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

Negative natural selection on deleterious mutations plays a key role in shaping human genetic variation. Understanding the dominance of deleterious mutations is critical as it can fundamentally impact the rate and efficiency of natural selection, the magnitude of inbreeding depression, and the prevalence and evolution of genetic diseases. Despite its inarguable importance, the dominance effects of mutations remain poorly understood in humans, primarily because existing statistical methods cannot distinguish them from the overall selective effects of mutations. In this work, we take a fundamentally different approach to infer dominance by leveraging the distribution of Neanderthal ancestry across the human genome. We show through simulations that recessive deleterious mutations lead to an increase in archaic introgressed ancestry in the absence of positive selection, contrary to what is expected when deleterious mutations are additive. Leveraging this unique pattern, we develop a machine learning classifier to infer dominance in genomic windows at a megabase resolution, trained on simulations of a human demographic model with Neanderthal introgression using fully recessive or additive mutations. Our method demonstrates robust accuracy at detecting genomic windows containing recessive deleterious mutations, with particularly high power in exon-dense regions. When applied to the non-African populations from the 1000 Genomes Project, we find that approximately 3-9% of the human genome is enriched for recessive mutations with most recessive regions shared across human populations. Furthermore, our method reveals that recessive deleterious mutations are not evenly distributed across the genome: regions enriched for recessive mutations are significantly depleted of haploinsufficient genes and runs of homozygosity, and are enriched with non-additive variants associated with complex traits. Overall, our Neanderthal ancestry-based approach reveals the presence of recessive deleterious mutations in the human genome and suggests that these mutations are found in regions containing genes associated with metabolism and immune-related traits.