Confirmation of a non-synonymous SNP in PNPLA8 as a candidate causal mutation for Weaver syndrome in Brown Swiss cattle.
Confirmation of a non-synonymous SNP in PNPLA8 as a candidate causal mutation for Weaver syndrome in Brown Swiss cattle.
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DOI：
10.1186/s12711-016-0201-5
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发表时间：
2016-03-18
期刊：
影响因子：
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通讯作者：
Medugorac I
中科院分区：
文献类型：
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作者：
Kunz E;Rothammer S;Pausch H;Schwarzenbacher H;Seefried FR;Matiasek K;Seichter D;Russ I;Fries R;Medugorac I
牛进行性退行性脊髓脑病(Weaver综合征)是一种棕色瑞士牛的神经退行性疾病，其特征是进行性后腿无力和共济失调，而感觉和脊髓反射仍未受到影响。虽然原因突变尚未确定，但基于6个微卫星标记的间接基因测试以及随后将Weaver携带者排除在育种之外，导致20多年来完全没有新病例。2013年发表的41个诊断性单核苷酸多态(SNPs)和一个常见的单倍型对疾病状况进行了评估，在当前的育种人群中发现了几个疑似携带者，这表明Weaver等位基因的频率高于预期。为了防止疾病的再次出现，这项研究旨在绘制韦弗综合征背后的基因图谱，从而为直接进行基因测试和监测今天的布劳恩维/布朗瑞士牛群提供基础。对43头牛、31头织纹虫携带者和86头非织纹虫牛的Illumina牛SNP50基因进行了4号染色体的连锁/连锁不平衡定位，在49,812,384个碱基上得到最大似然比检验统计值。通过2-LOD丢弃方法确定的可信区间(0.853 Mb)包含在扩展纯合性的1.72Mb片段内。对两个正式的Weaver携带者和1145头其他公牛的全基因组序列数据的利用表明，在1000头公牛基因组计划的Run4中，只有位于PNPLA8基因49,878,773位的非同义SNP(Rs800397662)与Weaver携带者的状态一致。靶向SNP基因分型证实该SNP是Weaver综合征的候选原因突变。对2334只当前Braunvieh动物的随机样本进行候选因果突变的基因检测表明，Weaver等位基因的频率为0.26%。通过结合使用详尽的测序数据和SNP基因分型结果，我们能够提供证据，支持49,878,773位碱基的非同义突变是Weaver综合征最可能的原因突变。需要进一步的研究来揭示这种综合征背后的确切机制。本文的在线版本(doi：10.1186/s12711-0160201-5)包含补充材料，授权用户可以使用。
Bovine progressive degenerative myeloencephalopathy (Weaver syndrome) is a neurodegenerative disorder in Brown Swiss cattle that is characterized by progressive hind leg weakness and ataxia, while sensorium and spinal reflexes remain unaffected. Although the causal mutation has not been identified yet, an indirect genetic test based on six microsatellite markers and consequent exclusion of Weaver carriers from breeding have led to the complete absence of new cases for over two decades. Evaluation of disease status by imputation of 41 diagnostic single nucleotide polymorphisms (SNPs) and a common haplotype published in 2013 identified several suspected carriers in the current breeding population, which suggests a higher frequency of the Weaver allele than anticipated. In order to prevent the reemergence of the disease, this study aimed at mapping the gene that underlies Weaver syndrome and thus at providing the basis for direct genetic testing and monitoring of today’s Braunvieh/Brown Swiss herds. Combined linkage/linkage disequilibrium mapping on Bos taurus chromosome (BTA) 4 based on Illumina Bovine SNP50 genotypes of 43 Weaver-affected, 31 Weaver carrier and 86 Weaver-free animals resulted in a maximum likelihood ratio test statistic value at position 49,812,384 bp. The confidence interval (0.853 Mb) determined by the 2-LOD drop-off method was contained within a 1.72-Mb segment of extended homozygosity. Exploitation of whole-genome sequence data from two official Weaver carriers and 1145 other bulls that were sequenced in Run4 of the 1000 bull genomes project showed that only a non-synonymous SNP (rs800397662) within the PNPLA8 gene at position 49,878,773 bp was concordant with the Weaver carrier status. Targeted SNP genotyping confirmed this SNP as a candidate causal mutation for Weaver syndrome. Genotyping for the candidate causal mutation in a random sample of 2334 current Braunvieh animals suggested a frequency of the Weaver allele of 0.26 %. Through combined use of exhaustive sequencing data and SNP genotyping results, we were able to provide evidence that supports the non-synonymous mutation at position 49,878,773 bp as the most likely causal mutation for Weaver syndrome. Further studies are needed to uncover the exact mechanisms that underlie this syndrome. The online version of this article (doi:10.1186/s12711-016-0201-5) contains supplementary material, which is available to authorized users.