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Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds.
PLoS Genet. 2018 12; 14(12):e1007850.PG

Abstract

Domestic dog breeds exhibit remarkable morphological variations that result from centuries of artificial selection and breeding. Identifying the genetic changes that contribute to these variations could provide critical insights into the molecular basis of tissue and organismal morphogenesis. Bulldogs, French Bulldogs and Boston Terriers share many morphological and disease-predisposition traits, including brachycephalic skull morphology, widely set eyes and short stature. Unlike other brachycephalic dogs, these breeds also exhibit vertebral malformations that result in a truncated, kinked tail (screw tail). Whole genome sequencing of 100 dogs from 21 breeds identified 12.4 million bi-allelic variants that met inclusion criteria. Whole Genome Association of these variants with the breed defining phenotype of screw tail was performed using 10 cases and 84 controls and identified a frameshift mutation in the WNT pathway gene DISHEVELLED 2 (DVL2) (Chr5: 32195043_32195044del, p = 4.37 X 10-37) as the most strongly associated variant in the canine genome. This DVL2 variant was fixed in Bulldogs and French Bulldogs and had a high allele frequency (0.94) in Boston Terriers. The DVL2 variant segregated with thoracic and caudal vertebral column malformations in a recessive manner with incomplete and variable penetrance for thoracic vertebral malformations between different breeds. Importantly, analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations. Analysis of the canine DVL2 variant protein showed that its ability to undergo WNT-induced phosphorylation is reduced, suggesting that altered WNT signaling may contribute to the Robinow-like syndrome in the screwtail breeds.

Authors+Show Affiliations

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America. Department of Clinical Pathology, School of Medicine, University of Mansoura, Mansoura Egypt.Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America. Integrative Genetics and Genomics Graduate Group, University of California Davis, Davis, CA, United States of America.Department of Cell Biology and Human Anatomy, School of Medicine, University of California Davis, Davis, CA, United States of America.Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.Department of Cell Biology and Human Anatomy, School of Medicine, University of California Davis, Davis, CA, United States of America.Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.Department of Cell Biology and Human Anatomy, School of Medicine, University of California Davis, Davis, CA, United States of America.Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America. Genome Center, University of California Davis, Davis, CA, United States of America.Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America. Genome Center, University of California Davis, Davis, CA, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30521570

Citation

Mansour, Tamer A., et al. "Whole Genome Variant Association Across 100 Dogs Identifies a Frame Shift Mutation in DISHEVELLED 2 Which Contributes to Robinow-like Syndrome in Bulldogs and Related Screw Tail Dog Breeds." PLoS Genetics, vol. 14, no. 12, 2018, pp. e1007850.
Mansour TA, Lucot K, Konopelski SE, et al. Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds. PLoS Genet. 2018;14(12):e1007850.
Mansour, T. A., Lucot, K., Konopelski, S. E., Dickinson, P. J., Sturges, B. K., Vernau, K. L., Choi, S., Stern, J. A., Thomasy, S. M., Döring, S., Verstraete, F. J. M., Johnson, E. G., York, D., Rebhun, R. B., Ho, H. H., Brown, C. T., & Bannasch, D. L. (2018). Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds. PLoS Genetics, 14(12), e1007850. https://doi.org/10.1371/journal.pgen.1007850
Mansour TA, et al. Whole Genome Variant Association Across 100 Dogs Identifies a Frame Shift Mutation in DISHEVELLED 2 Which Contributes to Robinow-like Syndrome in Bulldogs and Related Screw Tail Dog Breeds. PLoS Genet. 2018;14(12):e1007850. PubMed PMID: 30521570.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds. AU - Mansour,Tamer A, AU - Lucot,Katherine, AU - Konopelski,Sara E, AU - Dickinson,Peter J, AU - Sturges,Beverly K, AU - Vernau,Karen L, AU - Choi,Shannon, AU - Stern,Joshua A, AU - Thomasy,Sara M, AU - Döring,Sophie, AU - Verstraete,Frank J M, AU - Johnson,Eric G, AU - York,Daniel, AU - Rebhun,Robert B, AU - Ho,Hsin-Yi Henry, AU - Brown,C Titus, AU - Bannasch,Danika L, Y1 - 2018/12/06/ PY - 2018/06/21/received PY - 2018/11/24/accepted PY - 2018/12/21/revised PY - 2018/12/7/pubmed PY - 2019/3/5/medline PY - 2018/12/7/entrez SP - e1007850 EP - e1007850 JF - PLoS genetics JO - PLoS Genet VL - 14 IS - 12 N2 - Domestic dog breeds exhibit remarkable morphological variations that result from centuries of artificial selection and breeding. Identifying the genetic changes that contribute to these variations could provide critical insights into the molecular basis of tissue and organismal morphogenesis. Bulldogs, French Bulldogs and Boston Terriers share many morphological and disease-predisposition traits, including brachycephalic skull morphology, widely set eyes and short stature. Unlike other brachycephalic dogs, these breeds also exhibit vertebral malformations that result in a truncated, kinked tail (screw tail). Whole genome sequencing of 100 dogs from 21 breeds identified 12.4 million bi-allelic variants that met inclusion criteria. Whole Genome Association of these variants with the breed defining phenotype of screw tail was performed using 10 cases and 84 controls and identified a frameshift mutation in the WNT pathway gene DISHEVELLED 2 (DVL2) (Chr5: 32195043_32195044del, p = 4.37 X 10-37) as the most strongly associated variant in the canine genome. This DVL2 variant was fixed in Bulldogs and French Bulldogs and had a high allele frequency (0.94) in Boston Terriers. The DVL2 variant segregated with thoracic and caudal vertebral column malformations in a recessive manner with incomplete and variable penetrance for thoracic vertebral malformations between different breeds. Importantly, analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations. Analysis of the canine DVL2 variant protein showed that its ability to undergo WNT-induced phosphorylation is reduced, suggesting that altered WNT signaling may contribute to the Robinow-like syndrome in the screwtail breeds. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/30521570/Whole_genome_variant_association_across_100_dogs_identifies_a_frame_shift_mutation_in_DISHEVELLED_2_which_contributes_to_Robinow_like_syndrome_in_Bulldogs_and_related_screw_tail_dog_breeds_ L2 - https://dx.plos.org/10.1371/journal.pgen.1007850 DB - PRIME DP - Unbound Medicine ER -