Sex and the Genome: Divergent Genetic Architecture Across the Human Lifespan

Males and females share nearly identical genomes yet exhibit profound differences in disease susceptibility, progression, and treatment response across the lifespan. These sex differences arise from evolutionary conflicts in which genetic variants confer opposing fitness effects between sexes, maintained by balancing selection. This review examines how sex shapes complex trait architecture from early childhood through postreproductive life. Early childhood reveals intrinsic genetic sexual dimorphism before hormonal activation. During reproductive years, sex-specific metabolic programming manifests through divergent adipose distribution and cardiometabolic risk, while autoimmune diseases demonstrate a fourfold female bias driven by incomplete X-inactivation. Postreproductive phases reveal antagonistic pleiotropy, in which variants that are beneficial for early reproduction increase late-life disease vulnerability. Systematic exclusion of X chromosome data from ∼75% of genome-wide association studies has obscured critical therapeutic targets. Sex-stratified genomic analyses consistently uncover effect sizes and risk loci that are invisible in sex-combined models. We argue that precision medicine must incorporate sex as a fundamental axis of genomic stratification across development, rather than treating it as a covariate to be adjusted away.