The Fanconi anemia gene network is conserved from zebrafish to human.
The Fanconi anemia gene network is conserved from zebrafish to human.
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DOI：
10.1016/j.gene.2005.11.038
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发表时间：
2006-04
期刊：
影响因子：
3.5
通讯作者：
T. Titus;D. Selvig;B. Qin;Catherine A. Wilson;Amber M Starks;B. Roe;J. Postlethwait
中科院分区：
文献类型：
--
作者：
T. Titus;D. Selvig;B. Qin;Catherine A. Wilson;Amber M Starks;B. Roe;J. Postlethwait
范可尼贫血（FA）是一种复杂的疾病，涉及9个已鉴定和2个未鉴定的基因座，这些基因座定义了维持基因组稳定性所必需的网络。为了验证FA网络在脊椎动物基因组中是保守的这一假设，我们克隆并测序了斑马鱼（Danio rerio）cDNA和/或基因组BAC克隆，它们与所有9个克隆的FA基因（FANCA、FANCB、FANCC、FANCD 1、FANCD 2、FANCE、FANCF、FANCG和FANCL）是直向同源的，并在河豚的基因组数据库中鉴定了直向同源物。斑马鱼和人类所有基因的外显子和内含子的基因组结构几乎相同。疏水性图显示FA蛋白结构的保守性。进化上保守的区域确定了功能上重要的结构域，因为在人类疾病等位基因中突变的或在靶向诱变研究中显示为关键的许多氨基酸残基在斑马鱼和人类中是相同的。比较基因组分析表明，保守的同线性的所有FA基因。我们的结论是，FA基因网络保持完整，因为最后的共同祖先斑马鱼和人类的血统。强大的遗传，细胞和胚胎学方法的应用使斑马鱼成为发现FA基因功能，识别网络中的新基因和识别治疗化合物的有用模型。
Fanconi anemia (FA) is a complex disease involving nine identified and two unidentified loci that define a network essential for maintaining genomic stability. To test the hypothesis that the FA network is conserved in vertebrate genomes, we cloned and sequenced zebrafish (Danio rerio) cDNAs and/or genomic BAC clones orthologous to all nine cloned FA genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL), and identified orthologs in the genome database for the pufferfish Tetraodon nigroviridis. Genomic organization of exons and introns was nearly identical between zebrafish and human for all genes examined. Hydrophobicity plots revealed conservation of FA protein structure. Evolutionarily conserved regions identified functionally important domains, since many amino acid residues mutated in human disease alleles or shown to be critical in targeted mutagenesis studies are identical in zebrafish and human. Comparative genomic analysis demonstrated conserved syntenies for all FA genes. We conclude that the FA gene network has remained intact since the last common ancestor of zebrafish and human lineages. The application of powerful genetic, cellular, and embryological methodologies make zebrafish a useful model for discovering FA gene functions, identifying new genes in the network, and identifying therapeutic compounds.