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

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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.

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Data availability

Whole-genome sequence files are available at the NCBI Sequence Read Archive (SRA accession: PRJNA513064). Novel variants identified are annotated and available as project PRJEB31123, analyses ERZ805155, at the European Variation Archive (EVA).

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Acknowledgements

This work was supported by the Red Angus Association of America.

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Authors and Affiliations

  1. Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE, 68583-0908, USA

    Jessica L. Petersen, Shauna M. Tietze & Rachel M. Burrack

  2. School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583-0905, USA

    David J. Steffen

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  1. Jessica L. Petersen
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  2. Shauna M. Tietze
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  3. Rachel M. Burrack
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  4. David J. Steffen
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Correspondence to Jessica L. Petersen.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Nebraska-Lincoln.

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Accession IDs: Bos taurus—NCBI:txid9913; COL1A1—GeneID: 282187.

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Petersen, J.L., Tietze, S.M., Burrack, R.M. et al. Evidence for a de novo, dominant germ-line mutation causative of osteogenesis imperfecta in two Red Angus calves. Mamm Genome 30, 81–87 (2019). https://doi.org/10.1007/s00335-019-09794-4

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  • DOI: https://doi.org/10.1007/s00335-019-09794-4

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