Evaluating the effects of archaic protein-altering variants in living human adults

Advances in paleogenetics allowed the identification of protein-coding changes unique to Homo sapiens by comparing present-day and archaic hominin genomes. So far, experimental validation has been restricted to functional assays and model organisms. Large-scale biobanking now makes it possible to directly assess phenotypic consequences in living adults. Querying exomes of 455,000 UK Biobank participants at 37 sites with supposedly fixed human-specific changes, we identified 103 carriers at 17 positions, with variable allele counts across ancestries. We performed phenotypic evaluations for two example changes. Individuals carrying archaic SSH2 alleles showed no clear deviations in an array of health, neuropsychiatric, and cognitive traits. Carriers of a TKTL1 missense variant, previously linked to large effects on cortical neurogenesis, showed no obvious differences in brain anatomy, with many carriers holding college degrees. Our study demonstrates challenges associated with individual interrogation of key sites when seeking insights into the evolution of complex human traits and highlights the importance of including diverse ancestries in biobanking efforts.