Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection

Abstract

AbstractNew genes (or young genes) are structural novelties pivotal in mammalian evolution. Their phenotypic impacts on humans, however, remain elusive due to the technical and ethical complexities in functional studies. Through combining gene age dating with Mendelian disease phenotyping, our research reveals a steady integration of new genes with biomedical phenotypes into the human genome over macroevolutionary timescales (∼0.07% per million years). Despite this stable pace, we observe distinct patterns in phenotypic enrichment, pleiotropy, and selective pressures shaped by different gene ages. Notably, young genes show significant enrichment in the male reproductive system, indicating strong sexual selection. Young genes also exhibit functions in tissues and systems potentially linked to human phenotypic innovations, such as increased brain size, musculoskeletal phenotypes, and color vision. Our findings further reveal increasing levels of pleiotropy over evolutionary time, which accompanies stronger selective constraints. We propose a “pleiotropy-barrier” model that delineates different potentials for phenotypic innovation between young and older genes subject to natural selection. Our study demonstrates that evolutionary new genes are critical in influencing human reproductive evolution and adaptive phenotypic innovations driven by sexual and natural selection, with low pleiotropy as a selective advantage.