Transposon invasion of primate genomes shaped human inflammatory enhancers and susceptibility to inflammatory diseases

Human inflammatory response reflects adaptive alteration of immune-cell regulatory elements during human evolution. Yet the impact of the deeper evolutionary history of these elements, within primate genomes reshaped by transposon expansions, remains unclear. Tracing sequence changes in human immune-cell enhancers back to macaque and analysing proinflammatory transcription factor binding, we show that primate-specific endogenous retroviruses and Alu transposons introduced functional NF-κB and IRF1 motifs, contributing most to the great-ape-specific pool. After the human-macaque split, these motifs tend to evolve toward higher predicted binding affinity. In modern humans, positive selection favoured alleles, often Alu-derived, that increase enhancer affinity for NF-κB, and Alu-containing enhancers are enriched in signatures of adaptation. Highly mutable, Alus disproportionately contribute to the pool of adaptive alleles, including at enhancers linked to inflammatory diseases. We propose that primate-specific transposons facilitated the evolution of inflammatory responses in great apes, with Alus shaping adaptive potential in modern humans.