Single Gene Has Impact On Gait Of Horses And Mice

April Flowers for – Your Universe Online

An international consortium of researchers from Uppsala University, Swedish University of Agricultural Sciences and Texas A&M University have discovered a mutation in a single gene in horses that is critical for the ability to perform ambling gaits and pacing that has a major effect on performance in harness racing. The study, published in Nature, is a breakthrough for understanding spinal cord neuronal circuitry and locomotion in vertebrates.

A complex coordination of muscle contractions carried out by neuronal circuits in our spinal cords allow us to walk and run, but how does this work at the level of nerve cells and molecules?

There is a great variability in the pattern of locomotion for horses, including the three naturally occurring gaits: walk, trot and canter/gallop.  Some horses, however, have additional gaits such as ambling gaits or pace. For instance, Icelandic Horses can tolt (ambling gait) and flying pace. The team decided to investigate the genetic basis for these locomotive differences.

Gus Cothran, a professor in the Animal Genetic Lab of the College of Veterinary Medicine & Biomedical Sciences at Texas A&M, and the team used a process called “whole genome SNP analysis” to study the genes of 70 Icelandic horses that had either four gaits or five, with the pace being the fifth gait.

The team sequenced the DMRT3 gene of the test horses and found that in almost every case of gaited horses, there was mutation in the DMRT3 that caused a premature “stop codon” which causes the protein product of the gene to be terminated before the whole protein is completed. This alters the function of the protein, which leads to the differences associated with the gait.

“We suspected a strong genetic component, but were almost shocked when we discovered that a single gene, DMRT3, largely explained the genetic difference between pacers and non-pacers,” explains Lisa Andersson one of the PhD students involved in the project.

A separate group of researchers from Uppsala University, led by Klas Kullander, found that this particular gene, DMRT3, is expressed in a previously unknown type of neuron in the spinal cord of mice. The characteristics of these neurons, including their location, suggested that these neurons could take part in the neuronal circuitry that coordinates movement.

When the two groups of scientists compared their data, they realized an important biological finding was imminent.

“At that moment, we realized that our discovery did not only extend our understanding of spinal neuronal circuits in mice, but that we had discovered a tangible population of nerve cells that also seemed to be critical for the control of gaits in horses. The new type of nerve cell is dependent on DMRT3, and is tentatively named after this gene,” said Kullander.

A single base change in DMRT3 which resulted in the production of a truncated form of the DMRT3 protein, is the mutation associated with pacing in horses. The team developed a diagnostic test for the mutation and discovered that it is widespread among horses that show alternate gaits like the Tennessee Walking Horse in the U.S. or the Paso Fino in South America. The gene also seems very prevalent in horses bred for harness racing.

“The DMRT3 mutation shows a strong positive association with performance in harness racing,” states Leif Andersson who led the hunt for the DMRT3 mutation.

Cothran says with more research, the findings could have critical importance to horse breeding and horseracing.

“We need to examine the DMRT3 on certain breeds and see if it can directly affect the speed and movement of horses,” he adds. Naturally, it’s something that horse breeders and anyone involved with horse racing would be interested in and would want to know about. These findings could have a major impact on future horse breeding. We think it’s an exciting step in looking at motion, speed and limb movement, and it’s possible it could have implications in other species, too.”

As a horse speeds up, it will normally switch from trot to gallop. Gallop is the natural gait at high speed, but this leads to disqualification for trotters. Andersson explains that the mutation inhibits the transition from trot to gallop, which allows the horse to trot at a very high speed.

To explore this function further, the team took advantage of the tools of mouse neurobiology, which revealed that the DMRT3-neurons cross the midline of the spinal cord and thus connect the left with the right side. They also have a direct connection with motor neurons that control flexor and extensor muscles.

The team found that certain mice, knockout mice, lacked a functional DMRT3 gene. However, they also have an altered pattern of locomotion.

“Without DMRT3, the neural circuit that contributes to the coordination of the limbs is not formed in a normal way,” states PhD student Martin Larhammar, who participated in the characterization of the DMRT3 gene in both horses and in mice.

“At birth, these neural circuits are in a chaotic state and the mouse cannot coordinate its leg movements, but eventually other neural circuits seems to compensate for the loss of DMRT3 so that the adult mouse can again move relatively normally. This flexibility is interesting because it shows that our nervous system can adapt despite the loss of a key gene,” adds Kullander.

This gene mutation has had a major impact on the evolution of the domestic horse and most likely first appeared thousands of years ago.  Humans desired traits that they found in some horses, such as the smoother walk of the ambling gait, and bred for that trait, reinforcing the gene mutation.

“The discovery of the DMRT3 mutation is an outstanding example of how genetic studies of the evolution in domestic animals can lead to basic new knowledge concerning gene function and important biological mechanisms,” said Andersson.

“It is truly great when this type of interdisciplinary collaboration results in such ground breaking discoveries. There was no information in the scientific literature on the function of the DMRT3 prior to the publication of our article. This protein is present in all vertebrates for which data are available, and it is likely that DMRT3 nerve cells have a central role for coordinating movements in humans as well,” asserted Kullander.

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