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.

中文翻译：

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在两个红安格斯牛犊中发生新生，显性生殖系突变导致成骨不全的证据。

遗传性疾病成骨不全症（OI）的广泛特征是结缔组织异常和骨骼脆性，最常见的原因是I型胶原蛋白的改变。同一父本的两只红色安格斯犊牛表现出严重的骨骼和牙齿脆性，蓝色巩膜，以及子宫内骨折与OI先天性一致的证据。与人类病例的比较分析表明，这些小牛的OI与分类为II型OI的最相似。由于表型的分类和共同的亲子关系，尽管一个隐性基因型由于一头犊牛的父本和母本之间的密切关系而被认为是隐性基因型，但也假定该种为优势种系是致病的。全基因组测序显示I型胶原（COL1A1）的alpha 1链中存在错义突变，对于这两个小牛都是杂合的。该变体导致蛋白质的三重螺旋结构域中的甘氨酸残基被丝氨酸取代。在该区域中，甘氨酸通常占据每三个位置，这对于正确形成I型胶原分子至关重要。通过液滴数字PCR进行的等位基因特异性扩增进一步在其精液中以近4.4％的频率对该变体进行了定量，而该变体在他的血液中不存在，这支持了该父本种系的从头致病性变体的假说是马赛克。鉴定与牲畜中有害表型相关的新变体至关重要，因为种畜的高产有可能迅速传播不良变体。该变体导致蛋白质的三重螺旋结构域中的甘氨酸残基被丝氨酸取代。在该区域中，甘氨酸通常占据每三个位置，这对于正确形成I型胶原分子至关重要。通过液滴数字PCR进行的等位基因特异性扩增进一步在其精液中以近4.4％的频率对该变体进行了定量，而该变体在他的血液中不存在，这支持了该父本种系的从头致病性变体的假说是马赛克。鉴定与牲畜中有害表型相关的新变体至关重要，因为种畜的高产有可能迅速传播不良变体。该变体导致蛋白质的三重螺旋结构域中的甘氨酸残基被丝氨酸取代。在该区域中，甘氨酸通常占据每三个位置，这对于正确形成I型胶原分子至关重要。通过液滴数字PCR进行的等位基因特异性扩增进一步在其精液中以近4.4％的频率对该变体进行了定量，而该变体在他的血液中不存在，这支持了该父本种系的从头致病性变体的假说是马赛克。鉴定与牲畜中有害表型相关的新变体至关重要，因为种畜的高产有可能迅速传播不良变体。甘氨酸通常占据第三个位置，这对于正确形成I型胶原分子至关重要。通过液滴数字PCR进行的等位基因特异性扩增进一步在其精液中以近4.4％的频率对该变体进行了定量，而该变体在他的血液中不存在，这支持了该父本种系的从头致病性变体的假说是马赛克。鉴定与牲畜中有害表型相关的新变体至关重要，因为种畜的高产有可能迅速传播不良变体。甘氨酸通常占据第三个位置，这对于正确形成I型胶原分子至关重要。通过液滴数字PCR进行的等位基因特异性扩增进一步在其精液中以近4.4％的频率对该变体进行了定量，而该变体在他的血液中不存在，这支持了该父本种系的从头致病性变体的假说是马赛克。鉴定与牲畜中有害表型相关的新变体至关重要，因为种畜的高产有可能迅速传播不良变体。支持从头致病变体假说，其父本种系为镶嵌。鉴定与牲畜中有害表型相关的新变体至关重要，因为种畜的高产有可能迅速传播不良变体。支持从头致病变体假说，其父本种系为镶嵌。鉴定与牲畜中有害表型相关的新变体至关重要，因为种畜的高产有可能迅速传播不良变体。