Identification of a haplotype associated with cholesterol deficiency and increased juvenile mortality in Holstein cattle.
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.
Vereinigte Informationssysteme Tierhaltung w.V. (vit), 27283 Verden, Germany. Electronic address: sandra.kipp@vit.de.
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Kipp
Vereinigte Informationssysteme Tierhaltung w.V. (vit), 27283 Verden, Germany.
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Segelke
Vereinigte Informationssysteme Tierhaltung w.V. (vit), 27283 Verden, Germany.
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Schierenbeck
Vereinigte Informationssysteme Tierhaltung w.V. (vit), 27283 Verden, Germany.
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Reinhardt
Vereinigte Informationssysteme Tierhaltung w.V. (vit), 27283 Verden, Germany.
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Reents
Chair of Animal Breeding, Technische Universitaet Muenchen, 85354 Freising, Germany.
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Wurmser
Chair of Animal Breeding, Technische Universitaet Muenchen, 85354 Freising, Germany.
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Pausch
Chair of Animal Breeding, Technische Universitaet Muenchen, 85354 Freising, Germany.
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Fries
Chair of Animal Breeding, Christian-Albrechts-Universitaet zu Kiel, 24098 Kiel, Germany.
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Thaller
Chair of Animal Breeding, Christian-Albrechts-Universitaet zu Kiel, 24098 Kiel, Germany.
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J
Tetens
Masterrind GmbH, 27283 Verden, Germany.
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J
Pott
University Children's Hospital Heidelberg, Division of Neuropediatrics and Metabolic Diseases, Im Neuenheimer Feld 699, 69120 Heidelberg, Germany.
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Haas
Department of Pathology, University of Veterinary Medicine, Hannover, Foundation, Bünteweg 17, 30559 Hanover, Germany.
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Raddatz
Department of Pathology, University of Veterinary Medicine, Hannover, Foundation, Bünteweg 17, 30559 Hanover, Germany.
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Hewicker-Trautwein
Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hanover, Germany.
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Proios
Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hanover, Germany.
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Schmicke
Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, Bischofsholer Damm 15, 30173 Hanover, Germany.
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Grünberg
D000293:Adolescent; D000818:Animals; D002417:Cattle; D002784:Cholesterol / Q000172:deficiency*; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans
D002784:Cholesterol
calf survival; cholesterol deficiency; haplotype; hypobetalipoproteinemia