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

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.

[1]  B. Grant,et al.  A beak size locus in Darwin’s finches facilitated character displacement during a drought , 2016, Science.

[2]  C. Drögemüller,et al.  A Non-Synonymous HMGA2 Variant Decreases Height in Shetland Ponies and Other Small Horses , 2015, PloS one.

[3]  K. Lindblad-Toh,et al.  Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds , 2015, BMC Genomics.

[4]  B. Guldbrandtsen,et al.  Loci associated with adult stature also affect calf birth survival in cattle , 2015, BMC Genetics.

[5]  D. Altshuler,et al.  IGF2BP2/IMP2-Deficient mice resist obesity through enhanced translation of Ucp1 mRNA and Other mRNAs encoding mitochondrial proteins. , 2015, Cell metabolism.

[6]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[7]  Eric S. Lander,et al.  Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication , 2014, Science.

[8]  Holly C. Beale,et al.  Derived variants at six genes explain nearly half of size reduction in dog breeds , 2013, Genome research.

[9]  J. Tetens,et al.  A genome-wide association study indicates LCORL/NCAPG as a candidate locus for withers height in German Warmblood horses. , 2013, Animal genetics.

[10]  Yunyu Zhang,et al.  An HMGA2-IGF2BP2 axis regulates myoblast proliferation and myogenesis. , 2012, Developmental cell.

[11]  A. M. Barrio,et al.  Strong signatures of selection in the domestic pig genome , 2012, Proceedings of the National Academy of Sciences.

[12]  J. Gastier-Foster,et al.  12q14 microdeletion associated with HMGA2 gene disruption and growth restriction , 2012, American Journal of Medical Genetics. Part A.

[13]  E. Ostrander,et al.  The insulin-like growth factor 1 receptor (IGF1R) contributes to reduced size in dogs , 2012, Mammalian Genome.

[14]  R. Thieme,et al.  Insulin growth factor adjustment in preimplantation rabbit blastocysts and uterine tissues in response to maternal type 1 diabetes , 2012, Molecular and Cellular Endocrinology.

[15]  H. Simianer,et al.  A Genome-Wide Association Study Reveals Loci Influencing Height and Other Conformation Traits in Horses , 2012, PloS one.

[16]  Pablo Cingolani,et al.  © 2012 Landes Bioscience. Do not distribute. , 2022 .

[17]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[18]  Christopher A. Miller,et al.  VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. , 2012, Genome research.

[19]  Robert Kofler,et al.  PoPoolation2: identifying differentiation between populations using sequencing of pooled DNA samples (Pool-Seq) , 2011, Bioinform..

[20]  K. Lindblad-Toh,et al.  Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping , 2011, PLoS genetics.

[21]  H. Garreau,et al.  The genetic structure of domestic rabbits. , 2011, Molecular biology and evolution.

[22]  J. Avruch,et al.  mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. , 2011, Genes & development.

[23]  M. Goddard,et al.  Polymorphic Regions Affecting Human Height Also Control Stature in Cattle , 2011, Genetics.

[24]  A. Futschik,et al.  PoPoolation: A Toolbox for Population Genetic Analysis of Next Generation Sequencing Data from Pooled Individuals , 2011, PloS one.

[25]  Thomas J. Nicholas,et al.  Tracking footprints of artificial selection in the dog genome , 2010, Proceedings of the National Academy of Sciences.

[26]  R. Wilson,et al.  BreakDancer: An algorithm for high resolution mapping of genomic structural variation , 2009, Nature Methods.

[27]  J. Hescheler,et al.  The High Mobility Group Protein HMGA2: A Co-Regulator of Chromatin Structure and Pluripotency in Stem Cells? , 2009, Stem Cell Reviews and Reports.

[28]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[29]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[30]  N. de Leeuw,et al.  The 12q14 microdeletion syndrome: additional patients and further evidence that HMGA2 is an important genetic determinant for human height. , 2009, European journal of medical genetics.

[31]  Bjarni V. Halldórsson,et al.  Many sequence variants affecting diversity of adult human height , 2008, Nature Genetics.

[32]  K. Lindblad-Toh,et al.  Efficient mapping of mendelian traits in dogs through genome-wide association , 2007, Nature Genetics.

[33]  Denis Duboule,et al.  The role of Hox genes during vertebrate limb development. , 2007, Current opinion in genetics & development.

[34]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[35]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[36]  M. Narita,et al.  Oncogenic HMGA2: short or small? , 2007, Genes & development.

[37]  C. Bustamante,et al.  A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs , 2007, Science.

[38]  G. F. Wagner,et al.  Human stanniocalcin-2 exhibits potent growth-suppressive properties in transgenic mice independently of growth hormone and IGFs. , 2005, American journal of physiology. Endocrinology and metabolism.

[39]  K. Marchal,et al.  Differential regulation of the insulin‐like growth factor II mRNA‐binding protein genes by architectural transcription factor HMGA2 , 2004, FEBS letters.

[40]  C. Callou.  De la Garenne au Clapier: Étude Archéozoologique du Lapin en Europe Occidentale , 2003 .

[41]  Leif Andersson,et al.  A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig , 2003, Nature.

[42]  R. Reeves,et al.  Molecular biology of HMGA proteins: hubs of nuclear function. , 2001, Gene.

[43]  D J Prockop,et al.  Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes. , 1999, American journal of human genetics.

[44]  Xianjin Zhou,et al.  Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C , 1995, Nature.

[45]  N. Morris,et al.  A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis , 1995, Cell.

[46]  Juliet Clutton-Brock,et al.  Α Natural History of Domesticated Mammals , 1988 .

[47]  R. Robinson.  Genetic studies of the rabbit. , 1958 .

[48]  W. Castle,et al.  Genetic Linkage in the Rabbit. , 1941, Proceedings of the National Academy of Sciences of the United States of America.

[49]  H. Greene,et al.  A LETHAL DWARF MUTATION IN THE RABBIT WITH STIGMATA OF ENDOCRINE ABNORMALITY. , 1934, Science.