Fitness epistasis, the interaction effect of genes at different loci on fitness, has an important contribution for adaptive evolution. Although fitness interaction evidence has been observed in model organisms, it is less detectable and remains poorly understood in human populations owing to the limited statistical power and experimental constraints. Fitness epistasis is inferred from non-independence between unlinked loci. We previously observed ancestral block correlation between chromosomes

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... and 6 in African Americans. The same approach fails when examining ancestral blocks on the same chromosome due to strong confounding effect in a recently admixed population. Results: We developed a novel approach to eliminate the bias caused by admixture linkage disequilibrium when searching for fitness epistasis on the same chromosome. We applied this approach in 16,252 unrelated African Americans and identified significant ancestral correlations in two pairs of genomic regions (P-value<8.11×10 -7 ) on chromosomes 1 and 10. The ancestral correlations were not explained by population admixture. Historical African-European crossover events are reduced between pair of epistatic regions. We observed multiple pairs of co-expressed genes between the two regions on each chromosome, including ADAR being co-expressed with IFI44 in almost all tissues and DARC being co-expressed with VCAM1, S1PR1 and ELTD1 in multiple tissues in GTEx. Moreover, the co-expressed gene pairs are associated with the same diseases/traits in the GWAS Catalog, such as white blood cell count, blood pressure, lung function, inflammatory bowel disease and educational attainment. Conclusions: Our analyses revealed two instances of fitness epistasis on chromosomes 1 and 10, and the findings suggest a potential approach to better understand adaptive evolution.