Genomic dissection of hoof and leg conformation in Swiss dairy cattle populations reveals polygenic architecture and a recessive HYAL1 nonsense variant affecting longevity in Holstein cattle.

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Background The genetic architecture of bovine hoof and leg conformation traits remains incompletely understood, particularly in dairy cattle and with respect to non-additive effects. Moreover, the limited genetic resolution of previous studies hampered the identification of candidate variants. This study aimed to investigate traits in Swiss Holstein (HO) and Brown Swiss (BS), comprising bone structure, heel depth, foot angle, locomotion, rear leg rear view, and rear leg set in HO, and heel depth, foot angle, hock quality, and rear leg side view in BS, by (1) estimating trait heritabilities, (2) identifying QTL using additive and non-additive GWAS based on imputed whole-genome sequence (WGS) variants, (3) detecting candidate genes and variants using Bayesian fine-mapping, (4) assessing the effects of the recessive HYAL1 on conformation, longevity, and production traits in French HO, and (5) clinically characterizing HYAL1-homozygous HO.Results Heritability estimates ranged from 0.10 to 0.28 in HO and from 0.10 to 0.26 in BS. Additive and non-additive GWAS detected 25 significant associated regions (P ≤ 5 × 10-8) for bone structure and locomotion in HO and for heel depth and hock quality in BS. Conditional analyses reduced these to 15 unique QTL and Bayesian fine-mapping prioritised 17 candidate variants (3 in HO, 14 in BS), including 15 additive, one dominant, and one recessive effect. A nonsense variant in HYAL1 (NP_001017941.1:p.(Gln93*)) showed a significant recessive effect on bone structure in HO (P = 1.62 × 10-17). The harmful allele was observed predominantly in HO at 4.4% in Swiss and 8.4% in French HO. Analyses in the French population further showed adverse effects on six-year survival, indicating early culling after the first lactation, and 14 routinely recorded conformation and production traits, most notably locomotion and rear leg rear view. Clinical examination of HYAL1-homozygotes revealed polysynovitis.Conclusions This study indicates a predominantly polygenic architecture of hoof and leg conformation traits in HO and BS cattle and show that integrating imputed WGS data with non-additive analyses of proxy phenotypes improves the detection and refinement of QTL and candidate variants. In particular, the identification of a recessive HYAL1 nonsense variant associated with bone structure in HO uncovered a hidden Mendelian disorder.

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