title: The mammalian cervical vertebrae blueprint depends on the T (brachyury) gene.
abstract: A key common feature all but three known mammalian genera is the strict seven cervical vertebrae blueprint, suggesting the involvement of strong conserving selection forces during mammalian radiation. This is further supported by reports indicating that children with cervical ribs die before they reach reproductive age. Hypotheses were put up, associating cervical ribs (homeotic transformations) to embryonal cancer (e.g., neuroblastoma) or ascribing the constraint in cervical vertebral count to the development of the mammalian diaphragm. Here, we describe a spontaneous mutation c.196A > G in the Bos taurus T gene (also known as brachyury) associated with a cervical vertebral homeotic transformation that violates the fundamental mammalian cervical blueprint, but does not preclude reproduction of the affected individual. Genome-wide mapping, haplotype tracking within a large pedigree, resequencing of target genome regions, and bioinformatic analyses unambiguously confirmed the mutant c.196G allele as causal for this previously unknown defect termed vertebral and spinal dysplasia (VSD) by providing evidence for the mutation event. The nonsynonymous VSD mutation is located within the highly conserved T box of the T gene, which plays a fundamental role in eumetazoan body organization and vertebral development. To our knowledge, VSD is the first unequivocally approved spontaneous mutation decreasing cervical vertebrae number in a large mammal. The spontaneous VSD mutation in the bovine T gene is the first in vivo evidence for the hypothesis that the T protein is directly involved in the maintenance of the mammalian seven-cervical vertebra blueprint. It therefore furthers our knowledge of the T-protein function and early mammalian notochord development.
authors.affiliation: Leibniz-Institute for Farm Animal Biology, Institute for Genome Biology, 18196 Dummerstorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kromik
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Ulrich
authors.affiliation: Clinic for Cattle, University of Veterinary Medicine Hannover, 30173 Hannover, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Kusenda
authors.affiliation: Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tipold
authors.affiliation: Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Veronika M
authors.initials: VM
authors.lastname: Stein
authors.affiliation: Clinic for Horses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Hellige
authors.affiliation: Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Dziallas
authors.affiliation: Leibniz-Institute for Farm Animal Biology, Institute for Genome Biology, 18196 Dummerstorf, Germany.
authors.forename: Frieder
authors.initials: F
authors.lastname: Hadlich
authors.affiliation: Leibniz-Institute for Farm Animal Biology, Institute for Genome Biology, 18196 Dummerstorf, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Widmann
authors.affiliation: Leibniz-Institute for Farm Animal Biology, Institute for Genome Biology, 18196 Dummerstorf, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Goldammer
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.affiliation: Clinic for Cattle, University of Veterinary Medicine Hannover, 30173 Hannover, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rehage
authors.affiliation: Vereinigte Informationssysteme Tierhaltung w.V. (vit), 27283 Verden, Germany.
authors.forename: Dierck
authors.initials: D
authors.lastname: Segelke
authors.affiliation: Leibniz-Institute for Farm Animal Biology, Institute for Genome Biology, 18196 Dummerstorf, Germany.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Weikard
authors.affiliation: Leibniz-Institute for Farm Animal Biology, Institute for Genome Biology, 18196 Dummerstorf, Germany Faculty of Agricultural and Environmental Sciences, University Rostock, 18059 Rostock, Germany kuehn@fbn-dummerstorf.de.
authors.forename: Christa
authors.initials: C
authors.lastname: Kühn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle / Q000002:abnormalities / Q000235:genetics*; D002574:Cervical Vertebrae / Q000002:abnormalities*; D005260:Female; D005326:Fetal Proteins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D020825:T-Box Domain Proteins / Q000235:genetics*; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein
keywords: brachyury; genetic defect; homeotic transformation