Possibly relevant human trait(s) and/or gene(s) (MIM number): 614754 (gene)

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2012

Cross-species summary: All horses have three naturally occurring gaits, namely (in order of increasing speed) walk (four-beat, lateral), trot (two-beat, diagonal) and gallop (four-beat). Some breeds of horse exhibit more than one form of a particular gait, particularly at intermediate speeds. The alternate forms of intermediate-speed gait are classified as pace (a two-beat gait) or ambling (a four-beat gait), which can be regular (including the Tölt gait of Icelandic horses), lateral or diagonal. Some breeds are four-gaited (e.g. walk, tölt, trot and gallop) and others are five-gaited (e.g. walk, tölt, trot, gallop and pace). "Gaitedness" is the ability to exhibit alternate forms of gait. Gaited breeds included Icelandic horses, Kentucky mountain saddle horse, Missouri fox trotter, Paso fino, Peruvian paso, and Rocky mountain horse, Tennessee walking horse. Non-gaited breeds include Arabian horse, Gotland pony, North-Swedish draft horse, Przewalski’s horse, Shetland pony, Swedish ardennes, Swedish warmblood, and Thoroughbred. (Information taken from Andersson et al., 2012)

Markers: Noting that the DMRT3 likely causal variant "is nearly fixed in both American Standardbred trotters and pacers, which perform a diagonal and lateral gait, respectively, during harness racing", McCoy et al. (2019) realised that "This suggests that modifying alleles must influence the preferred gait at racing speeds in these populations." A GWAS enabled these authors to eventually identify seven SNPs located on six chromosomes (1, 6, 17, 23, 25, 30) that jointly "predicted status as a pacer or trotter with 99.1% accuracy and subsequently performed with 99.4% accuracy in an independently sampled population of 166 Standardbreds (n = 83 pacers, n = 83 trotters)". This is a classic illustration of the multifactorial nature of this trait.

Molecular basis: From a genome scan of 70 Icelandic horses (40 that can pace and 30 that can't pace), Andersson et al. (2012) identified a 684kb region of chromosome ECA23 showing a very strong association with ability to pace. Resequencing within this region eventually identified the causative mutation as a nonsense mutation (Ser301STOP) in DMRT3 (currently listed as LOC100147177 in NCBI), which encodes a transcription factor with a DM domain. Detailed analysis of wild-type and DMRT3-null mice revealed that Dmrt3 has "a pivotal role for configuring the spinal circuits controlling stride in vertebrates". In horses, "The [DMRT3] mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance". In Icelandic horses, "homozygosity for the DMRT3 nonsense mutation is required for the ability to pace in this breed".

Prevalence: Promerová et al. (2014) "genotyped 4396 horses representing 141 horse breeds for the DMRT3 stop mutation. More than half (2749) of these horses also were genotyped for a SNP situated 32 kb upstream of the DMRT3 nonsense mutation because these two SNPs are in very strong linkage disequilibrium. We show that the DMRT3 mutation is present in 68 of the 141 genotyped horse breeds at a frequency ranging from 1% to 100%. We also show that the mutation is not limited to a geographical area, but is found worldwide. The breeds with a high frequency of the stop mutation (>50%) are either classified as gaited or bred for harness racing."

Associated gene: