Rare variants drive high variance in human ancestral fitness at mutation-selection-drift balance

Under mutation-selection-drift balance, the contribution of segregating deleterious variation to fitness variance is dominated by rare variants. This preprint quantifies that contribution in humans: given a realistic genome-wide deleterious mutation rate and distribution of fitness effects, two people typically differ in ancestral fitness by roughly 17–33%, and most of that variation comes from variants below 1% frequency.

Because that variation sits largely outside what genome-wide association studies capture, the result bears on missing heritability and on how disease risk from deleterious load could be identified — through whole-genome scoring of rare variants rather than polygenic scores built on common ones.

Recommended citation: Hernández, U., Mawass, W., Matheson, J., and Masel, J. (2026). "Rare variants drive high variance in human ancestral fitness at mutation-selection-drift balance." bioRxiv, 2026.07.29.741368.