Identification of a nonsense mutation in CWC15 associated with decreased reproductive efficiency in Jersey cattle.
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 whole genome 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 SNP analysis of whole-genome sequences aligned to the JH1 interval and subsequent SNP validation a nonsense mutation in CWC15 was identified as the likely causative mutation underlying the fertility phenotype. No homozygous recessive individuals were found in 749 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. These results also show that carrier status can be imputed with high accuracy. 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.
Bovine Functional Genomics, United States Department of Agriculture, Agricultural Research Service, Beltsville, Maryland, USA.
Tad S
TS
Sonstegard
John B
JB
Cole
Paul M
PM
VanRaden
Curtis P
CP
Van Tassell
Daniel J
DJ
Null
Steven G
SG
Schroeder
Derek
D
Bickhart
Matthew C
MC
McClure
D000818:Animals; D001947:Breeding; D002417:Cattle; D002874:Chromosome Mapping; D018389:Codon, Nonsense / Q000235:genetics*; D005260:Female; D005298:Fertility / Q000235:genetics* / Q000502:physiology; D005804:Genes, Lethal / Q000235:genetics*; D016678:Genome; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*
D018389:Codon, Nonsense; D011506:Proteins