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对 100 只狗的全基因组变异进行关联分析,在盘状蛋白 2 中发现一个移码突变,该突变导致了斗牛犬和相关螺旋尾犬种中的罗宾诺综合征。

Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds.

机构信息

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, CA, United States of America.

Department of Clinical Pathology, School of Medicine, University of Mansoura, Mansoura Egypt.

出版信息

PLoS Genet. 2018 Dec 6;14(12):e1007850. doi: 10.1371/journal.pgen.1007850. eCollection 2018 Dec.


DOI:10.1371/journal.pgen.1007850
PMID:30521570
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6303079/
Abstract

Domestic dog breeds exhibit remarkable morphological variations that result from centuries of artificial selection and breeding. Identifying the genetic changes that contribute to these variations could provide critical insights into the molecular basis of tissue and organismal morphogenesis. Bulldogs, French Bulldogs and Boston Terriers share many morphological and disease-predisposition traits, including brachycephalic skull morphology, widely set eyes and short stature. Unlike other brachycephalic dogs, these breeds also exhibit vertebral malformations that result in a truncated, kinked tail (screw tail). Whole genome sequencing of 100 dogs from 21 breeds identified 12.4 million bi-allelic variants that met inclusion criteria. Whole Genome Association of these variants with the breed defining phenotype of screw tail was performed using 10 cases and 84 controls and identified a frameshift mutation in the WNT pathway gene DISHEVELLED 2 (DVL2) (Chr5: 32195043_32195044del, p = 4.37 X 10-37) as the most strongly associated variant in the canine genome. This DVL2 variant was fixed in Bulldogs and French Bulldogs and had a high allele frequency (0.94) in Boston Terriers. The DVL2 variant segregated with thoracic and caudal vertebral column malformations in a recessive manner with incomplete and variable penetrance for thoracic vertebral malformations between different breeds. Importantly, analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations. Analysis of the canine DVL2 variant protein showed that its ability to undergo WNT-induced phosphorylation is reduced, suggesting that altered WNT signaling may contribute to the Robinow-like syndrome in the screwtail breeds.

摘要

家犬品种表现出显著的形态变异,这些变异是数百年人工选择和繁殖的结果。鉴定导致这些变异的遗传变化,可以为组织和器官形态发生的分子基础提供关键见解。斗牛犬、法国斗牛犬和波士顿梗犬具有许多形态和疾病易感性特征,包括短头颅形态、眼睛宽距和矮小身材。与其他短头颅犬不同,这些品种还表现出导致尾巴截断、扭曲的脊柱畸形(螺旋尾)。对 21 个品种的 100 只狗进行全基因组测序,确定了 1240 万个符合纳入标准的双等位基因变异。使用 10 个病例和 84 个对照,对这些变异与螺旋尾的品种定义表型进行全基因组关联分析,鉴定出 WNT 通路基因 DVL2(Chr5:32195043_32195044del,p=4.37X10-37)中的移码突变是犬基因组中关联最强的变异。该 DVL2 变异在斗牛犬和法国斗牛犬中固定,在波士顿梗犬中的等位基因频率较高(0.94)。DVL2 变异以隐性方式与胸腰椎柱畸形分离,不同品种之间胸腰椎畸形的外显率不完全且可变。重要的是,人类 DVL1 和 DVL3 基因中的类似移码突变导致 Robinow 综合征,这是一种先天性疾病,其特征是颅面、肢体和脊柱畸形相似。对犬类 DVL2 变异蛋白的分析表明,其进行 WNT 诱导磷酸化的能力降低,表明改变的 WNT 信号可能导致螺旋尾品种的 Robinow 样综合征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a84/6303079/310b40c685af/pgen.1007850.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a84/6303079/0b328f294574/pgen.1007850.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a84/6303079/4cf30c984149/pgen.1007850.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a84/6303079/63c19e24458a/pgen.1007850.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a84/6303079/310b40c685af/pgen.1007850.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a84/6303079/0b328f294574/pgen.1007850.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a84/6303079/4cf30c984149/pgen.1007850.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a84/6303079/63c19e24458a/pgen.1007850.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a84/6303079/310b40c685af/pgen.1007850.g004.jpg

相似文献

[1]
Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds.

PLoS Genet. 2018-12-6

[2]
Canine DVL2 variant contributes to brachycephalic phenotype and caudal vertebral anomalies.

Hum Genet. 2021-11

[3]
DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome.

Am J Hum Genet. 2016-3-3

[4]
Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.

Am J Med Genet A. 2018-4

[5]
Prevalence and classification of congenital thoracic vertebral body abnormalities in neurologically normal brachycephalic 'screw-tail' dog breeds in referral practice in Australia.

Aust Vet J. 2024-10

[6]
Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome.

Am J Med Genet A. 2021-12

[7]
DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.

Am J Hum Genet. 2015-4-2

[8]
Clinical and molecular characterization of four patients with Robinow syndrome from different families.

Am J Med Genet A. 2021-4

[9]
Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.

Am J Hum Genet. 2015-4-2

[10]
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.

Am J Hum Genet. 2017-12-21

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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Evaluation of the influence of kyphosis and scoliosis on intervertebral disc extrusion in French bulldogs.

BMC Vet Res. 2018-1-5

[2]
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.

Am J Hum Genet. 2017-12-21

[3]
retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs.

Proc Natl Acad Sci U S A. 2017-10-11

[4]
A numerical classification system for cleft lip and palate in the dog.

J Small Anim Pract. 2017-11

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Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates.

Elife. 2017-9-8

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Clin Chim Acta. 2017-8

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Canine Brachycephaly Is Associated with a Retrotransposon-Mediated Missplicing of SMOC2.

Curr Biol. 2017-5-25

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Prevalence of thoracic vertebral malformations in French bulldogs, Pugs and English bulldogs with and without associated neurological deficits.

Vet J. 2017-3

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Genome Biol. 2016-6-6

[10]
Chromosomal Aberrations in Canine Gliomas Define Candidate Genes and Common Pathways in Dogs and Humans.

J Neuropathol Exp Neurol. 2016-7

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