Long-term survival of mutant gene could be explained by dressage benefits – study

Carriers of the gene behind Warmblood Fragile Foal Syndrome tend to do well in dressage, which may have driven generational breeding decisions.
Photo by Adrian Falcoianu

Have generations of sport-horse breeders been inadvertently selecting horses that carry the gene for Warmblood Fragile Foal Syndrome?

Researchers in Germany have raised the possibility in a two-tier study, which examined the reproductive performance of Warmblood stallions who harbour the mutant gene and explored the dressage performance of carriers.

Mirell Wobbe and her fellow researchers found evidence of reduced reproductive performance from stallion carriers, as well as indications of favourable dressage performance among carriers of the harmful gene.

They said they were able to identify a significant relationship between the dressage performance of young horses, in terms of gait quality and rideability, in carriers when compared with non-carriers.

This clear selection advantage may explain why the mutation had been retained in the Warmblood population at a frequency that has stabilized at higher levels, the study wrote in the journal PLOS ONE.

The syndrome, first described by a US research group in 2011, is an inherited defect of connective tissue characterized by fragile and overly flexible skin and mucous membranes, as well as weak, hypermobile joints. It is caused by a mutation in the PLOD1 gene.

Affected newborn foals either die or are euthanized shortly after birth because the condition is untreatable and the prognosis is poor.

Contrary to what the name suggests, the defect is not confined to Warmbloods and also occurs in Thoroughbreds and other equine breeds.

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“Although a genetic test for WFFS became commercially available only two years later, horse breeders have long paid little attention to the condition and opportunities of genetic testing,” the authors noted.

“This has changed drastically after a case of WFFS had occurred in the US sport horse population at the beginning of 2018. An intense and often highly emotional discussion started, was carried on in social media, and quickly spread within the horse breeding sector worldwide.”

This, they said, led to a substantial increase in the number of genetically tested horses, especially sport horses.

Because it is a recessive trait, only horses that inherit the mutant gene from both parents will have the syndrome. Thus, if a carrier sire is mated with a carrier mare,  there is a 50% chance that the offspring will be unaffected by the disease but will be a carrier (with one copy of the gene), a 25% chance it will inherit two copies of the mutant allele and therefore be affected, and a 25% chance of being free of the mutation.

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The authors said the numbers of reported cases of the syndrome worldwide are relatively small, which gives rise to the assumption that the genetic defect may also affect different earlier developmental stages, leading to abortion, prenatal, or premature foal loss. If so, this would be reflected in reduced foaling rates and smaller numbers of foals born with the syndrome, even though the carrier frequency among Warmbloods is 9.5 to 15%.

Recent results of necropsy studies using tissue from abortions and stillborn cases in horses have supported this assumption.

The study team set out to statistically look for associations between the syndrome and the reproductive performance of German riding horses. Further, they looked for possible differences between carriers and non-carriers in terms of performance traits.

For this purpose, 11 years of breeding information from 2008 to 2020 was provided by 10 German studbook registries. This covered almost 400,000 matings. The contributing associations ensured coverage of a large part of the Warmblood breeding population in Germany.

The published breeding values of stallions were used for respective comparisons of riding horse performance.

The results, they said, provide statistical evidence of detrimental effects of the syndrome-causing gene on the reproductive performance of Warmblood horses, with a 2.7% lower average foaling rate in carriers of the mutant allele than in sires free of the gene, if mated to an average mare population.

“Reported WFFS cases indicate only the tip of the iceberg,” they said, because properly assessing the impact of the mutant allele on reproduction requires consideration of premature foal losses.

Analysis work showed significant differences between matings with carriers of the mutant allele and sires free of the mutation, with regard to the probability of a living foal.

Discussing their findings, the authors said horse breeders should be aware of the WFFS status of at least one, and preferably both, of the suggested mating partners.

“Based on the study of the WFFS mutation in a wider range of horse breeds and populations, it has been suspected that the first occurrence of the WFFS mutation dates back several centuries and occurred for the first time in an early ancestor with substantial influence on multiple lines of breeds,” they said.

The question arises as to why the harmful effect of the WFFS mutation on reproductive performance has not taken effect according to basic evolutionary principles and promoted the loss of the mutant allele.

From an evolutionary point of view, the relatively high modern-day frequency of around 10% of WFFS carriers in different populations of riding horses, centuries after the probable first occurrence of the mutation, suggests that the reproductive disadvantage acting towards frequency reduction must have been counterbalanced by breeding selection pressure in the opposite direction.

Favorable dressage-related attributes linked with the mutation in the study may explain the long survival of the defect allele, they said.

“Concerning WFFS in the Warmblood horse, it has been speculated that it is especially the lines of very successful sport horses in which higher WFFS carrier rates are found.”

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To verify a relationship between WFFS and performance, the research team used the WFFS test results from this study and Estimated Breeding Values of sires, which are part of the routine genetic evaluation of German riding horses.

“We were able to identify a significant relationship with the dressage performance of young horses, i.e. quality of gaits and rideability, with on average higher Estimated Breeding Values in WFFS carriers than in WFFS-free horses.”

The genetic superiority seen in carriers of the WFFS mutation in terms of dressage traits among young riding horses, and the important role of dressage performance in the majority of the breeding organizations for riding horses, may explain the mutant allele’s long survival, they said. Further research is needed into the effects of the mutant allele on dressage performance.

The authors said that since the syndrome has been recognized as occurring more than just sporadically in Warmblood horses, as well as in horses of other breeds, scientists and breeding organizations have underlined their recommendations to use available testing to take WFFS into account when planning matings.

Active breeding stallions have been required to be tested for the WFFS mutation in the German population of riding horses since 2019, and similar regulations exist in other countries.

Thirty-eight breeds tested for gene variant behind Warmblood fragile foal syndrome

However, only with the known WFFS status of both mating partners, can responsible decisions can be taken that also consider longer-term effects of population-wide breeding measures against the syndrome.

As long as the mating of two carriers is avoided, no foals will be born with the fatal syndrome, meaning that the breeding will be safe and free of pregnancy losses because of the syndrome.

At the same time, there is no restriction on the gene pool, as would be the case if carriers were prohibited from continuing to breed.

Genetic testing allows management of genetic defects through a responsible and targeted use of carriers for breeding, they said. “The positive characteristics of these horses can then be preserved for the breeding program and development of homozygous offspring can be avoided.”

The results of the study suggest that confining breeding to WFFS-free broodmares and stallions may increase foaling rates by around 2.7%, corresponding to an improvement of reproductive success by about 4%.

In conclusion, the authors said their findings support the assumption that WFFS is a relevant cause of premature foal losses in the riding horse population. It is clear that the role of the mutant allele is underestimated if only reported cases (affected foals) are considered.

“The relatively high frequency of the defect allele implies crucial importance of genetic testing and responsible use of breeding animals.” It can be successfully managed, they said, by strictly avoiding mating of two carriers, while keeping valuable broodmares and sires regardless of their carrier status in the overall gene pool.

The study team, all from Germany, comprised Wobbe, Friedrich Reinhardt, Reinhard Reents and Kathrin Stock, all with the Genetic Evaluation Division, part of IT Solutions for Animal Production; and Jens Tetens, with the University of Goettingen. Wobbe and Stock are also affiliated with the University of Veterinary Medicine Hannover (Foundation).

Wobbe M, Reinhardt F, Reents R, Tetens J, Stock KF (2022) Quantifying the effect of Warmblood Fragile Foal Syndrome on foaling rates in the German riding horse population. PLoS ONE 17(7): e0267975. https://doi.org/10.1371/journal.pone.0267975

The study, published under a Creative Commons License, can be read here.



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