Ogurtsov Aleksey Y, Mariño-Ramírez Leonardo, Johnson Gibbes R, Landsman David, Shabalina Svetlana A, Spiridonov Nikolay A
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.
PLoS One. 2008;3(10):e3599. doi: 10.1371/journal.pone.0003599. Epub 2008 Oct 31.
Protein kinase (PK) genes comprise the third largest superfamily that occupy approximately 2% of the human genome. They encode regulatory enzymes that control a vast variety of cellular processes through phosphorylation of their protein substrates. Expression of PK genes is subject to complex transcriptional regulation which is not fully understood.
Our comparative analysis demonstrates that genomic organization of regulatory PK genes differs from organization of other protein coding genes. PK genes occupy larger genomic loci, have longer introns, spacer regions, and encode larger proteins. The primary transcript length of PK genes, similar to other protein coding genes, inversely correlates with gene expression level and expression breadth, which is likely due to the necessity to reduce metabolic costs of transcription for abundant messages. On average, PK genes evolve slower than other protein coding genes. Breadth of PK expression negatively correlates with rate of non-synonymous substitutions in protein coding regions. This rate is lower for high expression and ubiquitous PKs, relative to low expression PKs, and correlates with divergence in untranslated regions. Conversely, rate of silent mutations is uniform in different PK groups, indicating that differing rates of non-synonymous substitutions reflect variations in selective pressure. Brain and testis employ a considerable number of tissue-specific PKs, indicating high complexity of phosphorylation-dependent regulatory network in these organs. There are considerable differences in genomic organization between PKs up-regulated in the testis and brain. PK genes up-regulated in the highly proliferative testicular tissue are fast evolving and small, with short introns and transcribed regions. In contrast, genes up-regulated in the minimally proliferative nervous tissue carry long introns, extended transcribed regions, and evolve slowly.
CONCLUSIONS/SIGNIFICANCE: PK genomic architecture, the size of gene functional domains and evolutionary rates correlate with the pattern of gene expression. Structure and evolutionary divergence of tissue-specific PK genes is related to the proliferative activity of the tissue where these genes are predominantly expressed. Our data provide evidence that physiological requirements for transcription intensity, ubiquitous expression, and tissue-specific regulation shape gene structure and affect rates of evolution.
蛋白激酶（PK）基因构成了第三大基因超家族，约占人类基因组的2%。它们编码调控酶，通过对蛋白质底物进行磷酸化作用来控制各种各样的细胞过程。PK基因的表达受到复杂的转录调控，目前尚未完全了解。
我们的比较分析表明，调控PK基因的基因组组织不同于其他蛋白质编码基因的组织。PK基因占据更大的基因组位点，具有更长的内含子、间隔区，并且编码更大的蛋白质。与其他蛋白质编码基因类似，PK基因的初级转录本长度与基因表达水平和表达广度呈负相关，这可能是由于需要降低大量信息转录的代谢成本。平均而言，PK基因的进化速度比其他蛋白质编码基因慢。PK表达的广度与蛋白质编码区非同义替换率呈负相关。相对于低表达PK，高表达和普遍存在的PK的该比率较低，并且与非翻译区的差异相关。相反，不同PK组中沉默突变的速率是一致的，表明非同义替换率的差异反映了选择压力的变化。大脑和睾丸使用大量组织特异性PK，表明这些器官中磷酸化依赖性调控网络高度复杂。睾丸和大脑中上调的PK之间在基因组组织上存在相当大的差异。在高度增殖的睾丸组织中上调的PK基因进化迅速且较小，内含子和转录区域较短。相比之下，在增殖最少的神经组织中上调的基因具有长内含子、延伸的转录区域，并且进化缓慢。
结论/意义：PK基因组结构、基因功能域大小和进化速率与基因表达模式相关。组织特异性PK基因的结构和进化差异与这些基因主要表达的组织的增殖活性有关。我们的数据提供了证据，证明转录强度、普遍表达和组织特异性调控的生理需求塑造了基因结构并影响进化速率。
