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

Abstract

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.

Population structure, genetic diversity and selection signatures within seven indigenous Pakistani goat populations

“…; Carneiro et al . ). The BTAP and TAP breeds are shorter than other breeds, suggesting that HMGA2 may be a possible candidate gene responsible for the height difference in goats.…”

HMGA Genes and Proteins in Development and Evolution

“…A rather well characterized example of Hmga2 mutant is that of the dwarf phenotype in rabbits [85,86]. The dwarf mutation is a 12.1 kb deletion that removes the promoter and the three first exons of the rabbit Hmga2 gene; as the name implies, the mutation leads to reduction in size, shorter limbs, smaller ears and reduced weight; in addition, the mutation is also accompanied by craniofacial dysmorphologies [87]. However, differently from the hmga2 −/− pygmy phenotype in mice, the dwarf mutant rabbit is heterozygous for the deletion, implying that the mutation is semi-dominant.…”

La génomique du lapin : avancées, applications et perspectives

“…Le déterminisme génétique du lapin nain est également de type monogénique. Carneiro et al (2017) ont identifié une mutation de type délétion du gène HMGA2 qui code pour une protéine facteur de transcription du groupe de haute mobilité (HMG) conduisant à l'inactivation de ce gène. Il en résulte une altération de la croissance générale et du développement crano-facial.…”

“…Fontanesi et al (2006) ainsi que Fontanesi et al (2010b) ont séquencé le gène MC1R dans plusieurs races de Tableau 2. Résultats de génotypage pour la mutation de type délétion de 12,1 Kb du gène HMGA2 (Carneiro et al, 2017).…”

“…Phénotypes de lapins nains et sauvages(Carneiro et al, 2017 ; Photos : (A) Sara Gutiérez Albarran, (B-E) Javier Lopez)…”