Primate TNF Promoters Reveal Markers of Phylogeny and Evolution of Innate Immunity

Abstract

BackgroundTumor 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 findingsUsing 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/significanceHere, 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.

Tracking the complex flow of chromosome rearrangements from the Hominoidea Ancestor to extant Hylobates and Nomascus Gibbons by high-resolution synteny mapping

“…This result seems congruent with the conclusion from molecular work that Hylobates is the most recently evolved lesser ape genus (Roos and Geissmann 2001;Takacs et al 2005;Baena et al 2007;Whittaker et al 2007). Molecular research converges on a date for lesser apes origins around 17 to 18 million years ago (Mya) (Caccone and Powell 1989;Bailey et al 1991;Stauffer et al 2001;Hasegawa et al 2003;Raaum et al 2005;Baena et al 2007). According to these molecular analyses, crown species originated much later and Hoolock, Symphalangus, and Nomascus, whatever the exact order, diverged between 10 and 12 Mya.…”

“…However, recent biomolecular studies either place Hoolock or Nomascus as basal (Roos and Geissmann 2001;Muller et al 2003;Takacs et al 2005;Baena et al 2007), and most conclude that the genera Hylobates was the last and most recent genus to diverge (Takacs et al 2005;Baena et al 2007). In the present study, we have defined, using molecular cytogenetic tools, a high-resolution picture of synteny conservation and orientation in Hylobates lar.…”

Evolutionarily conserved primary TNF sequences relate to its primitive functions in cell death induction

“…TNF exists in different species within the vertebrate subphylum (Baena et al, 2007;Wiens and Glenney, 2011).…”

An extinct monkey from Haiti and the origins of the Greater Antillean primates

“…Note that there are two contrasting views on the taxonomic placement of Aotus, with the molecular studies indicating an affinity with the Cebinae (12,13) and morphological evidence suggesting a relationship with Pithecinae (14).…”