WNT10B: A locus increasing risk of brachygnathia inferior in Brown Swiss cattle

Abstract

Shortening of the mandible (brachygnathia inferior) is a congenital, often inherited and variably expressed craniofacial anomaly in domestic animals including cattle. Brachygnathia inferior can lead to poorer animal health and welfare and reduced growth, which ultimately affects productivity. Within the course of the systematic conformation scoring, cases with a frequency of about 0.1% were observed in the Brown Swiss cattle population of Switzerland. In contrast, this anomaly is almost unknown in the Original Braunvieh population, representing the breed of origin. Because none of the individually examined 46 living offspring of our study cohort of 145 affected cows showed the trait, we can most likely exclude a monogenic-dominant mode of inheritance. We hypothesized that either a monogenic recessive or a complex mode of inheritance was underlying. Through a genome-wide association study of 145 cases and 509 controls with imputed 624k SNP data, we identified a 4.5 Mb genomic region on bovine chromosome 5 significantly associated with this anomaly. This locus was fine-mapped using whole-genome sequencing data. A run of homozygosity analysis revealed a critical interval of 430 kb. A breed specific frameshift duplication in WNT10B (rs525007739; c.910dupC; p.Arg304ProfsTer14) located in this genomic region was found to be associated with a 21.5-fold increased risk of brachygnathia inferior in homozygous carriers. Consequently, we present for the first time a genetic locus associated with this well-known anomaly in cattle, which allows DNA-based selection of Brown Swiss animals at decreased risk for mandibular shortening. In addition, this study represents the first large animal model of a WNT10B-related inherited developmental disorder in a mammalian species.