A genome-wide association study indicates<i>LCORL/NCAPG</i>as a candidate locus for withers height in German Warmblood horses

Tetens, Jens; Widmann, Philipp; Kühn, Christa; Thaller, Georg

doi:10.1111/age.12031

Cited by 104 publications

(97 citation statements)

References 23 publications

(25 reference statements)

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“…LCORL-NCAPG are, together with HMGA2, two of the loci that are most consistently associated with stature and body size variation across multiple studies and species. The LCORL-NCAP region has previously been associated with body size in human, cattle, dog, pig, and horse (Gudbjartsson et al 2008;Pryce et al 2011;Vaysse et al 2011;Rubin et al 2012;Signer-Hasler et al 2012;Tetens et al 2013;Sahana et al 2015). Our results are consistent with a selective sweep at the LCORL-NCAP region related to selection for increased size in domestic rabbits, since all normal-sized rabbits included in this study are significantly larger than wild rabbits and were fixed for a single haplotype ( Figure 4B).…”

Section: Discussionsupporting

confidence: 89%

“…These regions varied largely in size (750,000-6,250,000 bp, median 1,500,000 bp), and contained 646 genes in total. Within the most differentiated regions we noticed several genes previously associated with size or skeletal features in other species including LCORL-NCAPG (e.g., Gudbjartsson et al 2008;Rubin et al 2012;Tetens et al 2013;Sahana et al 2015), STC2 (Gagliardi et al 2005;Rimbault et al 2013), HOXD cluster (Zakany and Duboule 2007), COL11A1 (Li et al 1995;Annunen et al 1999), and IGF2BP2 (Dai et al 2015) (Figure 4A). …”

Section: Genome-wide Scan For Signatures Of Selection In Netherland Dmentioning

confidence: 72%

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Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus

Carneiro

Archer

et al. 2017

Genetics

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The dwarf phenotype characterizes the smallest of rabbit breeds and is governed largely by the effects of a single dwarfing allele with an incompletely dominant effect on growth. Dwarf rabbits typically weigh under 1 kg and have altered craniofacial morphology. The dwarf allele is recessive lethal and dwarf homozygotes die within a few days of birth. The dwarf phenotype is expressed in heterozygous individuals and rabbits from dwarf breeds homozygous for the wild-type allele are normal, although smaller when compared to other breeds. Here, we show that the dwarf allele constitutes a 12.1 kb deletion overlapping the promoter region and first three exons of the HMGA2 gene leading to inactivation of this gene. HMGA2 has been frequently associated with variation in body size across species. Homozygotes for null alleles are viable in mice but not in rabbits and probably not in humans. RNA-sequencing analysis of rabbit embryos showed that very few genes (4-29 genes) were differentially expressed among the three HMGA2/dwarf genotypes, suggesting that dwarfism and inviability in rabbits are caused by modest changes in gene expression. Our results show that HMGA2 is critical for normal expression of IGF2BP2, which encodes an RNA-binding protein. Finally, we report a catalog of regions of elevated genetic differentiation between dwarf and normal-size rabbits, including LCORL-NCAPG, STC2, HOXD cluster, and IGF2BP2. Levels and patterns of genetic diversity at the LCORL-NCAPG locus further suggest that small size in dwarf breeds was enhanced by crosses with wild rabbits. Overall, our results imply that small size in dwarf rabbits results from a large effect, loss-of-function (LOF) mutation in HMGA2 combined with polygenic selection.

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Section: Discussionsupporting

confidence: 89%

Section: Genome-wide Scan For Signatures Of Selection In Netherland Dmentioning

confidence: 72%

Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus

Carneiro

Archer

et al. 2017

Genetics

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“…The overall goal for this study was to identify and map morphological features unique to TWH that are permissive for alternate performance traits in the TWH. The primary locus controlling body size in the TWH is the same ECA3 LCORL/NCAPG region previously identified in other breeds of horse (37,41,56,62). Relatively few loci influencing morphological traits are also observed in dogs (14,60) and can be attributed to typically small founder populations and selective breeding (23,45), resulting in longer LD compared with humans and the subsequent use of fewer individuals for association studies (23,45,46).…”

Section: Discussionmentioning

confidence: 73%

Skeletal variation in Tennessee Walking Horses maps to theLCORL/NCAPGgene region

Staiger

Al-Abri

Pflug

et al. 2016

Physiological Genomics

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Conformation has long been a driving force in horse selection and breed creation as a predictor for performance. The Tennessee Walking Horse (TWH) ranges in size from 1.5 to 1.7 m and is often used as a trail, show, and pleasure horse. To investigate the contribution of genetics to body conformation in the TWH, we collected DNA samples, body measurements, and gait/training information from 282 individuals. We analyzed the 32 body measures with a principal component analysis. Principal component (PC)1 captured 28.5% of the trait variance, while PC2 comprised just 9.5% and PC3 6.4% of trait variance. All 32 measures correlated positively with PC1, indicating that PC1 describes overall body size. We genotyped 109 horses using the EquineSNP70 bead chip and marker association assessed the data using PC1 scores as a phenotype. Mixed-model linear analysis (EMMAX) revealed a well-documented candidate locus on ECA3 (raw P = 3.86 × 10−9) near the LCORL gene. A custom genotyping panel enabled fine-mapping of the PC1 body-size trait to the 3′-end of the LCORL gene ( P = 7.09 × 10−10). This position differs from other reports suggesting single nucleotide polymorphisms (SNPs) upstream of the LCORL coding sequence regulate expression of the gene and, therefore, body size in horses. Fluorescent in situ hybridization analysis defined the position of a highly homologous 5 kb retrogene copy of LCORL (assigned to unplaced contigs of the EquCab 2.0 assembly) at ECA9 q12-q13. This is the first study to identify putative causative SNPs within the LCORL transcript itself, which are associated with skeletal size variation in horses.

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“…To make the picture even more tantalizing, a genome-wide analysis identified an association between the height of German warmblood horses and the non-SMC condensin I complex subunit NCAPG 47 Such correlation was also found in cattle, suggesting an evolutionarily conserved effect of condensin I on the growth of bones. 48 A recent study revealed a new link between the WNT pathway and condensin.…”

Section: Possible Involvement Of Smcs In Molecular Pathways Of Bone Dmentioning

confidence: 99%

“…The cohesin subunit STAG2 is as a transcriptional coactivator of TNF-a; 44,45 NCAPG Condensin complex subunit 3 Associated with height Non-SMC subunit of condensin I 47,48 Abbreviations: SMC, structural maintenance of chromosome; TNF-a, tumor necrosis factor-a.…”

Section: Promotes Osteolysis By Activation Of Osteoblastsmentioning

confidence: 99%

Structural maintenance of chromosome complexes and bone development: the beginning of a wonderful relationship?

Cohen-Zinder¹,

Karasik

Onn

2013

BoneKEy Reports

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Bone development depends on environmental, nutritional and hormonal factors. Yet, an ordered and timed activation of genes and their associated molecular pathways are central for the growth and development of healthy bones. The correct expression of genes depends on both cis-and trans-regulatory elements. Of these, the elusive role of chromatin ultrastructure is just beginning to become appreciated. Changes in the higher-order structure of chromatin are affecting the expression of genes in response to intrinsic and environmental signals. Cohesin and condensin are members of the structural maintenance of chromosome (SMC) family of protein complexes, which mediate higher-order chromatin structure by tethering distinct regions of chromatin either inter-or intra-molecularly. In recent years, SMCs had been identified for their function in the regulation of gene expression and developmental processes, whereas malfunction of cohesin or condensin has an impact on human health. However, little is known about the specific roles of SMC complexes in bone development and their possible effect on bone health. Here, we review studies that suggest an intimate link between SMCs and bone development, as well as a plausible effect, direct or indirect, on the bone health. We describe genetic syndromes associated with SMCs with distinctive bone phenotypes and identify links between SMCs and bone-related molecular pathways. Future studies of the relationship between SMCs and bone development will reveal new understandings of both the cellular and molecular roles of SMC complexes and provide new insights into the growth and developmental processes in the bone.

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A genome-wide association study indicatesLCORL/NCAPGas a candidate locus for withers height in German Warmblood horses

Cited by 104 publications

References 23 publications

Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus

Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus

Skeletal variation in Tennessee Walking Horses maps to theLCORL/NCAPGgene region

Structural maintenance of chromosome complexes and bone development: the beginning of a wonderful relationship?

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