Epsilon Open Archive

Abstract

Assigning function to genes is essential for a better understanding of biological
systems. To date, approximately half of the genes in the vertebrate genome have known
function. Domestic animals are a rich source for trait mapping and in this thesis we
have mapped three distinct equine phenotypes. The result provides increased
knowledge regarding gene function and importantly, practical implications for horse
welfare. In paper I and IV, we confirm that Equine Multiple Congenital Ocular
Anomalies (MCOA) syndrome is inherited as an incompletely dominant trait (p=
2.2x10-16). By first identifying a 208 kb identity-by decent (IBD) region and
subsequently excluding polymorphic sites identified through Illumina sequencing, we
conclude that the gene PMEL causes these defects in horse. Our findings, together with
functional analyses recently published, support that the cause of MCOA syndrome is a
missense mutation (Arg625Cys) near the transmembrane region of PMEL that results
in altered biochemical properties. In paper II we show that variants in the MHC-II
region influence the susceptibility to equine Insect Bite Hypersensitivity with the same
marker risk allele identified in two distinct populations, OR 4.19 (p= 2.3x10-5) and 1.48
(p= 0.04) for Icelandic horses and Exmoor ponies respectively. In addition,
homozygosity across the MHC-II region confers a higher risk of developing disease,
OR= 2.67 (p= 1.3x10-3). Finally, in paper III we utilize the EquineSNP50 BeadChip to
identify the first Gait locus in horse. A highly significant SNP (EMP2= 2.0x10-4) was
identified to be consistent with a recessive mode of inheritance for the lateral gait pace
in Icelandic horses, and confirmed in an independent sample set (p= 2.4x10-14).
Illumina sequencing of an established IBD region identified a nonsense mutation in the
gene DMRT3. A clearly dichotomous distribution in a panel of gaited and non-gaited
breeds revealed that the DMRT3 mutation is permissive for a variety of alternate gaits.
The mutation also has a favorable effect in harness racing horses. Functional
characterization of the truncated protein demonstrated correct localization and an intact
DNA binding profile. mRNA expression in a small population of commissural neurons
from the spinal cord was confirmed in mutant and wild type horses. Further, a DMRT3
null mouse displayed a change in spinal cord circuit signaling and locomotion. These
findings reveal a new molecule involved in the regulation of limb movement.