The Genetic Gender Gap: All Genes Are Not Created Equal

The springboard to equine research of the future is supported by the knowledge generated from futures past. Each advance occurred as researchers made new connections between the basic knowledge of the day and biological observations, then proposed a new theory to test and refine. That's what the Austrian monk Gregor Mendel did 135 years ago when he developed the fundamental laws of inheritance, and that's what Douglas Antczak D.V.M., Ph.D., director of the James A. Baker Institute for Animal Health, is doing today as he moves forward with the Horse Genome Project and links it to a whole new rule of inheritance.

Mendel taught us that offspring receive half of their genetic heritage from each parent.

Photo: Microsatellites—repetitive elements within a horse's DNA —serve as mileage markers that help scientists identify the location of genes controlling important functional traits. They also make it possible to tell which traits were contributed by the mother and which by the father.

Ten years ago, he noted a curious practice of horse breeders: they not only charted how well racehorses did as sires but they also how they did as sires of broodmares. Horse breeders said they had observed how some award-winning stallions became outstanding sires of broodmares but not of performers.

Antczak was puzzled; the phenomenon didn't make any sense according to any known laws of genetics. But then in 1986, a British researcher, Azim Surani, brought to light a genetic observation that had languished in the literature for 20 years. He startled the genetic world when he published findings stemming from impregnating mice with two sets of chromosomes from the same parent (instead of one set from the mother and one set from the father). All the fetuses failed but in new, predictable ways depending on whether the double set came from the mother or the father. For the first time, a genetic gender gap has been detected. Surani proposed that the outcomes of the pregnancies were predictable if you accepted that some genes get switched "on" and "off"depending on the gender of the parent contributing the genes.

"His experiment showed a whole new paradigm of inheritance that we hadn't imagined or expected. For the first time, scientists realized that it sometimes mattered whether particular genes came from the mother or father," Antczak said. "Evidently, some genes are transmitted either in an active or inactive form, like a light switch that's either on or off, depending on which parent they come from."

Antczak, who has been spearheading Cornell's contribution (largely funded by the Zweig fund) to the Horse Genome Project, has always made it a little hobby "to look for kernels of scientific truth in the practical, everyday activities of animal breeders. When I read about Surani's research, I realized that this so-called genetic imprinting mightexplain what horse breeders had been observing for years: that greatness skips a generation and gets passed down through daughters."

Secretariat is a prime example. His dam, Somethingroyal, had been sired by Princequillo, a leading sire of broodmares three decades ago. Secretariat was a racing superstar but not an exceptional sire himself; his offspring were disappointing performers. "But his daughters are some of the greatest broodmares in the world now," says Antczak. They've produced champions such as A. P. Indy, Summer Squall, Chief's Crown, Dehere, Gone West, and Storm Cat.

This is what geneticists now call the maternal-grandsire effect. Although most genes are "on" when they get passed down, or get expressed depending on their dominance or recessiveness, some get "switched off" when passed down through males. None of Secretariat's sons or the sons' offspring became exceptional performers. But when females passed the gene down, they somehow "reset" the gene, turning it on, and in this case it is evidently related to performance. And sure enough, Secretariat's daughters' offspring are, like their grandfather, outstanding athletes.

Antczak searches for markers that identify particular genes on equine chromosomes. Most of the imprinted genes discovered in several species so far are involved in early placental and fetal growth. In pigs, scientists have identified some imprinted genes that affect muscle and heart mass in utero. About 30 imprinted genes have been identified in humans and are linked to disorders such as Prader-Willi and Angelman syndromes (related to mental retardation), Turner's syndrome, Huntington's disease, bipolar depression, and schizophrenia.

"The activities of imprinted genes seem to be prenatal, affecting growth and in utero development, but their effects are significant enough to persist a lifetime. If we confirm that imprinted genes can affect muscle growth and heart mass in horses, for example, such knowledge could prove very important to racing and performance," said Antczak, pointing to Secretariat's heart for example. Although that racing superstar was of average size, his heart weighed 22 pounds, compared to the average 8.5-pound thoroughbred heart.

Antczak is currently studying four possible markers for imprinted genes in the horse, all that affect growth. Such research is now possible, thanks to Zweig funding of the Horse Genome Project, which is racing forward and allowing Cornell equine scientists to work on the worldwide frontiers of equine genomics.

"This funding provides us with a framework of genetic equine knowledge that we can use to identify markers for imprinted genes in the horse and to determine their effect on athleticism or other important physical traits," Antczak said.

On the cusp of a new millennium, we just might be facing a brave new world of equine genetics in which horse specialists will breed more efficiently for performance or bone and joint function and influence the incidence, for example, of allergic respiratory diseases such as COPD (chronic obstructive pulmonary disease), debilitating arthritis, and OCD (osteochondritis dissecans disease); all of which have genetic components.

"We might also explore a range of questions," Antczak noted, "such as: Are there examples of placental failures that are due to inherited genes from sires? Do some stallions transmit genes for a superior prenatal environment which would enhance fetal growth? Do certain maternal genes determine the pattern for fetal growth which can influence performance? Can we ultimately learn how to switch some beneficial genes on?"

The answers to these questions just may become evident in the century ahead.