‘True hybrid’ mice might reveal how new species emerge

Forty years ago, a postdoctoral researcher named James McGrath who would go on to spend more than three decades as a clinical geneticist and research scientist at Yale, made a discovery that advanced scientists' understanding of gene control and the rules governing genetic inheritance.

This week, in what is his final study, McGrath makes another key contribution to the field of genetics - one that may have implications for the evolution of a new species.

The findings, which appear in the journal Science Advances, are published posthumously for McGrath, who died in March.

The study, which McGrath conducted with Yale colleagues, explored a phenomenon of genetics that intrigued him. When a sperm cell fertilizes an egg, the resulting zygote has the genetic information from both cells but only cytoplasm - the substance that fills the cell - from the egg. That means that any of the organelles found in the cytoplasm of the male parent's cells don't carry over.

"Once the sperm enters the egg, the cytoplasm of the male is gone," said Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine at Yale School of Medicine and co-senior author of the study. "James wanted to know, what if it's not gone? What if you mix up the gene pool as well as the cytoplasm pool?"

To explore this question, the researchers crossed two different mouse species by creating zygotes that had the nuclear material and cytoplasm from both male Musdomesticus mice and female Musspretus mice. They crossed different species as the contributions from each parent's cytoplasm might be more apparent than taking the same approach in a male and female of the same species.

When a domesticus male is naturally bred with a spretus female, the females do not produce offspring. But through the researchers' blended zygote technique - an approach the researchers have dubbed "true hybridization" - offspring were born, indicating something in the male cytoplasm was able to overcome this reproductive barrier.

Interestingly, the offspring looked quite different from either parental species.

"Mules are the offspring of a horse and a donkey, and you can see that they're sort of in between the two parent species," said Horvath. "But the true hybrid mice were much larger than either parental species. They had completely different growth and metabolic patterns."

These physical and physiological differences suggest a potential mechanism for evolution, said Horvath. It's possible, he says, that the theoretical instance in which male cytoplasm enters the female's egg during fertilization might lead to the emergence of new species.

"This jump in phenotype that we see here in the true hybrid mice, in my view, represents a potential step for evolution," said Horvath. "And these findings give us new questions to pursue in evolution, which otherwise is a very conceptual enterprise."

Some mysteries remain. The true hybrid mice in this study were, curiously, all male and they were all sterile. More research will be needed to uncover why that is and to explore what components of cytoplasm underlie the findings of the current study.

Throughout his career, McGrath was interested in fundamental biological mechanisms and how they affect development and disease. In 1984, he discovered genomic imprinting, in which certain genes carry "imprints" - small genetic modifications that occur during the formation of eggs and sperm - that determine whether they will be on or off in offspring.

His latest work has shown different egg cytoplasm environments could lead to different offspring development.

"James was a clinician. He was a geneticist. He looked after kids with genetic complications. And he had an amazing interest in science," said Horvath. "He was such a remarkable human being and we're going to make sure we continue his work forward."

The study was supported by the National Institutes of Health and Yale's Department of Comparative Medicine. Leyla Sati of the Akdeniz University School of Medicine in Turkey was first author of the study. Luis Varela of Yale School of Medicine was a coauthor.

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