造血生长因子分子进化的系统分析

SYSTEMATIC ANALYSIS FOR MOLECULAR EVOLUTION OF HEMATOPOIETIC GROWTH FACTORS

系统分析了18种造血生长因子的分子进化。结果表明,其蛋白质进化速率以IL-3最高,往下依次为IL-6、IL-4、GM-CSF、IL-9、IL-1α、IL-12(p35)、IL-2、IL-12(p4O)、IL-7、M-CSF、IL-5、G-CSF、IL-Ira、SCI、LIF、IL-1β、EPO、IL-11、SCF;蛋白质进化速率较高的IL-3、-4、-6其cDNA编码区的进化速率亦高,但其基因、基因旁侧序列及cDNA中5′-、3′-非翻译区的进化速率均出乎意料地低于编码区,从而表明调控造血生长因子表达的序列在进化上较编码区保守;多种系IL-3、GM-CSF的进化分析揭示,它们在进化过程中不以恒定速度进化,在低等动物中进化较快,在高等动物中进化则较慢,因而不遵守“分子进化钟”的规律。

Most hematopoietic growth factors(HGFs) have been wellcharacterized for their sequences, functions and regulation except their molecular evolution. Recently we found that the molecular evolutionary pattern of 6 myeloid differentiating factors(IL-3, GM-CSF, G-CSF, M-CSF, IL-5 and EPO) correlated with the hierarchy of myelopoiesis, and also that cytokines evolved together with their own receptors in a concerted fashion. In this paper, molecular evolution of 18 HGFs was systematically studied by the standard methods of evolutionary analysis. According to the evolutionary rate in protein sequence, IL-3 was the biggest, and followed by IL-6, IL-4, GM-CSF, IL-9, IL-la, IL-12(p35), IL-2, IL-12(p40), IL-7, M-CSF, IL-5, G-CSF, IL-lra, SCI, LIF, IL-1β, EPO, IL-11, SCF one after another. The results implied that HGFs(IL-3, -6, -4) differentiating stem cells or multi-potential progenitors were less conservative, those(such as IL-2, IL-7, M-CSF, IL-5, G-CSF and EPO) differentiating later progenitors were more conservative, and those (including SCI, LIF, IL-11, SCF) regulating stem cell proliferation (not differentiation) were also more conservative. The evolutionary rates of cDNA coding regions for rapidly evoluting IL-3, -4, -6 were correspondingly high; on the contrary, their genes, flanking regions of their genes as well as 5'-and 3'-non- translated regions in their cDNAs which would play a role in their gene regulation were surprisingly more conservative in evolution than their cDNA coding regions. These data put forward a challenge for natural theory of molecular evolution. The evolutionary analysis of both IL-3 and GM-CSF among multiple species indicated that both of them evolved at a lower speed in rodents than in primates. This result would argue on ' molecular evolutionary clock'. The biological significance of different evolutionary rates for HGFs was discussed. The results above suggested that the evolutionary patterns of HGFs would be much different from those of block proteins such as hemoglobin, myosin and histones.