for months or even years by changing the storage environment, which stacks the odds in favor of one male. Many female birds, including domestic chickens, have the ability to expel sperm after mating, allowing them to select the best male during fertilization.

However, all of these methods merely provide females the chance to choose from a variety of male sperm. Which sperm fertilized the egg inside an ejaculate still appeared to be up to chance.

In fact, the first law of genetics, which dates back to Gregor Mendel, the principle of segregation, contains an implicit statement about the randomness of fertilization. Each gene has two copies in each parent, and these copies are randomly distributed into gametes, each of which has only one copy. It is what gives birth to many of the probability that high school biology students learn. Half of the kids would also be heterozygotes if both parents are heterozygotes, which means they both carry two different copies of the same gene. One version would be present in two copies in one-fifth of the kids, while the other one-fifth would be homozygotes bearing the other version.

It's one of biology's most universally applicable laws, according to Nadeau.

But only if fertilization is random do these probability make sense. Those ratios may be considerably different if the sperm or the egg has any ability to change the other gamete involved in conception. Nadeau was first drawn to this obvious distinction in 2005. The probability were all wrong when he started examining how two specific genes in mice are inherited. He started to ponder at his lab in Seattle: Could Mendel have been wrong?

Nadeau hadn't intended to query Mendel about the Mendelian Lawbreakers. As testicular cancer is one of the most heritable types of cancer, he was more interested in how interactions between two genes (Apobec1 and Dnd1) altered risk factors for the disease. Everything seemed to obey Mendel's laws when Nadeau and his doctorate student Jennifer Zechel crossed female mice bearing one normal and one mutant copy of Dnd1 with heterozygote Apobec1 males. Good news thus far, They discovered that only 27% of the anticipated progeny possessed copies of mutant Apobec1, mutant Dnd1, or both, in contrast to the 75% they had anticipated to observe when they reversed the breeding (a female Apobec1 heterozygote mated with a male Dnd1 heterozygote).

Nadeau was aware of a wide range of variables that may impact Mendel's ratios as a scholar who had spent many years researching heredity. The resultant embryo might not survive development if a fertilized egg ended up with two mutant copies of a recessive gene. The ratio of homozygotes to heterozygotes would change as a result of such embryonic-lethal mutations, but the average number of mouse pups in each litter would also decrease. However, Zechel and Nadeau discovered no indication of early embryonic death in any of their mice, all of which had typical litter sizes.

Nadeau reasoned that perhaps the issue was with the sperm rather than the egg. In order to test if the mutation affected sperm development, he bred male mice with and without the mutation to healthy, mutant-free females, but discovered no changes in the males' fertility. If the mutation had an impact on sperm creation, this would have been clear. Nadeau and his team gradually ruled out all potential causes of these odd ratios of child genotypes, with the exception of one: that the egg and sperm were genetically biased towards the mutant genotype during fertilization.

Nadeau reasoned that someone else must have already noticed this, so he looked through the scholarly literature. He could identify several instances of unusual offspring ratios, but no one had really looked at genetically biased fertilization as a potential solution.

Everyone basically assumed it to be embryonic lethality, according to Nadeau, since we see what we look for and explain things using our knowledge.

One of the cases Nadeau discovered came from the University of Alberta lab of cancer researcher Roseline Godbout. Godbout investigated how the retinoblastoma, a highly heritable pediatric disease, is influenced by a protein called DDX1. Mice having one functioning copy of the DDX1 gene removed (but with a second, completely functional gene as a backup) seemed healthy and normal. Even though straightforward Mendelian math would indicate that 25% of the progeny should lack both copies of DDX1, Godbout and Devon Germain, a postdoctoral fellow at the Max F. Perutz Laboratories in Vienna, found that none of the kids lacked both copies of the gene. The fact that the gene is crucial for DNA replication, however, meant that this wasn't shocking: The homozygotes lacking DDX1 most likely perished soon after conception. Additionally, Godbout and Germain discovered fewer homozygote children with two copies of DDX1 than they anticipated. The scientists proposed that their findings were the consequence of a rare mutation that had happened in the DDX1 gene during their tests after a complex series of mating trials.

Nadeau was not persuaded. He asked Godbout in a letter how her lab had shown that the "knockout" homozygotes without the DDX1 gene had perished during embryonic development. Not at all. Additionally, he enquired as to whether they had thought of genetically biased fertilization, in which the egg would prefer to mate with a sperm carrying the opposing DDX1 genotype.

Germain remembered, "We genuinely assumed it was just an odd pattern of heredity." We had not given nonrandom fertilization any attention.

Later, on a whim, Germain made the choice to examine all of the experiment's raw data. He thought back to Godbout's inquiries that had been sparked by Nadeau's email as he reviewed the findings. The more he examined the data, the more "the most reasonable explanation"—genetically biased fertilization—appeared, he claimed.

In "Can Gametes Woo?," an essay that was published in October in Genetics, Nadeau outlined his theory after becoming frustrated at how little research had been done on genetically biased fertilization as a possible explanation for their findings. He stated that his intention was to encourage more study in this field and ascertain whether and how interactions between sperm and egg might affect conception.

"Our preconceived notions have rendered us blind. It has extremely distinct ramifications for the fertilization process and requires a different way of thinking about fertilization, according to Nadeau.

Nadeau's concept is fascinating and even conceivable, according to other scientists like Manier of George Washington University, but they draw attention to the fact that no one has provided any supporting data. Nadeau concurs and suggests two scenarios.

The first involves the metabolism of B vitamins, including folic acid, which helps sperm and eggs produce key signaling molecules. These chemicals have a significant impact on fertilization, according to Nadeau's research, and he thinks defects in certain signaling genes may affect how much the sperm and egg are attracted to one another.

A rival theory is based on the observation that sperm are frequently present in the female reproductive tract prior to the last round of cell divisions that results in the egg. These cell divisions may be influenced by signals from the sperm, which may also bias the identity of the cell that develops into the egg.

This work challenges the widespread belief that female physiology is passive during fertilization, whatever the mechanism may be. Females were previously thought of as passive, helpless objects, but now, according to evolutionary scientist Renee Firman of the University of Western Australia, they will have a stake in the success of conception. Although there is still much to learn about this process, I don't believe we really get how often and commonplace it is.

It could be difficult to find evidence to prove or disprove this idea, according to Manier. It will be necessary to demonstrate that the sperm's surface chemicals are affected by genes, and that the egg can detect these variations. Such outcomes need for in-depth biochemical analyses of individual sperm cells and genome sequencing data.

When Nadeau delivers the findings of his mouse research and his theory for what is happening, he is ready for naysayers since he has faced many of them at conferences. After the discussion, critics frequently come up to him and start asking him questions. Uncertain of whether they leave persuaded, Nadeau believes they are less sure that biased fertilization doesn't occur. The circumstance is the perfect Sherlock Holmes scenario, according to Harmit Malik, a geneticist and virologist at the Fred Hutchinson Cancer Research Center.

He joked, "If you've ruled out the impossible, then what's left, however doubtful, must be the truth."

This article was reprinted on TheAtlantic.com.