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THE MATERNAL GRANDSIRE
by Cindy Vogels
 

For years, horsemen have acknowledged a phenomenon called the maternal-grandsire effect, when outstanding males do not immediately reproduce their greatness in the next generation. Instead, they produce daughters who are outstanding dams. An oft-cited example is Secretariat, perhaps the greatest thoroughbred of all time. Secretariat's achievement was not matched by his direct get, who by and large were unremarkable, but rather was passed on through his daughters, many of whom went on to produce great performers. Dog breeders, too, have noted that an extraordinary male, while not producing extraordinary offspring, will often produce daughters who are prolific and exceptional dams. For years, there was absolutely no scientific explanation of this phenomenon in which traits skip a generation and are passed along only by female offspring. Recently, however, an article documenting scientific evidence of the maternal-grandsire effect appeared in issue number 242 of Equus, an outstanding horse publication. I acknowledge that article for providing me with much of the information in this column.

Some Genetics Background
In each cell of a dog's body there are 39 pairs of chromosomes, one set from each parent. Each chromosome pairs off with a corresponding chromosome of the other parent, and in each chromosome there are thousands of genes, which contain the protein codes that determine every physical trait. Within a pair of chromosomes will be pairs of genes from each parent that determine various traits. When the genes are not in conflict with each other - both expressing brown eyes, for example - there is no problem. However, if one chromosome contains the gene for brown eyes but another one contains the genes for green eyes, long-accepted Mendelian theory states that only the genetically dominant chromosome will be expressed. The theory also states that genetic dominance is unrelated to the sex of the gene donor. When both genes are expressed, they are considered to be co-dominant. Coat color, for example, is an area in which both genes can sometimes exert influence. Other times, both genes are recessive, but one is nonetheless more dominant than the other, thus allowing a recessive gene to be expressed. Recessive genes may also be expressed when both contain the same protein code for a trait.

A Startling Study
In 1969, Dr. W.R. Allen startled the world with a study that seemed to indicate certain genes might be gender-related in their expression. Allen bred horses and donkeys, and during pregnancy measured levels of the pregnancy hormone called equine chorionic gonadotrophin (ECG). Normally this level is high in horse-horse crosses and low in donkey-donkey crosses. According to Mendel, it should not have made any difference which species served as sire or dam. The levels should reflect a combination of the two species, and would either be a moderate level (indicating co-dominance), or if one species dominated, the level would be either high or low. Surprisingly, the mares (horse females) bred to donkeys exhibited low levels of ECG, much like a donkey-donkey cross, and the jennies (female donkeys) bred to horses registered high levels of ECG, as in a horse-horse cross. Although no definitive conclusions were reached, it appeared that the sires' genes were the only factor affecting the ECG levels in the females. The females' genes were silent.

It was not until 1986 that the topic reappeared in the literature. A research team headed by Dr. Azim Surani used mice to create embryos in which all the genetic material was received entirely from either one parent or the other. Since the material was transmitted in appropriately matched pairs, Mendelian theory would have predicted that the embryos would develop normally, since it was only the presence of two genes for each trait, and not the sex of the gene donors, that was considered relevant. Again, however, Mendelian expectations were confounded, as the all-female gene pairings resulted in large placentas with little embryonic material. The all-male gene pairings produced the opposite result: small placentas with large embryos. Surani's team concluded that some genes do not follow Mendel's laws. Some are "switched on" before fertilization and are always expressed, while others are "switched off" and never expressed. The sex of the gene donor is the factor that determines which mode a gene will fall into. A theory called "genome imprinting" was created to account for this previously unformulated phenomenon.

For example, say there is a canine gene that is paternally imprinted and, when expressed, produces three-eared dogs. When the gene is not expressed, the dog has two ears. A three-eared male inherits the gene from his mother, but because a gene that is paternally imprinted is switched off when passed on by a male to its offspring, he will have all two-eared offspring. His male two-eared offspring will not produce three-eared dogs, but his daughters will, because a gene that is paternally imprinted will be switched on in females.

Questions and Implications
Many questions still remain, and the literature is vague on why the phenomenon might occur. Researchers point to the significance of gender-related functions. For example, it appears that males strive to produce virulent, robust get, while females, for their own well-being, control the size of their offspring. Imprinted genes are quite possibly involved in traits inherited polygenically. If only some of the genes are switched on, the work of the geneticist tracking inheritance becomes more complicated.

The implications of this finding go far beyond the world of Thoroughbred racers. Already, a number of imprinted human genes have been pinpointed. Ongoing mapping of the canine genome should increase the likelihood of detecting imprinted genes in dogs. The most important contribution would probably be in the realm of canine health, but eventually we might have the tools to track the inheritance of many canine characteristics that seem capricious in their skipping of generations.

Dog breeders should be aware of this possible maternal-grandsire effect. Keep in mind, however, that outstanding males tend to be bred to outstanding females, so even if some of the male's desirable genes are paternally imprinted, the offspring of such matings will probably inherit some excellent traits from their exceptional dams. For example, this year's Kentucky Derby and Preakness winner, Charismatic, was sired by 1990 Preakness winner Summer Squall, who is out of a Secretariat daughter. While Summer Squall's prowess on the track could be traced to the maternal-grandsire effect, he seemed to pass his greatness along directly to Charismatic. However, Secretariat's mother appears another time in Charismatic's pedigree and Secretariat's sire Bold Ruler appears twice. So, the talented colt's lineage points back to many outstanding individuals. A pedigree, whether for dogs or horses, always contains many influences and variables. We dog breeders tend to be impatient and are disappointed when an outstanding male does not immediately reproduce his excellence. Remember the maternal-grandsire effect, and wait a generation. 

Equus Magazine #242 December 1997

On Saturday afternoon in April 1977 a record crowd of 22,000 spectators converged on Kentucky 's Keeneland Racecourse to, see a chestnut filly named Sexetary contest the day's third race. The filly was an unlikely focal point for such attention. She had never run a race, and her preparatory workouts had been decidedly ordinary. But she was greeted with pomp and circumstance, mobbed and cheered in the saddling enclosure, and bet down to the role of overwhelming favorite for one reason alone: her sire. Sexetary was the first foal of Triple Crown winner Secretariat to race. As the filly was loaded into the staffing gate, the fans had every expectation that through this filly and legions of foals to come, Secretariat would prove himself as impressive as a sire as he had been as a runner.

But Sexetary's fourth-place finish proved to be a harbinger of performances to come. In the succeeding years, Secretariat's offspring would do better than average at the races, and several would excel. Still, though mated to the world's best mares, Secretariat never approached the same greatness as a sire of racehorses that he displayed on the track. In turn, nearly all of his sons would be unexceptional sires. Secretariat died in 1989, and as his last, aging runners go into retirement, the book is closing on a stud career that has often been described, in light of the initial expectations, as a disappointment.

Still, even before Secretariat's death, breeders had begun to notice a trend among his progeny's progeny. Secretariat's daughters, even those who floundered on the track, had become and continue to be some of the greatest broodmares in the world, producing elite runners, including champions A.P. Indy and Summer Squall(both sons of 1992 Broodmare of the Year Weekend Surprise), Chief's Crown, Dehere, Gone West and Storm Cat. Even Sexetary, who never won a race and earned a paltry $1,425 at the track, produced a stakes winner. Secretariat's exceptional athleticism lives on, it seems, in the second-generation offspring produced by his daughters.

Known as the maternal-grandsire effect, this generation-skipping, female-linked phenomenon is far from exclusive to Secretariat. Other racetrack greats, including Buckpasser, Key to the Mint and Graustark, were similarly unspectacular as sires of runners and as sires of sires, but they displayed uncommon brilliance as broodmare sires. For generations, the effect has baffled breeders, and even the most prominent geneticists could come up with no credible theory to account for it. "It made no sense at all," says genetics and reproduction researcher Doug Antczak, VMD, PhD, the Dorothy Havemeyer McConville professor of equine medicine at Cornell University , director of the university's James A. Baker Institute for Animal Health and participant in the Horse Genome Project. "It didn't follow any known rules of genetics." But after 20 years of puzzling over the effect, Antczak, a lifelong horseman, believes recent genetic breakthroughs may finally offer an answer. His theory: Because of a quirk of genetic inheritance, some horses may exhibit their line's high level of athleticism only when the genes for it are contributed by females, while corresponding genes contributed by males always pass down to the offspring in "mute," inactive form. This theory draws on "the cutting edge of genetic investigations," says Antczak, but its effects could be of significance to breeders and buyers of every kind of Performance horse.

Genetic exceptions

Within the nucleus of each equine body cell are 32 pairs of rod-shaped chromosomes. Thousand of genes, which contain the chemical codes to produce every trait and direct the body's every function, are arranged linearly on each chromosome. An offspring receives one complete set of 32 chromosomes, containing genes for every possible trait, from each parent, and those chromosomes connect to create 32 chromosome pairs. (For definitions of genetic terms, turn to page 28.)

In some cases, only one of the two parental genes is expressed outwardly in the offspring, as when horses inherit one coat-color gene from the sire and a different coat-color gene from the dam. Conventional genetic theory, developed through the 1865 pea-breeding experiments of Austrian monk and botanist Gregor Mendel, has held that the gender of the gene's donor-father or mother-is irrelevant in determining which gene is expressed. Instead, Mendel's theory says, genetic dominance is the determiner: Many genes come in either dominant or recessive forms, and dominant genes override recessive ones. Recessive genes may be passed down through many generation but are expressed only when paired with other recessive genes. Other genes are expressed co-dominantly-that is, the effects of both parental copies of such genes are expressed.

For more than a century, Mendel's theory of genetic dominance and the irrelevance of the gender of the donor parent held up with only minor modifications. But in 1969, W.R. Allen-then a young New Zealand veterinarian pursuing a PhD degree at England 's Cambridge University , and now a professor there conduced studies with different equid species that seemed to turn Mendel's work on its ear. Using mares pregnant with mules, which are sired by donkeys, and jenny donkeys pregnant with hinnies, which are sired by horses, Mien measured the levels of equine chorionic gonadotrophin (ECG). This pregnancy hormone is always present in high levels in horse-horse pregnancies and in low levels in donkey pregnancies. The expected result of this experiment was either that the levels of ECG in maternal blood would be a blend of the two parent species' levels (co-dominant) or that one or the other form, either high or low, would be dominant in both types of hybrid pregnancy. According to Mendelian genetics, the horse-donkey pregnancies, regardless of which species was sire and which was dam, should be identical, producing the same ECG levels in the pregnant mares and pregnant jennies.

But that was not what happened. In a complete reversal of expectations, the mares had the low hormone levels seen in donkey-donkey pregnancies, while the jennies had the high levels seen in horse pregnancies. Apparently, the sires' genes were the sole determiners of ECG levels in the pregnant females, whose genes, in this case, were silent. Contrary to Mendel's laws, the gender of the parent contributing the gene for this particular trait appeared to influence the expression of the trait. No one knew what to make of the study. "It was very hard to explain," says Antczak. "The finding languished in the literature for almost 20 years."

Gender effects

Fast forward to 1986, when Dr. Azim Surani and his colleagues at the Agriculture and Food Research Council's Institute of Animal Physiology in Cambridge conducted a series of studies that finally offered some explanation for Allen's unaccountable findings. By micromanipulating mouse sperm and eggs, the researchers created fertilized eggs in which the paired chromosomes were either entirely from the mother (gynogenetic) or entirely from the father (androgenetic). According to Mendelian theory, since each embryo contained the necessary two genes for every trait and since the gender of origin for each gene was considered irrelevant, the resulting pregnancies should have developed normally.

As with Allen's experiments, the unexpected occurred: The androgenetic pregnancies developed large placentas but almost no embryonic tissue, while the gynogenetic pregnancies developed large embryos but very little placental tissue. In each set of embryos, neither of the paired genes for one trait was being expressed. It was as if these genetic instructions had been switched off.

Surani and his colleagues posited a stunning hypothesis to explain the results. Some genes, they argued, don't follow Mendel's law. Instead, they are programmed to be switched on before fertilization of the egg, so that they are always expressed in the offspring, or switched off, so that they are never expressed. Then came the kicker: The factor that determines whether this kind of gene is passed to the offspring in the "on" or "off" mode is the gender of the parent who donates the gene.

In other words, some genes are never expressed in the offspring when donated by the father, because in male parents, these genes are automatically switched off before transmission. The androgenetic mouse embryos failed to develop because some of the genes critical to the development of that trait had been transmitted in mute form by males and lacked the female parents' genes for embryonic development. The gynogenetic mouse embryos were without placental support because some of the genes critical to the development of that trait were switched off in the female transmitters.

The phenomenon, says Antczak, amounts to a reproductive "distribution of labor," with some of the female's genes primarily responsible for particular duties in the offspring's development and some of the male's genes primarily responsible for other duties. Researchers named the phenomenon "genomic imprinting." A "maternally imprinted" gene is switched off when transmitted by the mother, leaving the father's gene to be expressed; a "paternally imprinted" gene is inoperative when donated by the sire, allowing the maternal influence to prevail. Finally, Allen's curious findings of 20 years earlier had an explanation. "The horse was out there trying to tell us something fundamental about genetics," says Antczak. "This is one of the few truly new concepts in genetic inheritance developed since Mendel grew his peas. It is an entirely new paradigm."

Since Surani's studies, a handful of imprinted genes have been identified. Several human diseases have been found to be governed by imprinted genes, including the nervous disorder Huntington's chorea, some developmental behavioral abnormalities, certain facial deformities and some tumors. In each case, the critical gene's activity, and the resulting course of the disease, is determined by the sex of the parent donating it.

In addition, research into an abnormal type of human pregnancy called a trophoblastic mole has revealed a case strikingly similar to Surani’s mouse findings. This type of pregnancy, which occurs when two sperm penetrate an egg and their chromosomes pair to form an embryo lacking female genetic material, results in the development of a partial placenta but no fetus.

Why does genomic imprinting exist?

One hypothesis holds that it offers a mechanism by which males and females can control the most essential traits. In fetal development, for example, the father's reproductive "goal" is to sire the largest, most vigorous offspring possible, but for the mother, delivering an overly large foal could be deadly. Perhaps for this reason, some genes critical to fetal development are switched off by paternal imprinting, allowing the mother's genes complete control over many aspects of fetal size.

Skipping generations

Genomic imprinting creates an inheritance pattern whose expression "skips a generation." Just for illustration, imagine a human gene that, when expressed, produces blue hair. When the gene is not expressed, the offspring's hair color is brown. Because the gene also happens to be paternally imprinted, the trait would be expressed as follows: A man inherits the blue-hair gene in active form from his mother and has blue hair. Because he is a male, the blue-hair gene is "switched off" in transmission, so his children inherit the gene in inactive form and all have brown hair. When the sons reproduce, the gene remains switched off, so their children are all brown-haired. But when his daughters reproduce, the gene, in its active form, causes all of their children-male as well as female to have blue hair. The result: The trait reappears in the third generation, but only in the offspring of the blue-haired man's daughters.

As a reproductive and genetic researcher, Antczak was thrilled with the footnote to Mendel's law and the new research avenues it opened up. What if there was an imprinted gene controlling some critical aspect of equine athletic performance that was switched off when transmitted by males? Its expression, he realized, would produce precisely the same generation-skipping excellence as seen in the production records of Secretariat, Graustark and other sires. Antczak had hit upon the first plausible explanation for the maternal-grandsire effect.

"If you take this theoretical framework and put into it the observations of the matemal-grandsire effect, it fits," says Antczak, who cites Secretariat's lineage as a prime example. "Princequillo was a leading sire of broodmares three decades ago, and he sired Somethingroyal. She inherited this peculiar, imprinted performance gene and transmitted it to Secretariat in active form, contributing to his outstanding athletic performance. But when the father transmits it, the gene is transmitted in the switched-off state. Therefore, Secretariat's offspring don't perform as well as he did. When his sons transmit the gene, it is still in the off state, so his sons likewise are not great sires of performers. But Secretariat's daughters switch the gene around so that it is transmitted in the active state. His daughters are among the best broodmares in the world right now."

Other Influences

Though they were standouts as broodmare sires, all the sires linked to the maternal-grandsire effect were certainly decent or even very good sires of runners. But if genomic imprinting was at work in these sires, how were they able to produce any good performers at all? One contributor is probably the extraordinary mares to which these stallions were bred. Another, says Antczak, may be that many genes contribute to outstanding performance, only some of which are imprinted. Though a stallion with imprinted genes may not be able to pass them on in active form, he still transmits-a potent package of nonimprinted genes that, in combination with the mare's genes, can produce championship performance an4 reproductive excellence in the next generation. But the daughters of sires with imprinted genes still come out with the greatest genetic performance package to pass along in active form to their foals.

Antczak does not yet know what performance4elated gene or set of genes might be controlled by genomic imprinting, if imprinting is indeed responsible for the maternal-grandsire effect. Genes related to growth and development are likely possibilities, in part because they are central to athleticism and in part because so many of the genes already identified as genomically imprinted are growth related. Secretariat's case suggests that optimal heart development could be one such critical athletic characteristic passed on in active form only through females: While the average Thoroughbred heart weighs 8 1/2 pounds, Secretariat's heart weighed an astonishing 22 pounds, the largest equine heart ever measured.

Does the performance influence of genomic imprinting extend beyond the world of Thoroughbred runners? Coveted athletic attributes in other disciplines and breeds may be expressed in alternating-generation fashion, but in the absence of detailed, multigenerational record keeping of easily quantifiable performance data, the effect may escape notice. "The maternal-grandsire effect may be manifest in other breeds," says Antczak, "but it may be unnoticed because of the way those horses are bred." And imprinting likely affects far more than horses' athleticism. In people, mice and sheep, as well as in Allen's research equids, imprinted genes have been identified that have significant influence on individuals' development, health and even appearance. The same types of genomic imprinting may well occur in horses.

Reality checks

The first step in verifying the role of genomic imprinting in the maternal-grandsire effect or any other equine characteristic is to locate which genes might be subject to imprinting and test horses who exhibit the effect. It is a tall order: The maternal-grandsire effect, for example, appears to become diluted and disappear very quickly, so observations must be made over just a few generations. Furthermore, locating genes is an intensely painstaking, expensive project. But by embarking on the new Horse Genome Project, which seeks to create a gene map of the horse, Antczak and fellow researchers have already taken a major step in that direction. "If we can identify the genes that determine the maternal-grandsire effect, then we can find out if they are imprinted or not," he says. "If we do, that will close the loop. This is a reason for horsemen to be enthusiastic about the Horse Genome Project. Without the genetic tools we are building, we won't be able to answer that question."

If researchers do identify imprinted genes, the information will take a great deal of guesswork out of breeders' decisions. Poorly performing mares from sire lines featuring maternal-grandsire effects could be kept in breeding programs, when in the past they might have been culled. And, says Antczak, "it might help you identify two kinds of sires: sires who can run and transmit their abilities, and sires who can run but probably wouldn't transmit their abilities to their sons and daughters and instead will skip a generation and transmit the ability through their daughters." Finally, other characteristics controlled by genomic imprinting could be more effectively bred for, or-in the case of undesirable traits-perhaps even be bred out of the gene pool.

 As enthusiastic as he is about the possible link between genomic imprinting and the maternal-grandsire effect, Antczak stresses that the connection is still an intriguing theory awaiting more thorough exploration. If the theory holds, however, it will lift the onus from the great performers who never quite live up to expectations in their second careers as sires. Standout athleticism will always be a rare trait in an essentially athletic species, but horse breeders may have the assurance that if they wait just one more generation, a daughter of the great one may produce another world-beater.

EQUUS thanks Secretariat historian Brian Windham for his assistance in the preparation of this article.

~ Source: Equus Magazine #242 December 1997

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