Human Sex Chromosome Biology in the Genomic Era

Recent research has significantly advanced our understanding of how variation in the genome shapes human biology, yet the sex chromosomes remain among its least explored regions. Technical and conceptual challenges have historically limited their inclusion in genomic studies, despite their influence on gene regulation, development, and disease. Here, we review key aspects of sex chromosome biology, beginning with their evolutionary origins as ordinary autosomes. We highlight how variation in sex chromosome copy number, including typical differences between males and females as well as aneuploidies, provides insight into the roles of the X and Y chromosomes across the human life span, from early embryonic events, such as X chromosome inactivation, to later processes, including reproduction and aging. Finally, we outline emerging innovations that are enabling more comprehensive integration of the sex chromosomes into genomic research, laying the foundation for a more inclusive and mechanistic understanding of their contributions to human diversity.