A missense mutation in TUBD1 is associated with high juvenile mortality in Braunvieh and Fleckvieh cattle

Background Haplotypes with reduced or missing homozygosity may harbor deleterious alleles that compromise juvenile survival. A scan for homozygous haplotype deficiency revealed a short segment on bovine chromosome 19 (Braunvieh haplotype 2, BH2) that was associated with high juvenile mortality in Braunvieh cattle. However, the genetic underpinnings and pathophysiology of BH2 have yet to be elucidated. Results The frequency of BH2 was 6.5 % in 8,446 Braunvieh animals from the national bovine genome database. Both perinatal and juvenile mortality of BH2 homozygous calves were higher than average values in Braunvieh cattle resulting in a depletion of BH2 homozygous adult animals (P=9.3x10-12). The analysis of whole-genome sequence data from 54 Braunvieh animals uncovered a missense mutation in TUBD1 (rs383232842, p.H210R) that was compatible with recessive inheritance of BH2. Exploiting sequence data from 236 animals from diverse bovine populations revealed that the candidate causal mutation also segregated at a low frequency (1.7 %) in the Fleckvieh breed. A validation study in 37,314 Fleckvieh animals confirmed the high juvenile mortality of homozygous calves (P=2.2x10-15). We demonstrate that rs383232842 is located on an ancestral haplotype that segregates in both Braunvieh and Fleckvieh cattle. To unravel the pathophysiology of BH2, six homozygous animals were examined at the animal clinic. Clinical and pathological findings revealed that homozygous calves suffered from chronic airway disease possibly because of defective cilia in the respiratory tract. Conclusions A missense mutation in TUBD1 was associated with high perinatal and juvenile mortality in Braunvieh and Fleckvieh cattle. Although we found no evidence for an admixture of both breeds, the mutation was located on a common haplotype indicating it originated from an ancient ancestor of Braunvieh and Fleckvieh cattle. Such findings demonstrate for the first time that deleterious alleles may segregate across apparently unrelated cattle breeds. Homozygous calves suffered from chronic airway disease resulting in poor growth performance and high juvenile mortality. The respiratory manifestations resembled key features of diseases resulting from impaired function of airway cilia.