Identification of a nonsense mutation in CWC15 associated with decreased reproductive efficiency in Jersey cattle

Authors: Sonstegard, Tad; Cole, John; Vanraden, Paul; Van Tassell, Curtis - Curt; Null, Daniel; Schroeder, Steven - Steve; Bickhart, Derek; McClure, Matthew

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/17/2012
Publication Date: 1/22/2013
Citation: Sonstegard, T.S., Cole, J.B., Van Raden, P.M., Van Tassell, C.P., Null, D.J., Schroeder, S.G., Bickhart, D.M., Mcclure, M.C. 2013. Identification of a nonsense mutation in CWC15 associated with decreased reproductive efficiency in Jersey cattle. PLoS One. 8(1):e54872.

Interpretive Summary: Several recessive conditions affecting fertility in dairy cattle have recently been identified using genomic tools. The location of a newly discovered recessive haplotype affecting fertility in Jersey cattle, and the causative mutation, have been identified using crossover analysis and targeted resequencing. In targeted resequencing, homozygous animals are selected for full genome sequencing based on such factors as their relationship to the breed and the frequency of their haplotypes in the population. The causative mutation is associated with the JH1 haplotype, and results in increased rates of embryonic death, and affects a protein (CWC15) that is involved in gene transcription. No homozygous recessive individuals were found in a group of 753 animals genotyped using a custom-designed assay in a validation step. However, all known carriers and carrier haplotypes possessed one copy of the mutant allele. The mutation originated in a very influential Jersey bull born in 1962 who fathered many sons used in artificial insemination programs, and this lethal has resulted in many spontaneous abortions in Jersey cattle over the past 50 years. With the mutation identified, selection against the deleterious allele in breeding schemes will aid in reducing the incidence of this defect in the population. These results suggest that whole-genome resequencing is a powerful strategy for rapidly identifying causal variants associated with undesirable haplotypes.

Technical Abstract: With the recent advent of genomic tools for cattle, several recessive conditions affecting fertility have been identified and selected against, such as deficiency of uridine monophosphate synthase, complex vertebral malformation, and brachyspina. The current report refines the location of a recessive haplotype affecting fertility in Jersey cattle using crossover haplotypes, discovers the causative mutation using targeted sequencing, and examines the gene’s role in embryo loss. In an attempt to identify unknown recessive lethal alleles in the current dairy population, a search using deep Mendelian sampling of 5,288 Jersey cattle was conducted for high-frequency haplotypes that have a deficit of homozygotes at the population level. This search led to the discovery of a putative recessive lethal in Jersey cattle on Bos taurus autosome 15. The haplotype, denoted JH1, was associated with reduced fertility, and further investigation identified one highly-influential Jersey bull as the putative source ancestor. By combining whole-genome resequencing, high-density genotyping and haplotyping techniques, a nonsense mutation in CWC15 was identified. No homozygous recessive individuals were found in 753 genotyped animals, whereas all known carriers and carrier haplotypes possessed one copy of the mutant allele. This newly identified lethal has been responsible for a substantial number of spontaneous abortions in Jersey dairy cattle throughout the past half-century. With the mutation identified, selection against the deleterious allele in breeding schemes will aid in reducing the incidence of this defect in the population. Whole-genome resequencing proved to be a powerful strategy to rapidly identify a previously mapped deleterious mutation in a known carrier of a recessive lethal allele.