Analysis of canine gene constraint identifies new variants for orofacial clefts and stature
- Reuben M. Buckley1,
- Nüket Bilgen2,
- Alexander C. Harris1,
- Peter Savolainen3,
- Cafer Tepeli4,
- Metin Erdoğan5,
- Aitor Serres Armero1,
- Dayna L. Dreger1,
- Frank G. van Steenbeek6,
- Marjo K. Hytönen7,8,9,
- Heidi G. Parker1,
- Jessica Hale1,
- Hannes Lohi7,8,9,
- Bengi Çınar Kul2,
- Adam R. Boyko10,11 and
- Elaine A. Ostrander1
- 1National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
- 2Department of Animal Genetics, Faculty of Veterinary Medicine, University of Ankara, Ankara 06110, Türkiye;
- 3KTH Royal Institute of Technology, School of Chemistry, Biotechnology and Health, Science for Life Laboratory, SE-100 44 Stockholm, Sweden;
- 4Department of Animal Science, Faculty of Veterinary Medicine, University of Selcuk, Konya 42100, Türkiye;
- 5Department of Veterinary Biology and Genetics, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar 03200, Türkiye;
- 6Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands;
- 7Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland;
- 8Department of Veterinary Biosciences, University of Helsinki, 00014 Helsinki, Finland;
- 9Folkhälsan Research Center, 00290 Helsinki, Finland;
- 10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA;
- 11Embark Veterinary, Inc., Boston, Massachusetts 02210, USA
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 2000 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 is 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 are 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 are not associated with genomic signatures for breed differentiation, as these regions are 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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.280092.124.
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Freely available online through the Genome Research Open Access option.
- Received October 4, 2024.
- Accepted March 10, 2025.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
