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Horse GWAS Helps to Track Down Coordination-Related Gene

NEW YORK (GenomeWeb News) – Alterations in just one gene appear to be enough to influence the kinds of movements that horses and other vertebrate animals can muster, according to a study appearing online today in Nature.

Researchers from the Swedish University of Agricultural Sciences, Uppsala University, and elsewhere did a genome-wide association study involving dozens of Icelandic horses capable of either four or five different gait motions.

In addition to the three natural gaits that all horses are known for, these horses were capable of another, atypical four-beat gait known as ambling. Some could also perform a fifth "flying pace" gait — a speedy two-beat gait in which the legs on the same side of the body take turns moving forward in unison. The GWAS led to a "flying pace"-associated region on chromosome 23 that contained the transcription factor gene DMRT3, while the team's follow-up experiments pointed to a nonsense mutation in DMRT3 as the basis for this association.

The mutation was subsequently shown to be over-represented in other horse breeds with unusual gaits, including the Tennessee Walking Horse and the Paso Fino from South America. Similar changes in the gene also turned up in horses bred for their ability to excel at harness racing, which requires horses to maintain a high speed trot or pace without breaking into a gallop.

"The DMRT3 mutation shows a strong positive association with performance in harness racing," co-senior author Leif Andersson, an animal breeding and genetics researcher affiliated with the Swedish University of Agricultural Sciences and Uppsala University, said in a statement. "Our interpretation is that the mutation inhibits the transition from trot to gallop and thereby allows the horse to trot at very high speed."

Through a series of functional experiments done in parallel in mice, members of the group determined that DMRT3 gets expressed in a previously unappreciated group of spinal neurons, nicknamed DMRT3 neurons based on the apparent importance of the gene to their function. In the absence of this gene, they found, mouse locomotion changes — apparently due to rearrangements in the network of neurons relaying information to the muscles that control an animal's limbs.

"At birth, these neural circuits are in a chaotic state and the mouse cannot coordinate its leg movements," co-senior author Klas Kullander, the Uppsala University neuroscience researcher who led the mouse studies, said in a statement, "but eventually other neural circuits seems to compensate for the loss of DMRT3 so that the adult mouse can again move relatively normally."

The horse GWAS and mouse experiments, which began as distinct studies that were eventually merged, indicate that DMRT3 contributes to movement-related neural circuits in horses, mice, and, presumably, in other vertebrates as well.

On the genetics side, the study authors explained, the project began as an effort to understand the underpinnings of alternative movement methods using horses as a model.

Whereas most horses have three main natural gaits — a walk, a trot, and a canter/gallop — a few breeds are known for their ability to move in gaits with distinct speed, footfall, and/or foot placement combinations, they noted.

To look at this in more detail, the team started by doing an association study involving
30 Icelandic horses that could walk, trot, gallop, and amble or "tölt," and another 40 Icelandic horses that could do those four and move at the two-beat pace gait.

Amongst the horses capable of pacing, the researchers found a significant association involving a region on chromosome 23. More extensive analyses indicated that five-gaited Icelandic horses typically share several SNPs in the region, including a nonsense mutation that introduces a premature stop codon in DMRT3.

When the team screened hundreds more Icelandic horses, it identified the same alteration affecting both copies of the DMRT3 gene in almost all of the five-gaited horses tested.

In Icelandic horses with four gaits — those that could tölt but did not perform the pace gait — the DMRT3 mutation was still more common than it is in many other horse breeds. But the change was far less likely to be homozygous.

The nonsense mutation in DMRT3 turned up in some other breeds too, the researchers reported, though it tended to be more common among those with uncommon gaits and in breeds developed for harness racing, consistent with the notion that DMRT3 function contributes to the way coordinated movement is controlled.

Because the transcription factor was found to be expressed in a group of newly identified inter-neurons around the spine, those involved in the study speculated that DMRT3 might influence movement coordination by affecting the development of these neurons.

"The horse phenotype indicates that DMRT3 neurons not only have a critical role for left/right coordination but also for coordinating the movement of the fore- and hindlegs," researchers noted.

In mice, meanwhile, animals missing the gene exhibited differences in everything from early limb coordination to stride length and motion — changes suspected to stem from rearrangements to neural networks in the absence of DMRT3.

Based on findings so far in both animals, the study authors concluded that DMRT3 likely has a "pivotal role for configuring the spinal circuits controlling stride in vertebrates."

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