Distribution analysis of nonsynonymous polymorphisms within the human kinase gene family.
Distribution analysis of nonsynonymous polymorphisms within the human kinase gene family.
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DOI：
10.1016/j.ygeno.2007.03.006
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发表时间：
2007-07
期刊：
影响因子：
4.4
通讯作者：
A. Torkamani;N. Schork
中科院分区：
文献类型：
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作者：
A. Torkamani;N. Schork
人类激酶基因家族由 518 个基因组成，涉及多种生理功能。它们还与多种疾病有关，涵盖了当前药物靶点的 10%。现代高通量测序工作已经鉴定出激酶中天然存在的单核苷酸多态性 (SNP) 的丰富来源，其中一部分出现在基因编码区 (cSNP)，并导致编码的氨基酸序列发生变化（非同义编码 SNP；nscSNP）。这种自然发生的变异的哪一部分是人类疾病的基础，很大程度上是未知的（uDC），并且其中大部分被认为不会引起疾病（DC）。我们对激酶基因家族中 1463 个 nscSNP 和 999 个 DC nscSNP 的分布进行了全面的计算分析，发现 DC 在激酶催化结构域和受体结构中的比例过高。此外，DC和uDC之间特定氨基酸变化发生的频率不同，这意味着两组人类多态性具有不同的生物学特征。我们的结果提供了对与导致人类疾病的天然激酶nscSNP相关的序列和结构现象的见解。
The human kinase gene family is composed of 518 genes that are involved in a diverse spectrum of physiological functions. They are also implicated in a number of diseases and encompass 10% of current drug targets. Contemporary, high-throughput sequencing efforts have identified a rich source of naturally occurring single nucleotide polymorphisms (SNPs) in kinases, a subset of which occur in the coding region of genes (cSNPs) and result in a change in the encoded amino acid sequence (nonsynonymous coding SNP; nscSNPs). What fraction of this naturally occurring variation underlies human disease is largely unknown (uDC), and much of it is assumed not to be disease causing (DC). We pursued a comprehensive computational analysis of the distribution of 1463 nscSNPs and 999 DC nscSNPs within the kinase gene family and have found that DCs are overrepresentated in the kinase catalytic domain and in receptor structures. In addition, the frequencies with which specific amino acid changes occur differ between the DCs and the uDCs, implying different biological characteristics for the two sets of human polymorphisms. Our results provide insights into the sequence and structural phenomena associated with naturally occurring kinase nscSNPs that contribute to human diseases.