title: Elucidating the genetic basis of an oligogenic birth defect using whole genome sequence data in a non-model organism, Bubalus bubalis.
abstract: Recent strong selection for dairy traits in water buffalo has been associated with higher levels of inbreeding, leading to an increase in the prevalence of genetic diseases such as transverse hemimelia (TH), a congenital developmental abnormality characterized by absence of a variable distal portion of the hindlimbs. Limited genomic resources available for water buffalo required an original approach to identify genetic variants associated with the disease. The genomes of 4 bilateral and 7 unilateral affected cases and 14 controls were sequenced. A concordance analysis of SNPs and INDELs requiring homozygosity unique to all unilateral and bilateral cases revealed two genes, WNT7A and SMARCA4, known to play a role in embryonic hindlimb development. Additionally, SNP alleles in NOTCH1 and RARB were homozygous exclusively in the bilateral cases, suggesting an oligogenic mode of inheritance. Homozygosity mapping by whole genome de novo assembly also supported oligogenic inheritance; implicating 13 genes involved in hindlimb development in bilateral cases and 11 in unilateral cases. A genome-wide association study (GWAS) predicted additional modifier genes. Although our data show a complex inheritance of TH, we predict that homozygous variants in WNT7A and SMARCA4 are necessary for expression of TH and selection against these variants should eradicate TH.
authors.affiliation: Informatics Institute, University of Missouri, Columbia, Missouri, USA.|Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA.
authors.forename: Lynsey K
authors.initials: LK
authors.lastname: Whitacre
authors.affiliation: Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA.
authors.forename: Jesse L
authors.initials: JL
authors.lastname: Hoff
authors.affiliation: Informatics Institute, University of Missouri, Columbia, Missouri, USA.|Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schnabel
authors.affiliation: Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Albarella
authors.affiliation: Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ciotola
authors.affiliation: Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Peretti
authors.affiliation: Parco Tecnologico Padano, Lodi, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Strozzi
authors.affiliation: Parco Tecnologico Padano, Lodi, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ferrandi
authors.affiliation: Department of Agriculture, University of Naples Federico II, Portici, Napoli, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ramunno
authors.affiliation: Recombinetics, St. Paul, Minnesota, USA.
authors.forename: Tad S
authors.initials: TS
authors.lastname: Sonstegard
authors.affiliation: Davies Research Centre, School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Williams
authors.affiliation: Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA.
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Taylor
authors.affiliation: Informatics Institute, University of Missouri, Columbia, Missouri, USA.|Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA.
authors.forename: Jared E
authors.initials: JE
authors.lastname: Decker
mesh_terms: D000820:Animal Diseases / Q000235:genetics*; D000818:Animals; D002020:Buffaloes / Q000502:physiology*; D002417:Cattle; D004265:DNA Helicases / Q000235:genetics*; D004480:Ectromelia / Q000235:genetics*; D060045:Genes, Modifier / Q000235:genetics; D055106:Genome-Wide Association Study; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide; D051881:Receptor, Notch1 / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000073336:Whole Genome Sequencing; D051153:Wnt Proteins / Q000235:genetics*
chemical_list: D051881:Receptor, Notch1; D018168:Receptors, Retinoic Acid; D051153:Wnt Proteins; C082925:retinoic acid receptor beta; D004265:DNA Helicases