Identification of a haplotype associated with cholesterol deficiency and increased juvenile mortality in Holstein cattle

Abstract

Over the last decades, several genetic disorders have been discovered in cattle. However, the genetic background of disorders in calves is less reported. Recently, German cattle farmers reported on calves from specific matings with chronic diarrhea and retarded growth of unknown etiology. Affected calves did not respond to any medical treatment and died within the first months of life. These calves were underdeveloped in weight and showed progressive and severe emaciation despite of normal feed intake. Hallmark findings of the blood biochemical analysis were pronounced hypocholesterolemia and deficiency of fat-soluble vitamins. Results of the clinical and blood biochemical examination had striking similarities with findings reported in human hypobetalipoproteinemia. Postmortem examination revealed near-complete atrophy of the body fat reserves including the spinal canal and bone marrow. To identify the causal region, we performed a genome-wide association study with 9 affected and 21,077 control animals genotyped with the Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA), revealing a strong association signal on BTA 11. Subsequent autozygosity mapping identified a disease-associated haplotype encompassing 1.01 Mb. The segment of extended homozygosity contains 6 transcripts, among them the gene APOB, which is causal for cholesterol disorders in humans. However, results from multi-sample variant calling of 1 affected and 47 unaffected animals did not detect any putative causal mutation. The disease-associated haplotype has an important adverse effect on calf mortality in the homozygous state when comparing survival rates of risk matings vs. non-risk matings. Blood cholesterol values of animals are significantly associated with the carrier status indicating a codominant inheritance. The frequency of the haplotype in the current Holstein population was estimated to be 4.2%. This study describes the identification and phenotypic manifestation of a new Holstein haplotype characterized by pronounced hypocholesterolemia, chronic emaciation, growth retardation, and increased mortality in young cattle, denominated as cholesterol deficiency haplotype. Our genomic investigations and phenotypic examinations provide additional evidence for a mutation within the APOB gene causing cholesterol deficiency in Holstein cattle.

APOB‐associated cholesterol deficiency in Holstein cattle is not a simple recessive disease

“…So far, the defect is clinically identifiable only in the homozygote form: Kipp et al . () reported nine cases homozygous for the disease‐associated haplotype, and Duff et al . (), Mock et al .…”

“…Recently, numerous calves showing retarded growth and intermittent diarrhea, accompanied by pronounced hypocholesterolemia and low triglyceride concentrations, were observed in the global Holstein population (Kipp et al . ; Mock et al . ; Schütz et al .…”

“…After a genome‐wide association study uncovering a disease‐associated haplotype on chromosome 11 (Kipp et al . ), a 1.3‐kb insertion of a transposable LTR element in the coding sequence of the bovine APOB gene was identified as a disease‐causing variant (Menzi et al . ).…”

A Review of Selected Genes with Known Effects on Performance and Health of Cattle

“…Calves show severe hypocholesterolemia and die soon after birth due to diarrhea (89). Kipp et al (89) identified a region of chromosome 11 associated with this condition on chromosome 11.…”

“…Calves show severe hypocholesterolemia and die soon after birth due to diarrhea (89). Kipp et al (89) identified a region of chromosome 11 associated with this condition on chromosome 11. The analysis of the pedigree of calves, known to have died from this condition, where traced to a predominant Canadian Holstein bull (Maughlin Storm).…”