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A Non-Synonymous HMGA2 Variant Decreases Height in Shetland Ponies and Other Small Horses.

Frischknecht M, Jagannathan V, Plattet P, Neuditschko M, Signer-Hasler H, Bachmann I, Pacholewska A, Drögemüller C, Dietschi E, Flury C, Rieder S, Leeb T - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Genotype-phenotype correlation.The box plot displays the height at withers of Shetland ponies with the three different genotypes at the HMGA2:c.83G>A variant. The medians, which are indicated as solid horizontal lines in the box plot, were A/A: 84 cm, A/G: 98 cm, G/G: 104 cm. The mean heights per genotype were: A/A: 84 cm, A/G: 95 cm, G/G: 103 cm.
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pone.0140749.g004: Genotype-phenotype correlation.The box plot displays the height at withers of Shetland ponies with the three different genotypes at the HMGA2:c.83G>A variant. The medians, which are indicated as solid horizontal lines in the box plot, were A/A: 84 cm, A/G: 98 cm, G/G: 104 cm. The mean heights per genotype were: A/A: 84 cm, A/G: 95 cm, G/G: 103 cm.

Mentions: We obtained height measurements on 110 genotyped Shetland ponies. The average height at withers of these animals was 89.3 cm. We then compared the height distributions between the different genotype classes at HMGA2:c.83G>A. The differences between all three genotype classes were significant (p < 2.5 x 10−4). The correlation plot suggested a largely additive mode of inheritance with a mean reduction of the height at withers of 9.5 cm per copy of mutant A allele (Fig 4).


A Non-Synonymous HMGA2 Variant Decreases Height in Shetland Ponies and Other Small Horses.

Frischknecht M, Jagannathan V, Plattet P, Neuditschko M, Signer-Hasler H, Bachmann I, Pacholewska A, Drögemüller C, Dietschi E, Flury C, Rieder S, Leeb T - PLoS ONE (2015)

Genotype-phenotype correlation.The box plot displays the height at withers of Shetland ponies with the three different genotypes at the HMGA2:c.83G>A variant. The medians, which are indicated as solid horizontal lines in the box plot, were A/A: 84 cm, A/G: 98 cm, G/G: 104 cm. The mean heights per genotype were: A/A: 84 cm, A/G: 95 cm, G/G: 103 cm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608717&req=5

pone.0140749.g004: Genotype-phenotype correlation.The box plot displays the height at withers of Shetland ponies with the three different genotypes at the HMGA2:c.83G>A variant. The medians, which are indicated as solid horizontal lines in the box plot, were A/A: 84 cm, A/G: 98 cm, G/G: 104 cm. The mean heights per genotype were: A/A: 84 cm, A/G: 95 cm, G/G: 103 cm.
Mentions: We obtained height measurements on 110 genotyped Shetland ponies. The average height at withers of these animals was 89.3 cm. We then compared the height distributions between the different genotype classes at HMGA2:c.83G>A. The differences between all three genotype classes were significant (p < 2.5 x 10−4). The correlation plot suggested a largely additive mode of inheritance with a mean reduction of the height at withers of 9.5 cm per copy of mutant A allele (Fig 4).

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.