Congenital syndromic Chiari-like malformation (CSCM) in Holstein cattle: towards unravelling of possible genetic causes.

IF 1.9 2区 农林科学 Q2 VETERINARY SCIENCES
Joana Goncalves Pontes Jacinto, Anna Letko, Irene Monika Häfliger, Cord Drögemüller, Jørgen Steen Agerholm
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引用次数: 0

Abstract

Background: Chiari malformation type II (CMII) was originally reported in humans as a rare disorder characterized by the downward herniation of the hindbrain and towering cerebellum. The congenital brain malformation is usually accompanied by spina bifida, a congenital spinal anomaly resulting from incomplete closure of the dorsal aspect of the spinal neural tube, and occasionally by other lesions. A similar disorder has been reported in several animal species, including cattle, particularly as a congenital syndrome. A cause of congenital syndromic Chiari-like malformation (CSCM) in cattle has not been reported to date. We collected a series of 14 CSCM-affected Holstein calves (13 purebred, one Red Danish Dairy F1 cross) and performed whole-genome sequencing (WGS). WGS was performed on 33 cattle, including eight cases with parents (trio-based; group 1), three cases with one parent (group 2), and three single cases (solo-based; group 3).

Results: Sequencing-based genome-wide association study of the 13 Holstein calves with CSCM and 166 controls revealed no significantly associated genome region. Assuming a single Holstein breed-specific recessive allele, no region of shared homozygosity was detected suggesting heterogeneity. Subsequent filtering for protein-changing variants that were only homozygous in the genomes of the individual cases allowed the identification of two missense variants affecting different genes, SHC4 in case 4 in group 1 and WDR45B in case 13 in group 3. Furthermore, these two variants were only observed in Holstein cattle when querying WGS data of > 5,100 animals. Alternatively, potential de novo mutational events were assessed in each case. Filtering for heterozygous private protein-changing variants identified one DYNC1H1 frameshift variant as a candidate causal dominant acting allele in case 12 in group 3. Finally, the presence of larger structural DNA variants and chromosomal abnormalities was investigated in all cases. Depth of coverage analysis revealed two different partial monosomies of chromosome 2 segments in cases 1 and 7 in group 1 and a trisomy of chromosome 12 in the WDR45B homozygous case 13 in group 3.

Conclusions: This study presents for the first time a detailed genomic evaluation of CSCM in Holstein cattle and suggests an unexpected genetic and allelic heterogeneity considering the mode of inheritance, as well as the type of variant. For the first time, we propose candidate causal variants that may explain bovine CSCM in a certain proportion of affected calves. We present cattle as a large animal model for human CMII and propose new genes and genomic variants as possible causes for related diseases in both animals and humans.

荷斯坦牛先天性综合症恰里样畸形 (CSCM):揭示可能的遗传原因。
背景:奇拉氏畸形 II 型(Chiari malformation II,CMII)最初是一种罕见的人类疾病,其特征是后脑向下疝出和小脑高耸。这种先天性脑畸形通常伴有脊柱裂,脊柱裂是一种先天性脊柱畸形,由脊神经管背侧未完全闭合所致,偶尔也会伴有其他病变。据报道,包括牛在内的几种动物也患有类似的疾病,尤其是先天性综合征。迄今为止,还没有关于牛先天性综合征恰里样畸形(CSCM)病因的报道。我们收集了 14 头受 CSCM 影响的荷斯坦牛犊(13 头纯种,1 头红色丹麦奶牛 F1 杂交),并进行了全基因组测序(WGS)。对 33 头牛进行了全基因组测序,其中包括 8 头有父母的病例(三人组;第 1 组)、3 头有单亲的病例(第 2 组)和 3 头单亲的病例(单人组;第 3 组):结果:对 13 头患有CSCM的荷斯坦牛犊和 166 头对照组牛犊进行的基于测序的全基因组关联研究发现,没有明显相关的基因组区域。假设存在一个荷斯坦品种特异性隐性等位基因,但未检测到共享同源性区域,这表明存在异质性。随后对单个病例基因组中仅存在的改变蛋白质的变体进行筛选,发现了两个影响不同基因的错义变体,即第 1 组第 4 例中的 SHC4 和第 3 组第 13 例中的 WDR45B。此外,在查询超过 5100 头牲畜的 WGS 数据时,仅在荷斯坦牛中观察到这两种变异。此外,还对每个病例中潜在的从头突变事件进行了评估。通过筛选杂合的改变蛋白质的私有变异体,在第 3 组的病例 12 中发现了一个 DYNC1H1 框移变异体,它是一个候选的致病显性等位基因。最后,对所有病例中是否存在较大的 DNA 结构变异和染色体异常进行了调查。覆盖深度分析显示,第 1 组病例 1 和 7 中的 2 号染色体有两个不同的部分单体,而第 3 组病例 13 中的 WDR45B 同源染色体则有 12 号染色体三体:本研究首次对荷斯坦牛 CSCM 进行了详细的基因组学评估,并考虑到遗传方式和变异类型,提出了意想不到的遗传和等位基因异质性。我们首次提出了候选因果变异,这些变异可能解释了一定比例的牛CSCM。我们将牛作为人类 CMII 的大型动物模型,并提出了可能导致动物和人类相关疾病的新基因和基因组变异。
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来源期刊
Acta Veterinaria Scandinavica
Acta Veterinaria Scandinavica 农林科学-兽医学
CiteScore
3.60
自引率
0.00%
发文量
28
审稿时长
18-36 weeks
期刊介绍: Acta Veterinaria Scandinavica is an open access journal encompassing all aspects of veterinary research and medicine of domestic and wild animals.
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