Restrictome-EVOLVE: population-resolved haplotype architecture of human antiviral restriction-factor loci

Abstract Human antiviral restriction factors act across multiple stages of viral replication, but whether their population-resolved haplotype architecture differs systematically from comparable genomic regions is unclear. We tested this using phased public human genomic data from 660 individuals in seven African and African-diaspora populations, representing 30 canonical restriction-factor units and 436 target windows. Each canonical unit was compared with 80 exact matched genomic controls, yielding 2,400 frozen controls and 4,429,760 target-control endpoint comparisons across 19 retained haplotype endpoints. All 30 canonical units showed lower differentiation effects and lower robust population-private haplotype effects than their matched controls. Within-population diversity effects were higher in 19 of 30 units, whereas dominant-haplotype concentration effects were lower in 22 of 30. Nineteen units occupied a deconcentrated/high-diversity state, eight a concentrated/low-diversity state, and three a lower-diversity/lower-concentration state. Of 127 global endpoint/context summaries, 88 reached a global false-discovery-rate q value below 0.05; 76 were lower in restriction-factor targets and 12 were higher. Directional sign-test inference detected widespread repeated displacement relative to matched controls, whereas no matched-cell empirical-rank test reached global false-discovery-rate significance. These results show that human antiviral restriction-factor loci occupy a reproducible matched-control haplotype architecture characterized by attenuated population partitioning and reduced robust private structure, together with substantial locus-specific variation in within-population diversity and haplotype concentration. The comparative framework separates population-genomic structure from claims of functional or adaptive causality.