Evidence for a de novo, dominant germ-line mutation causative of osteogenesis imperfecta in two Red Angus calves

Jessica L. Petersen, Shauna M. Tietze, Rachel M. Burrack, David J. Steffen

Research output: Contribution to journalArticle

Abstract

A genetic disorder, osteogenesis imperfecta (OI) is broadly characterized by connective tissue abnormalities and bone fragility most commonly attributed to alterations in Type I collagen. Two Red Angus calves by the same sire presented with severe bone and dental fragility, blue sclera, and evidence of in utero fractures consistent with OI congenita. Comparative analyses with human cases suggested the OI in these calves most closely resembled that classified as OI Type II. Due to the phenotypic classification and shared paternity, a dominant, germ-line variant was hypothesized as causative although recessive genotypes were also considered due to a close relationship between the sire and dam of one calf. Whole-genome sequencing revealed the presence of a missense mutation in the alpha 1 chain of collagen Type I (COL1A1), for which both calves were heterozygous. The variant resulted in the substitution of a glycine residue with serine in the triple helical domain of the protein; in this region, glycine normally occupies every third position as is critical for correct formation of the Type I collagen molecule. Allele-specific amplification by droplet digital PCR further quantified the variant at a frequency of nearly 4.4% in the semen of the sire while it was absent in his blood, supporting the hypothesis of a de novo causative variant for which the germ line of the sire was mosaic. The identification of novel variants associated with unwanted phenotypes in livestock is critical as the high prolificacy of breeding stock has the potential to rapidly disseminate undesirable variation.

Original languageEnglish (US)
Pages (from-to)81-87
Number of pages7
JournalMammalian Genome
Volume30
Issue number3-4
DOIs
StatePublished - Apr 1 2019

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Osteogenesis Imperfecta
Germ-Line Mutation
Collagen Type I
Germ Cells
Glycine
Bone and Bones
Paternity
Inborn Genetic Diseases
Sclera
Livestock
Missense Mutation
Semen
Connective Tissue
Serine
Breeding
Tooth
Alleles
Genotype
Genome
Phenotype

ASJC Scopus subject areas

  • Genetics

Cite this

Evidence for a de novo, dominant germ-line mutation causative of osteogenesis imperfecta in two Red Angus calves. / Petersen, Jessica L.; Tietze, Shauna M.; Burrack, Rachel M.; Steffen, David J.

In: Mammalian Genome, Vol. 30, No. 3-4, 01.04.2019, p. 81-87.

Research output: Contribution to journalArticle

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