Tumor necrosis factor-alpha gene regulation and genetics.

Inducer and cell type specific regulation of the human TNF-alpha gene
occurs through the recruitment of distinct higher order transcription
enhancer complexes, or enhanceosomes. Through a variety of in vitro
and in vivo approaches and a cross-species analysis of the TNF-alpha
genomic sequence in the primate lineage we show that regulatory
regions occur in highly conserved regions of the TNF-alpha locus. We
present a primate TNF-alpha gene tree and a map of single nucleotide
polymorphisms (SNPs) in the human tumor necrosis factor (TNF)-alpha
promoter based upon exploratory sequencing of 333 human TNF-alpha gene
promoters from individuals of distinct ancestral backgrounds.  We
detect ten TNF-alpha promoter SNPs that occur with distinct
frequencies in populations of different ancestry and demonstrate that
several occur as fixed differences in the primate lineage. These
differences are both markers of speciation and subspeciation in the
great apes.  The correlation of nucleotide sequence variation with
TNF-alpha transcriptional activation and genetic polymorphism provides
insight into the evolution of non-coding sequences and into how TNF-alpha
is controlled in response to different extracellular stimuli.