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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.


Mapping of height QTL in Shetland ponies.A: Manhattan plot of GWAS using 48 Shetland ponies and height at withers as a quantitative trait. B: Zoom of GWAS results on ECA 6. C: Haplotype analysis of the 19 smallest Shetland ponies. Each line represents one haplotype and the length of the lines represents the length of the shared haplotype block, which was defined based on a small Shetland pony that was homozygous for all significantly associated SNPs on ECA 6. D: NCBI MapViewer gene annotation in the critical interval (Annotation release 101, EquCab 2 genome assembly). The HMGA2 gene is currently not annotated in the NCBI MapViewer. Its position and orientation was determined by comparisons with the orthologous human genome segment.
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pone.0140749.g001: Mapping of height QTL in Shetland ponies.A: Manhattan plot of GWAS using 48 Shetland ponies and height at withers as a quantitative trait. B: Zoom of GWAS results on ECA 6. C: Haplotype analysis of the 19 smallest Shetland ponies. Each line represents one haplotype and the length of the lines represents the length of the shared haplotype block, which was defined based on a small Shetland pony that was homozygous for all significantly associated SNPs on ECA 6. D: NCBI MapViewer gene annotation in the critical interval (Annotation release 101, EquCab 2 genome assembly). The HMGA2 gene is currently not annotated in the NCBI MapViewer. Its position and orientation was determined by comparisons with the orthologous human genome segment.

Mentions: We performed a quantitative genome wide association study (GWAS) with respect to height at withers in Shetland ponies. We investigated 29 Shetland ponies with height at withers ≥87 cm and 19 Shetland ponies with height at withers <87 cm. Our final data set for the analysis thus consisted of 48 animals and their genotypes at 41,683 SNPs. This analysis revealed two QTL on ECA 6 and ECA 9 that exceeded the Bonferroni-corrected significance threshold (Fig 1, S1 Table). It has to be cautioned that the genomic inflation was high at 1.95 indicating substantial population stratification in our cohort. We also performed the initial association study with a mixed model analysis that corrects for the population stratification by considering genome-wide IBD (S1 Fig, S1 Table).


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)

Mapping of height QTL in Shetland ponies.A: Manhattan plot of GWAS using 48 Shetland ponies and height at withers as a quantitative trait. B: Zoom of GWAS results on ECA 6. C: Haplotype analysis of the 19 smallest Shetland ponies. Each line represents one haplotype and the length of the lines represents the length of the shared haplotype block, which was defined based on a small Shetland pony that was homozygous for all significantly associated SNPs on ECA 6. D: NCBI MapViewer gene annotation in the critical interval (Annotation release 101, EquCab 2 genome assembly). The HMGA2 gene is currently not annotated in the NCBI MapViewer. Its position and orientation was determined by comparisons with the orthologous human genome segment.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140749.g001: Mapping of height QTL in Shetland ponies.A: Manhattan plot of GWAS using 48 Shetland ponies and height at withers as a quantitative trait. B: Zoom of GWAS results on ECA 6. C: Haplotype analysis of the 19 smallest Shetland ponies. Each line represents one haplotype and the length of the lines represents the length of the shared haplotype block, which was defined based on a small Shetland pony that was homozygous for all significantly associated SNPs on ECA 6. D: NCBI MapViewer gene annotation in the critical interval (Annotation release 101, EquCab 2 genome assembly). The HMGA2 gene is currently not annotated in the NCBI MapViewer. Its position and orientation was determined by comparisons with the orthologous human genome segment.
Mentions: We performed a quantitative genome wide association study (GWAS) with respect to height at withers in Shetland ponies. We investigated 29 Shetland ponies with height at withers ≥87 cm and 19 Shetland ponies with height at withers <87 cm. Our final data set for the analysis thus consisted of 48 animals and their genotypes at 41,683 SNPs. This analysis revealed two QTL on ECA 6 and ECA 9 that exceeded the Bonferroni-corrected significance threshold (Fig 1, S1 Table). It has to be cautioned that the genomic inflation was high at 1.95 indicating substantial population stratification in our cohort. We also performed the initial association study with a mixed model analysis that corrects for the population stratification by considering genome-wide IBD (S1 Fig, S1 Table).

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.