Informatics Institute, University of Missouri, Columbia, Missouri, USA.
Division of Animal Sciences, University of Missouri, Columbia, Missouri, USA.
Sci Rep. 2017 Jan 3;7:39719. doi: 10.1038/srep39719.
Recent strong selection for dairy traits in water buffalo has been associated with higher levels of inbreeding, leading to an increase in the prevalence of genetic diseases such as transverse hemimelia (TH), a congenital developmental abnormality characterized by absence of a variable distal portion of the hindlimbs. Limited genomic resources available for water buffalo required an original approach to identify genetic variants associated with the disease. The genomes of 4 bilateral and 7 unilateral affected cases and 14 controls were sequenced. A concordance analysis of SNPs and INDELs requiring homozygosity unique to all unilateral and bilateral cases revealed two genes, WNT7A and SMARCA4, known to play a role in embryonic hindlimb development. Additionally, SNP alleles in NOTCH1 and RARB were homozygous exclusively in the bilateral cases, suggesting an oligogenic mode of inheritance. Homozygosity mapping by whole genome de novo assembly also supported oligogenic inheritance; implicating 13 genes involved in hindlimb development in bilateral cases and 11 in unilateral cases. A genome-wide association study (GWAS) predicted additional modifier genes. Although our data show a complex inheritance of TH, we predict that homozygous variants in WNT7A and SMARCA4 are necessary for expression of TH and selection against these variants should eradicate TH.
最近，水牛的乳制品性状选择压力增大与更高的近交程度有关，这导致了一些遗传疾病的流行，如横（侧）骨（肢）发育不全（TH），这是一种先天性发育异常，其特征是后肢的可变远端部分缺失。由于水牛的基因组资源有限，因此需要采用一种原始的方法来识别与该疾病相关的遗传变异。对 4 例双侧和 7 例单侧患病个体和 14 例对照的基因组进行了测序。对 SNP 和 INDEL 进行一致性分析，需要所有单侧和双侧病例所特有的纯合性，结果发现了两个基因，WNT7A 和 SMARCA4，已知它们在胚胎后肢发育中发挥作用。此外，NOTCH1 和 RARB 中的 SNP 等位基因仅在双侧病例中纯合，提示存在寡基因遗传模式。通过全基因组从头组装进行的纯合性映射也支持寡基因遗传；双侧病例涉及 13 个参与后肢发育的基因，单侧病例涉及 11 个基因。全基因组关联研究（GWAS）预测了其他修饰基因。尽管我们的数据显示 TH 具有复杂的遗传方式，但我们预测 WNT7A 和 SMARCA4 的纯合变异是 TH 表达所必需的，而对这些变异的选择应该可以消除 TH。
