Copy number variation in the horse genome.
Copy number variation in the horse genome.
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DOI：
10.1371/journal.pgen.1004712
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发表时间：
2014-10
期刊：
影响因子：
4.5
通讯作者：
Raudsepp T
中科院分区：
文献类型：
--
作者：
Ghosh S;Qu Z;Das PJ;Fang E;Juras R;Cothran EG;McDonell S;Kenney DG;Lear TL;Adelson DL;Chowdhary BP;Raudsepp T
我们为马构建了 400K WG 平铺寡阵列，并将其应用于发现 16 个不同品种的 38 匹正常马和普氏野马的拷贝数变异 (CNV)。阵列上的探针代表 18,763 个常染色体和 X 连锁基因，以及基因间、亚端粒和 chrY 序列。我们在所有常染色体、chrX 和 chrUn 中鉴定了 258 个 CNV 区域 (CNVR)，但在 chrY 中没有。 CNV 占马基因组的 1.3%，其中 chr12 最为丰富。与纯种马相比，美国小型马的 CNV 数量最高，美国夸特马的 CNV 数量最低。普氏野马与本土小马和役用马相似。大多数 CNVR 涉及基因，20% 位于基因间区域。与之前对马和其他哺乳动物的研究类似，CNV 相关基因的分子功能主要集中在感觉知觉、免疫和繁殖方面。这些发现与之前的研究相结合，生成了包含 1476 个 CNVR 的复合全基因组数据集。其中，301 个 CNVR 在研究之间共享，而 1174 个 CNVR 是新颖的，需要进一步验证。综合数据显示，迄今为止，已经对400多个品种的家马中的41个品种进行了CNV分析，其中本研究增加了11个新品种。最后，复合 CNV 数据集应用于一项初步研究，在 6 匹患有 XY 性发育障碍的马中发现了 CNV。由于 AKR1C 基因在睾丸雄激素合成和性发育中的已知作用，两匹受影响的马的第 29 号染色体上涉及 AKR1C 基因簇的纯合性缺失被认为可能是致病原因。虽然这些发现改进并整合了马匹 CNV 的知识，但它们也表明，为了有效发现具有生物医学重要性的变异，需要使用可比较的方法学方法对更多品种和个体进行分析。一个物种中个体的基因组有很多方面的差异，其中之一是 DNA 拷贝数变异 (CNV)。这包括删除、重复和通常大于 50 个碱基对的复杂重排。 CNV 是正常遗传变异的一部分，有助于表型多样性，但也可能具有致病性并与疾病和病症相关。为了区分两者，需要详细了解感兴趣物种中的 CNV。在这里，我们研究了 16 个不同品种的 38 匹正常马的基因组，并鉴定了 258 个 CNV 区域。我们将我们的发现与之前发表的马 CNV 相结合，生成了约 1400 个 CNVR 的复合数据集。尽管数量庞大，但我们的分析表明，马匹 CNV 研究需要进一步改进，因为当前数据基于 10% 的马品种，而且大多数 CNVR 都是特定于研究的，需要验证。最后，我们分析了患有性发育障碍的马的 CNV，发现在两个雄性假雌雄同体中存在大量缺失，破坏了一组涉及性激素代谢和性分化的基因。这些发现强调了 CNV 在发育和生殖等复杂疾病中可能发挥的作用。
We constructed a 400K WG tiling oligoarray for the horse and applied it for the discovery of copy number variations (CNVs) in 38 normal horses of 16 diverse breeds, and the Przewalski horse. Probes on the array represented 18,763 autosomal and X-linked genes, and intergenic, sub-telomeric and chrY sequences. We identified 258 CNV regions (CNVRs) across all autosomes, chrX and chrUn, but not in chrY. CNVs comprised 1.3% of the horse genome with chr12 being most enriched. American Miniature horses had the highest and American Quarter Horses the lowest number of CNVs in relation to Thoroughbred reference. The Przewalski horse was similar to native ponies and draft breeds. The majority of CNVRs involved genes, while 20% were located in intergenic regions. Similar to previous studies in horses and other mammals, molecular functions of CNV-associated genes were predominantly in sensory perception, immunity and reproduction. The findings were integrated with previous studies to generate a composite genome-wide dataset of 1476 CNVRs. Of these, 301 CNVRs were shared between studies, while 1174 were novel and require further validation. Integrated data revealed that to date, 41 out of over 400 breeds of the domestic horse have been analyzed for CNVs, of which 11 new breeds were added in this study. Finally, the composite CNV dataset was applied in a pilot study for the discovery of CNVs in 6 horses with XY disorders of sexual development. A homozygous deletion involving AKR1C gene cluster in chr29 in two affected horses was considered possibly causative because of the known role of AKR1C genes in testicular androgen synthesis and sexual development. While the findings improve and integrate the knowledge of CNVs in horses, they also show that for effective discovery of variants of biomedical importance, more breeds and individuals need to be analyzed using comparable methodological approaches. Genomes of individuals in a species vary in many ways, one of which is DNA copy number variation (CNV). This includes deletions, duplications, and complex rearrangements typically larger than 50 base-pairs. CNVs are part of normal genetic variation contributing to phenotypic diversity but can also be pathogenic and associated with diseases and disorders. In order to distinguish between the two, detailed knowledge about CNVs in the species of interest is needed. Here we studied the genomes of 38 normal horses of 16 diverse breeds, and identified 258 CNV regions. We integrated our findings with previously published horse CNVs and generated a composite dataset of ∼1400 CNVRs. Despite this large number, our analysis shows that CNV research in horses needs further improvement because the current data are based on 10% of horse breeds and that most CNVRs are study-specific and require validation. Finally, we analyzed CNVs in horses with disorders of sexual development and found in two male pseudo-hermaphrodites a large deletion disrupting a group of genes involved in sex hormone metabolism and sexual differentiation. The findings underline the possible role of CNVs in complex disorders such as development and reproduction.
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