002 Gene flow from archaic hominins causes psoriasis, ankylosing spondylitis, and Behçet's disease

Gene variants derived from Neanderthals or Denisovans can be associated with polygenic traits, validating the utility of notion about archaic gene flow. Endoplasmic reticulum aminopeptidase 1 (ERAP1) haplotypes control disease risk primarily mediated by HLA-C*06:02, HLA-B*27 and HLA-B*51 for psoriasis, ankylosing spondylitis (AS) Behçet's (BD). In this genetic interaction corresponds to different autoantigen amounts generated ERAP1 HLA-C*06:02 presentation activate CD8+ T cells (Arakawa et al. 2021). Here we traced evolutionary history pathogenic interaction. We identified that Haplotype1 is Neanderthals, whereas Haplotype10 Denisovan share origin weaker enzymatic activities. Haplotypes 2 3 likely evolved in Homo sapiens. have inferred ancestry, while Neanderthal. 1-3 Neanderthal sapiens increase Denisovan-derived HLA-B*27. ancestry reduces AS psoriasis Denisovan-related HLA-B*27, it increases BD HLA-B*51. Thus, origins HLA HLA-mediated risk, same protective. This may reflect uncoordinated evolution two functionally interacting genes human lineages, which causes disproportionate ERAP1-dependent supplies HLA-class I presentation. Our results demonstrate flow hominins creates primary association essential complexity diseases. Taking advantage cutting-edge knowledge Novel prize awarded, study presents stronger evidence how explanation advance our understanding common