title: A Non-Synonymous HMGA2 Variant Decreases Height in Shetland Ponies and Other Small Horses.
abstract: The identification of quantitative trait loci (QTL) such as height and their underlying causative variants is still challenging and often requires large sample sizes. In humans hundreds of loci with small effects control the heritable portion of height variability. In domestic animals, typically only a few loci with comparatively large effects explain a major fraction of the heritability. We investigated height at withers in Shetland ponies and mapped a QTL to ECA 6 by genome-wide association (GWAS) using a small cohort of only 48 animals and the Illumina equine SNP70 BeadChip. Fine-mapping revealed a shared haplotype block of 793 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 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 affects DNA binding in vivo and thus leads to reduced growth and a smaller stature in Shetland ponies. The identified HMGA2 variant also segregates in several other pony breeds but was not found in regular-sized horse breeds. We therefore conclude that we identified a quantitative trait nucleotide for height in horses.
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland; Agroscope, Swiss National Stud Farm, 1580, Avenches, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Frischknecht
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Division of Experimental and Clinical Research, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Plattet
authors.affiliation: Agroscope, Swiss National Stud Farm, 1580, Avenches, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Neuditschko
authors.affiliation: Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland; Bern University of Applied Sciences, School of Agricultural, Forest and Food Sciences, 3052, Zollikofen, Switzerland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Signer-Hasler
authors.affiliation: Agroscope, Swiss National Stud Farm, 1580, Avenches, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Bachmann
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland; Swiss Institute of Equine Medicine, Vetsuisse Faculty, University of Bern and Agroscope, 3001, Bern, Switzerland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Pacholewska
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dietschi
authors.affiliation: Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland; Division of Experimental and Clinical Research, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Flury
authors.affiliation: Agroscope, Swiss National Stud Farm, 1580, Avenches, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rieder
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL & Agroscope, 3001, Bern, Switzerland.
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000818:Animals; D005091:Exons; D025743:HMGA2 Protein / Q000235:genetics*; D006736:Horses / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D013557:Switzerland
chemical_list: D025743:HMGA2 Protein