How three genes you’ve never heard of may influence human fertility

Hart's interest in the genetics of reproduction has focused mostly on sea stars and sea urchins. As a zoologist and population geneticist, he wants to know: how does one species split into two?

In a recent project working on these unassuming invertebrates, Hart and his colleagues discovered an exciting new piece of this evolutionary puzzle: the fertility rate of mated sea stars depends on what forms of reproductive genes they have. In other words, male and female sea stars with certain types of genes might successfully produce offspring, whereas sea stars with other combinations of gene pairs fail to reproduce.

To Hart, this finding suggested that, over time, genetic incompatibility could cause populations of sea stars to gradually separate into different species. But it also had wider implications about fertility, and he wondered if researchers of fertilization biology and population genetics had found similar evidence of selection for certain combinations of genes in other study systems.

Indeed, in mice and in humans, researchers have been examining two kinds of genes: genes expressed in the mammalian egg coat -- which Hart describes as the "fibrous, sugary, sticky mass" that binds the sperm to the egg -- and genes expressed in the sperm, in order to understand how evolution may be proceeding in the genetic code.

In humans, Hart is working on three specific genes. ZP2 and ZP3 are egg coat genes, named for the zona pellucida, the technical term for the egg coat. Nearly all mammals have these genes, which make the proteins that interact to form the egg coat. C4BPA is responsible for producing a sperm protein that binds to the egg coat.

Back in 2010, Dr. Rori Rohlfs, who now works for the University of California, Berkeley, found that certain forms of the ZP3 gene occur alongside certain forms of the C4BPA gene more often than one would expect due to chance alone. Such associations between genes located on completely different chromosomes -- as ZP2, ZP3, and C4BPA are -- are rare in nature, and usually occur when the genes involved do something very important for the organism. From the perspective of evolutionary fitness, perhaps no function is more important than the ability to reproduce.

Fascinated by Rohlf's results, Hart and his colleagues set out to follow up on her work, temporarily leaving sea stars and sea urchins behind to delve into the human genome.

Their most recent findings -- which hint at something special about human evolution -- startled him.

The slow march towards species divergence is evolution's hallmark. Yet, Hart and his team's evidence points to just the opposite process in humans. "Human populations are not evolving to become reproductively isolated from each other," he says.

"There are some really important, highly conserved functions of those proteins," Hart says of the proteins encoded by ZP2 and ZP3. The absolute necessity of those proteins to an individual's ability to reproduce leads researchers to expect that most sites in the genes encoding those proteins will be relatively unchanged through generations, a phenomenon called negative selection.

"But there are a few that seem to be highly variable, and where the variation appears to be maintained by positive selection," he adds. "That's what we seem to have found."

Some of the most intriguing evidence in support of this idea has come from paleogeneticists. These scientists, who study ancient human genomes, have identified exactly the same genetic variants from modern humans in the genetic data of Neanderthals and Denisovans, human lineages that migrated out of Africa hundreds of thousands to a million years ago.

The consistency of these specific genes through much of human history connects Hart's work to the broad, interwoven story of evolution -- from invertebrates to vertebrates -- in unexpected ways.

In his work on sea stars and sea urchins, Hart did not have cause to reflect on the discrepancy between how individuals choose a mate and whether they can reproduce successfully. "In a lot of marine animals that spawn sperm and eggs into the plankton, the adult organisms never really 'meet' each other," he says. "Instead, mate selection, to the extent that it happens, happens at the level of these kinds of biochemical interactions between sperm and eggs."

"Now, we don't really think about mammalian mate selection happening that way," he adds, pointing out that human 'mates' are usually chosen through behavioral interactions, be they in the office or at the bar. "So it's sort of surprising to find this molecular signature of selection acting on these genes that seem most likely to affect the fitness of individuals."

In this way, Hart's current research prompts us to reflect on how natural selection operates in the evolution of the human species -- perhaps as much at the level of invisible molecules as at the level of attributes we can see.

Hart presented this research at the 2016 annual meeting of the Society for Integrative and Comparative Biology in Portland, Oregon.