Ellen Lavorando1,2,5, Michael C. Owens1,2,5 and Kathy Fange Liu1,2,3,4 1Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 2Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 3Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 4Penn Center for Genome Integrity, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Corresponding author: liufgpennmedicine.upenn.edu

↵5 These authors contributed equally to this work.

Abstract

The X and Y chromosomes play important roles outside of human reproduction; namely, their potential contribution to human sex biases in physiology and disease. While sex biases are often thought to be an effect of hormones and environmental exposures, genes encoded on the sex chromosomes also play a role. Seventeen homologous gene pairs exist on the X and Y chromosomes whose proteins have critical functions in biology, from direct regulation of transcription and translation to intercellular signaling and formation of extracellular structures. In this review, we cover the current understanding of several of these sex chromosome-encoded protein homologs that are involved in transcription and chromatin regulation: SRY/SOX3, ZFX/ZFY, KDM5C/KDM5D, UTX/UTY, and TBL1X/TBL1Y. Their mechanisms of gene regulation are discussed, including any redundancies or divergent roles of the X- and Y-chromosome homologs. Additionally, we discuss associated diseases related to these proteins and any sex biases that exist therein in an effort to drive further research into how these pairs contribute to sexually dimorphic gene regulation in health and disease.