OMIA 001968-9796 : Height, HMGA2 associated body size variation in Equus caballus

In other species: dog

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 600698 , 611547

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Considered a defect: no

Key variant known: no

Cross-species summary: Height has frequently been used as a textbook example for a polygenic trait. In humans, hundreds of loci with relatively small effects have been identified. In several domestic animal species, a handful of genetic loci has been repeatedly found to have comparatively large effects on height and/or body size.

Species-specific name: Height at withers

History: A genome-wide association study (GWAS) identified two height QTL in Franches-Monatgnes horses near the LCORL/NCAPG genes on on chromosome 3 and the ZFAT gene on chromosome 9 (Signer-Hasler et al. 2012). A multi-breed GWAS for body size using 48 Throughbreds and 3 horses each out of 16 different other breeds identified 4 major QTL for this trait on chromosomes 3, 6, 9, and 11. The functional knowledge from other species suggested LCORL/NCAPG as underlying genes for the QTL on chromosome 3, HMGA2 underlying the QTL on chromosome 6, and ZFAT on chromosome 9, while the causative gene underlying the QTL on chromosome 11 is still unknown (Makvandi-Nejad et al. 2012). The GWAS study by Makvandi-Nejad et al. 2012 included several very small horse and pony breeds such as American Miniature horses, Falabella, Caspian, Shetland Pony, Welsh Mountain Pony, Welsh Pony, and Dartmoor Pony.

The LCORL/NCAPG QTL has been confirmed in two independent studies in German Warmblood horses and seems to be the only segregating major size QTL in Warmblood populations (Tetens et al. 2013; Metzger et al. 2013).

Inheritance: Height at withers or body size in general are considered quantitative traits with high heritability and a polygenic mode of inheritance. The HMGA2 gene can be considered a "major gene" with large effect on this trait. The HMGA2 28-Glu allele acts in an additive manner and the mode of inheritance of this particular quantitative trait variant can be described as autosomal semidominant.

Mapping: Frischknecht et al. (2015) performed a genome-wide association study (GWAS) using a cohort of 48 Shetland Ponies and illumina equine SNP70 data ("illumina 65 k SNP chip"). The animals were selected from the extreme ends of the size distribution. The authors used 29 very small Shetland Ponies (height at withers <87 cm) and 19 large Shetland Ponies (height at withers ≥87 cm). With 41,683 SNPs that passed quality control and using a simple association analysis without consideration of the populaton stratification, the authors found markers on chromosomes 6, 9, and 11 that reached a Bonferroni-corrected significance threshold of p<0.05. The strongest association was on chromosome 6 near the HMGA2 gene and had a raw p-value of 1.34 Exp-08 (Bonferroni-corrected p = 0.0006). The authors further delineated a shared 793 kb homozygous haplotype in all the small Shetland Ponies at Chr6:81,004,787–81,798,590 (EquCab 2 assembly).

Molecular basis: Frischknecht et al. (2015) obtained whole genome sequence information from one small and one large Shetland Pony at 25x coverage and compared the data to the genome sequences of 51 control horses. Variant calling was performed with respect to the EquCab 2 assembly. However, the small Shetland Pony did not carry any private non-synonymous in the critical interval on chromosome 6. Loss-of-function HMGA2 variants are known in other species to result in small body size, e.g. in the pygmy mouse mutant. The authors therefore focused on HMGA2 as the most likely functional candidate gene within the critical interval. The EquCab 2 reference assembly has a gap in the region of the first exon of HMGA2 and thus this region was not covered by the whole genome re-sequencing experiment. Frischknecht et al. (2015) then sequenced the missing region by conventional PCR amplification and Sanger sequencing and identified a non-synonymous variant in exon 1 of the HMGA2 gene (c.83G>A). This variant is predicted to replace a highly conserved gylcine by a glutamic acid (p.Gly28Glu). The amino acid exchange affects the first of three so-called AT-hook DNA binding domains of the HMGA2 protein. The introduction of a negatively charged glutamate side chain is predicted to decrease the binding affinity of HMGA2 to DNA. Frischknecht et al. (2015) confirmed this experimentally with an electrophoretiv mobility shift assay: A peptide with the wildtype sequence bound stronger to DNA than a peptide with the mutant sequence. The authors investigated the size of the effect of the HMGA2 variant in a cohort of 110 Shetland Ponies (including the 48 animals used for the initial GWAS). In this cohort that variant showed an addititive effect and all three genotype classes were significantly different from each other. The mean heights at withers for the different genotype classes were A/A: 84 cm, A/G: 95 cm, and G/G 103 cm. The authors concluded that one copy of the mutant A-allele leads to a reduction of ~9.5 cm in height at withers in Shetland Ponies.

The site of the variation sits within a gap of the EquCab 2 reference genome assembly and the HMGA2 gene is currently not correctly annotated in the EquCab 2 assembly. HMGA2 reference sequences spanning this region have been deposited in the nucleotide databases under accessions LN849000 and LN849001.

Breeds: German Riding Pony, New Forest Pony, Shetland Pony.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
HMGA2 high mobility group AT-hook 2 Equus caballus 6 NC_009149.3 (82552985..82681843) HMGA2 Homologene, Ensembl, NCBI gene

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2016 Kader, A., Li, Y., Dong, K., Irwin, D.M., Zhao, Q., He, X., Liu, J., Pu, Y., Gorkhali, N.A., Liu, X., Jiang, L., Li, X., Guan, W., Zhang, Y., Wu, D.D., Ma, Y. :
Population Variation Reveals Independent Selection toward Small Body Size in Chinese Debao Pony. Genome Biol Evol 8:42-50, 2016. Pubmed reference: 26637467. DOI: 10.1093/gbe/evv245.
2015 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. :
A Non-Synonymous HMGA2 Variant Decreases Height in Shetland Ponies and Other Small Horses. PLoS One 10:e0140749, 2015. Pubmed reference: 26474182. DOI: 10.1371/journal.pone.0140749.
2013 Metzger, J., Schrimpf, R., Philipp, U., Distl, O. :
Expression levels of LCORL are associated with body size in horses. PLoS One 8:e56497, 2013. Pubmed reference: 23418579. DOI: 10.1371/journal.pone.0056497.
Tetens, J., Widmann, P., Kühn, C., Thaller, G. :
A genome-wide association study indicates LCORL/NCAPG as a candidate locus for withers height in German Warmblood horses. Anim Genet 44:467-71, 2013. Pubmed reference: 23418885. DOI: 10.1111/age.12031.
2012 Makvandi-Nejad, S., Hoffman, G.E., Allen, J.J., Chu, E., Gu, E., Chandler, A.M., Loredo, A.I., Bellone, R.R., Mezey, J.G., Brooks, S.A., Sutter, N.B. :
Four loci explain 83% of size variation in the horse. PLoS One 7:e39929, 2012. Pubmed reference: 22808074. DOI: 10.1371/journal.pone.0039929.
Signer-Hasler, H., Flury, C., Haase, B., Burger, D., Simianer, H., Leeb, T., Rieder, S. :
A genome-wide association study reveals loci influencing height and other conformation traits in horses. PLoS One 7:e37282, 2012. Pubmed reference: 22615965. DOI: 10.1371/journal.pone.0037282.

Edit History


  • Created by Tosso Leeb on 27 Oct 2015
  • Changed by Tosso Leeb on 27 Oct 2015
  • Changed by Tosso Leeb on 30 Oct 2015
  • Changed by Tosso Leeb on 31 Oct 2015
  • Changed by Frank Nicholas on 22 Apr 2016
  • Changed by Frank Nicholas on 26 Oct 2016