Sudan's complex genetic admixture history drives adaptation to malaria in Sudanese Copts.

Sudan lies at the crossroads of Africa and the Middle East, with rich cultural, linguistic, and ecological diversity shaped by a complex demographic history. We present a whole-genome sequencing (WGS) study of Sudanese populations, analyzing high-coverage genomes (~30×) from 125 individuals representing five ethnolinguistic groups across three language families. Our results reveal deep population structure, involving Nilo-Saharan, West Eurasian, Northern African, and Western African ancestral components, as well as signatures of the Arab expansion. We report over one million novel variants, including population-specific deleterious alleles, highlighting the need for broader African genomic representation. Notably, local ancestry inference reveals a strong signal of adaptive admixture on chromosome 1 in Sudanese Copts, marked by a peak of Nilo-Saharan ancestry introduced via genetic admixture 1,000 to 1,500 y ago. At this locus, we estimate a remarkably strong selection coefficient (s = 0.0996) for SNP rs2814778 within the ACKR1 gene, which is responsible for the Duffy-null blood group that provides resistance to Plasmodium vivax malaria. These findings reveal Sudan as a genomic mosaic shaped by ancient and recent migrations and provide clear evidence of admixture-driven adaptation in an understudied region of Africa.