CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2007 Jul 18;2(7):e621. doi: 10.1371/journal.pone.0000621.
Tumor necrosis factor (TNF) is a critical cytokine in the immune response whose transcriptional activation is controlled by a proximal promoter region that is highly conserved in mammals and, in particular, primates. Specific single nucleotide polymorphisms (SNPs) upstream of the proximal human TNF promoter have been identified, which are markers of human ancestry.
METHODOLOGY/PRINCIPAL FINDINGS: Using a comparative genomics approach we show that certain fixed genetic differences in the TNF promoter serve as markers of primate speciation. We also demonstrate that distinct alleles of most human TNF promoter SNPs are identical to fixed nucleotides in primate TNF promoters. Furthermore, we identify fixed genetic differences within the proximal TNF promoters of Asian apes that do not occur in African ape or human TNF promoters. Strikingly, protein-DNA binding assays and gene reporter assays comparing these Asian ape TNF promoters to African ape and human TNF promoters demonstrate that, unlike the fixed differences that we define that are associated with primate phylogeny, these Asian ape-specific fixed differences impair transcription factor binding at an Sp1 site and decrease TNF transcription induced by bacterial stimulation of macrophages.
CONCLUSIONS/SIGNIFICANCE: Here, we have presented the broadest interspecies comparison of a regulatory region of an innate immune response gene to date. We have characterized nucleotide positions in Asian ape TNF promoters that underlie functional changes in cell type- and stimulus-specific activation of the TNF gene. We have also identified ancestral TNF promoter nucleotide states in the primate lineage that correspond to human SNP alleles. These findings may reflect evolution of Asian and African apes under a distinct set of infectious disease pressures involving the innate immune response and TNF.
肿瘤坏死因子 (TNF) 是免疫反应中的关键细胞因子，其转录激活受哺乳动物中高度保守的近端启动子区域控制，特别是在灵长类动物中。已经鉴定出近端人 TNF 启动子上游的特定单核苷酸多态性 (SNP)，它们是人类祖先的标志。
方法/主要发现：我们使用比较基因组学方法表明，TNF 启动子中的某些固定遗传差异可作为灵长类动物物种形成的标志。我们还证明，大多数人 TNF 启动子 SNP 的不同等位基因与灵长类 TNF 启动子中的固定核苷酸相同。此外，我们在亚洲猿类的 TNF 近端启动子中鉴定出与非洲猿类或人类 TNF 启动子中不存在的固定遗传差异。引人注目的是，比较这些亚洲猿类 TNF 启动子与非洲猿类和人类 TNF 启动子的蛋白-DNA 结合测定和基因报告测定表明，与我们定义的与灵长类动物系统发育相关的固定差异不同，这些亚洲猿类特有的固定差异会损害 Sp1 位点的转录因子结合，并降低巨噬细胞细菌刺激诱导的 TNF 转录。
结论/意义：在这里，我们提出了迄今为止对先天免疫反应基因调节区进行的最广泛的种间比较。我们已经确定了亚洲猿类 TNF 启动子中与 TNF 基因的细胞类型和刺激特异性激活的功能变化相关的核苷酸位置。我们还鉴定了灵长类动物谱系中 TNF 启动子核苷酸的祖先状态，这些状态与人类 SNP 等位基因相对应。这些发现可能反映了亚洲和非洲猿类在涉及先天免疫反应和 TNF 的不同传染病压力下的进化。
