A nonsense mutation in the COL7A1 gene causes epidermolysis bullosa in Vorderwald cattle

BACKGROUND: The widespread use of individual sires for artificial insemination promotes the propagation of recessive conditions. Inadvertent matings between unnoticed carriers of deleterious alleles may result in the manifestation of fatal phenotypes in their progeny. Breeding consultants and farmers reported on Vorderwald calves with a congenital skin disease. The clinical findings in affected calves were compatible with epidermolysis bullosa. RESULTS: Pedigree analysis indicated autosomal recessive inheritance of epidermolysis bullosa in Vorderwald cattle. We genotyped two diseased and 41 healthy animals at 41,436 single nucleotide polymorphisms and performed whole-genome haplotype-based association testing, which allowed us to map the locus responsible for the skin disease to the distal end of bovine chromosome 22 (P = 8.0 × 10-14). The analysis of whole-genome re-sequencing data of one diseased calf, three obligate mutation carriers and 1682 healthy animals from various bovine breeds revealed a nonsense mutation (rs876174537, p.Arg1588X) in the COL7A1 gene that segregates with the disease. The same mutation was previously detected in three calves with dystrophic epidermolysis bullosa from the Rotes Höhenvieh cattle breed. We show that diseased animals from Vorderwald and Rotes Höhenvieh cattle are identical by descent for an 8.72 Mb haplotype encompassing rs876174537 indicating they inherited the deleterious allele from a recent common ancestor. CONCLUSIONS: Autosomal recessive epidermolysis bullosa in Vorderwald and Rotes Höhenvieh cattle is caused by a nonsense mutation in the COL7A1 gene. Our findings demonstrate that deleterious alleles may segregate across cattle populations without apparent admixture. The identification of the causal mutation now enables the reliable detection of carrier animals. Genome-based mating strategies can avoid inadvertent matings of carrier animals thereby preventing the birth of homozygous calves that suffer from a painful skin disease

Additional file 1: of A nonsense mutation in the COL7A1 gene causes epidermolysis bullosa in Vorderwald cattle

Annotation of variants compatible with recessive inheritance. Description: The functional consequences of 702 sequence variants compatible with recessive inheritance of epidermolysis bullosa were obtained from Ensembl using the Variant Effect Predictor tool. (TXT 383 kb

Additional file 2: of A nonsense mutation in the COL7A1 gene causes epidermolysis bullosa in Vorderwald cattle

R script that implements the haplotype-based GWAS to map epidermolysis bullosa. Description: R script that reads haplotypes, SNP-positions, eigenvectors and phenotypes to perform a haplotype-based association study. A small dataset to perform the association study between epidermolysis bullosa in 43 VWD animals and haplotypes on chromosome 22 is provided in the Additional files 3, 4, 5 and 6. The script was tested in an unix environment. (TXT 4 kb

Additional file 5: of A nonsense mutation in the COL7A1 gene causes epidermolysis bullosa in Vorderwald cattle

Positions of 1009 SNPs on bovine chromosome 22. Description: The SNPs are ordered according to their chromosomal position and correspond to the haplotype phases in Additional file 4. (TXT 32 kb

Rapid Discovery of De Novo Deleterious Mutations in Cattle Enhances the Value of Livestock as Model Species

In humans, the clinical and molecular characterization of sporadic syndromes is often hindered by the small number of patients and the difficulty in developing animal models for severe dominant conditions. Here we show that the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock. We report on the identification of seven dominant de novo mutations in CHD7, COL1A1, COL2A1, COPA, and MITF and exploit the structure of cattle populations to describe their clinical consequences and map modifier loci. Moreover, we demonstrate that the emergence of recessive genetic defects can be monitored by detecting de novo deleterious mutations in the genome of bulls used for artificial insemination. These results demonstrate the attractiveness of cattle as a model species in the post genomic era, particularly to confirm the genetic aetiology of isolated clinical case reports in humans.ISSN:2045-232