title: 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.
authors.affiliation: CIBIO/InBIO (Centro de Investigação em Biodiversidade e Recursos Genéticos), Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal leif.andersson@imbim.uu.se miguel.carneiro@cibio.up.pt.|Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Carneiro
authors.affiliation: Science for Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden leif.andersson@imbim.uu.se miguel.carneiro@cibio.up.pt.
authors.forename: Dou
authors.initials: D
authors.lastname: Hu
authors.affiliation: CIBIO/InBIO (Centro de Investigação em Biodiversidade e Recursos Genéticos), Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal.
authors.forename: John
authors.initials: J
authors.lastname: Archer
authors.affiliation: Science for Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden.
authors.forename: Chungang
authors.initials: C
authors.lastname: Feng
authors.affiliation: CIBIO/InBIO (Centro de Investigação em Biodiversidade e Recursos Genéticos), Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Afonso
authors.affiliation: Science for Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden.|State Key Laboratory of Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, 330045, Nanchang, China.
authors.forename: Congying
authors.initials: C
authors.lastname: Chen
authors.affiliation: CIBIO/InBIO (Centro de Investigação em Biodiversidade e Recursos Genéticos), Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal.|Instituto de Investigacion en Recursos Cinegéticos (IREC-CSIC-UCLM-JCCM), 13071, Ciudad Real, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Blanco-Aguiar
authors.affiliation: INRA, UMR1388 Génétique, Physiologie et Systèmes d'Elevage, University of Toulouse, F-31326 Castanet-Tolosan, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Garreau
authors.affiliation: Fédération Française de Cuniculiculture (FFC), 75009 Paris, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Boucher
authors.affiliation: Departmento de Anatomia, Universidade do Porto, Portugal and ICBAS (Instituto de Ciências Biomédicas Abel Salazar)UMIB (Unidade Multidisciplinar de Investigação Biomédica), Universidade do Porto, 4050-343 Porto, Portugal.
authors.forename: Paula G
authors.initials: PG
authors.lastname: Ferreira
authors.affiliation: CIBIO/InBIO (Centro de Investigação em Biodiversidade e Recursos Genéticos), Campus Agrário de Vairão, Universidade do Porto, 4485-661, Vairão, Portugal.|Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal.|Department of Zoology, Faculty of Sciences, University of Johannesburg, Auckland Park 2006, South Africa.
authors.forename: Nuno
authors.initials: N
authors.lastname: Ferrand
authors.affiliation: Science for Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden.
authors.forename: Carl-Johan
authors.initials: CJ
authors.lastname: Rubin
authors.affiliation: Science for Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden leif.andersson@imbim.uu.se miguel.carneiro@cibio.up.pt.|Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden.|Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843.
authors.forename: Leif
authors.initials: L
authors.lastname: Andersson
mesh_terms: D000818:Animals; D004392:Dwarfism / Q000235:genetics*; D005091:Exons; D017353:Gene Deletion; D025743:HMGA2 Protein / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D011817:Rabbits / Q000235:genetics* / Q000254:growth & development
chemical_list: D025743:HMGA2 Protein; D016601:RNA-Binding Proteins
keywords: IGF2BP2; RNA-seq; body size; mtDNA; whole-genome sequencing