Analysis of canine gene constraint identifies new variants for orofacial clefts and stature
- Reuben M. Buckley1,
- Nuket Bilgen2,
- Alexander C. Harris1,
- Peter Savolainen3,
- Cafer Tepeli4,
- Metin Erdoğan5,
- Aitor Serres Armero1,
- Dayna L. Dreger1,
- Frank G. van Steenbeek6,
- Marjo K. Hytönen7,
- Heidi G Parker1,
- Jessica Hale1,
- Hannes Lohi7,
- Bengi Çınar Kul8,
- Adam R. Boyko9 and
- Elaine A. Ostrander1,10
- 1 National Human Genome Research Institute, NIH;
- 2 Ankara University;
- 3 KTH Royal Institute of Technology;
- 4 University of Selcuk;
- 5 Afyon Kocatepe University;
- 6 Utrecht University;
- 7 University of Helsinki, Folkhälsan Research Center;
- 8 University of Ankara;
- 9 Cornell University, Embark Veterinary, Inc.
Abstract
Dog breeding promotes within-group homogeneity through conformation to strict breed standards, while simultaneously driving between-group heterogeneity. There are over 350 recognized dog breeds that provide the foundation for investigating the genetic basis of phenotypic diversity. Typically, breed standard phenotypes such as stature, pelage, and craniofacial structure are analyzed through genetic association studies. However, such analyses are limited to assayed phenotypes only, leaving difficult to measure phenotypic subtleties easily overlooked. We investigated coding variation from over 2,000 dogs, leading to discoveries of variants related to craniofacial morphology and stature. Breed-enriched variants were prioritized according to gene constraint, which was calculated using a mutation model derived from trinucleotide substitution probabilities. Among the newly found variants was a splice-acceptor variant in PDGFRA associated with bifid nose, a characteristic trait of Çatalburun dogs, implicating the gene's role in midline closure. Two additional LCORL variants, both associated with canine body size were also discovered: a frameshift that causes a premature stop in large breeds (>25 kg) and an intronic substitution found in small breeds (<10 kg), thus highlighting the importance of allelic heterogeneity in selection for breed traits. Most variants prioritized in this analysis were not associated with genomic signatures for breed differentiation, as these regions were enriched for constrained genes intolerant to nonsynonymous variation. This indicates trait selection in dogs is likely a balancing act between preserving essential gene functions and maximizing regulatory variation to drive phenotypic extremes.
- Received October 4, 2024.
- Accepted March 10, 2025.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International license), as described at http://creativecommons.org/licenses/by-nc/4.0/.
