A non-synonymous HMGA2 variant decreases height in Shetland ponies and other small horses. SPH041

Most traits of economic or biomedical interest are quantitative traits. The identification of quantitative trait loci (QTL) and their underlying causative variants is still challenging and often requires large sample sizes. Height has been frequently studied as a quantitative model trait. In humans hundreds of loci with small effects control the heritable portion of height variability. In contrast, in domestic animals, typically only a few loci with comparatively large effects are responsible for the major fraction of the trait’s heritability. We investigated height at withers in Shetland ponies and mapped a QTL to ECA 6 by genome-wide association (GWAS). Fine-mapping revealed a shared haplotype block of roughly 790 kb in small Shetland ponies. The HMGA2 gene, known to be associated with height in horses and many other species, was located in the associated haplotype. After closing a gap in the equine reference genome we identified a non-synonymous variant in the first exon of HMGA2 in small Shetland ponies. The variant was predicted to affect the functionally important first AT-hook DNA binding domain of the HMGA2 protein (c.83G>A; p.G28E). We assessed the functional impact of the variant and found impaired DNA binding of a peptide with the mutant sequence in an electrophoretic mobility shift assay. This suggests that the HMGA2 variant also has an impact on DNA binding in vivo and thus leads to reduced growth and a smaller stature in Shetland ponies. We therefore conclude that we identified a quantitative trait nucleotide for height in horses.