Neanderthal introgressed ancestry reveals human genomic regions enriched with recessive deleterious mutations

Abstract

Negative selection on deleterious mutations plays a key role in shaping human genetic variation, yet the dominance effects of these mutations remain poorly understood because existing statistical methods often cannot distinguish dominance effects from the overall selective effects. In this work, we take a fundamentally different approach by leveraging the distribution of Neanderthal ancestry across the human genome. Simulations show that recessive deleterious mutations can increase archaic introgressed ancestry through heterosis in the absence of positive selection, in contrast to the depletion expected under additive effects. We use this signal to develop DominL, a machine learning classifier trained on simulations of human demography with Neanderthal introgression to identify megabase-scale genomic windows enriched with recessive mutations. DominL demonstrates robust accuracy, with particularly high power in exon-dense regions. Applied to 7 non-African populations from the 1000 Genomes Project, DominL identifies approximately 3-9% of the genome as enriched for recessive mutations, with most high-confidence regions shared across populations. Predicted regions show patterns consistent with expected signatures from recessive mutations, including weakened background selection, depletion of runs of homozygosity, and enrichment of non-additive trait-associated variants. These regions also contain genes associated with metabolic and immune-related functions.