Positionally cloned human disease genes: Patterns of evolutionary conservation and functional motifs
Positionally cloned human disease genes: Patterns of evolutionary conservation and functional motifs
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DOI：
10.1073/pnas.94.11.5831
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发表时间：
1997-05-27
影响因子：
11.1
通讯作者：
Koonin, EV
中科院分区：
文献类型：
--
作者：
Mushegian, AR;Bassett, DE;Koonin, EV
定位克隆已经产生了与特定疾病相关的70多个人类基因的序列，除了它们的医学重要性之外，这些基因作为一组仅基于各自突变的表型效应而分离的人类基因也令人感兴趣。我们使用结合几种敏感计算机方法的迭代策略分析了定位克隆的疾病基因编码的蛋白质序列，与完整的序列数据库以及线虫、酵母和细菌蛋白质的单独数据库的比较表明，对于大多数疾病基因产物，具有统计显着性在每个模型生物中都可以检测到序列相似性，只有线虫基因组编码大多数疾病基因具有保守结构域结构的明显直向同源物，在酵母和细菌同源物中，结构域组织通常不保守，序列相似性仅限于单个结构域，一般来说，人类基因仅在直向同源酵母基因中补充突变，大多数位置克隆基因编码具有多个球状和非球状结构域的大蛋白质，其中一些或全部功能尚不清楚。我们在疾病基因编码的许多蛋白质中检测到了以前未描述过的保守结构域和基序，并预测了其中一些的功能。这些预测包括遗传性非息肉病结肠癌基因（MutL同源物）产物中的ATP结合结构域，该结构域在伴侣蛋白、II型DNA拓扑异构酶和组氨酸激酶的HS90家族中保守，以及与细菌RNase D同源的核酸酶结构域和Werner 综合征基因产物中 DNA 聚合酶 I 的 3'-5' 核酸外切酶结构域。
Positional cloning has already produced the sequences of more than 70 human genes associated with specific diseases, In addition to their medical importance, these genes are of interest as a set of human genes isolated solely on the basis of the phenotypic effect of the respective mutations, We analyzed the protein sequences encoded by the positionally cloned disease genes using an iterative strategy combining several sensitive computer methods, Comparisons to complete sequence databases and to separate databases of nematode, yeast, and bacterial proteins showed that for most of the disease gene products, statistically significant sequence similarities are detectable in each of the model organisms, Only the nematode genome encodes apparent orthologs with conserved domain architecture for the majority of the disease genes, In yeast and bacterial homologs, domain organization is typically not conserved, and sequence similarity is limited to individual domains, Generally, human genes complement mutations only in orthologous yeast genes, Most of the positionally cloned genes encode large proteins with several globular and nonglobular domains, the functions of some or all of which are not known. We detected conserved domains and motifs not described previously in a number of proteins encoded by disease genes and predicted functions for some of them, These predictions include an ATP-binding domain in the product of hereditary nonpolyposis colon cancer gene (a MutL homolog), which is conserved in the HS90 family of chaperone proteins, type II DNA topoisomerases, and histidine kinases, and a nuclease domain homologous to bacterial RNase D and the 3'-5' exonuclease domain of DNA polymerase I in the Werner syndrome gene product.