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Sex chromosome-encoded protein homologs: current progress and open questions

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Abstract

The complexity of biological sex differences is markedly evident in human physiology and pathology. Although many of these differences can be ascribed to the expression of sex hormones, another contributor to sex differences lies in the sex chromosomes beyond their role in sex determination. Although largely nonhomologous, the human sex chromosomes express seventeen pairs of homologous genes, referred to as the ‘X–Y pairs.’ The X chromosome-encoded homologs of these Y-encoded proteins are crucial players in several cellular processes, and their dysregulation frequently results in disease development. Many diseases related to these X-encoded homologs present with sex-biased incidence or severity. By contrast, comparatively little is known about the differential functions of the Y-linked homologs. Here, we summarize and discuss the current understanding of five of these X–Y paired proteins, with recent evidence of differential functions and of having a potential link to sex biases in disease, highlighting how amino acid-level sequence differences may differentiate their functions and contribute to sex biases in human disease.

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Fig. 1: Roles for the sexually dimorphic proteins in healthy cellular function and disease.
Fig. 2: Highlighted nuclear X–Y pairs: UTX–UTY and KDM5C–KDM5D.
Fig. 3: Highlighted cytoplasmic and membrane X–Y pairs: DDX3X–DDX3Y, eIF1AX–eIF1AY and NLGN4X–NLGN4Y.

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Acknowledgements

This work was supported by the National Institutes of Health (R35GM133721 and R01HL160726-01A1 to K.F.L., T32GM132039 to M.C.O. and A.Y. and R35GM133721-03S1 to A.Y.), the American Cancer Society (RSG-22-064-01-RMC to K.F.L.), the Damon Runyon Innovator Award (01) and the Linda Pechenik Montague Investigator Award (to K.F.L.). All figures were created with https://www.biorender.com.

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M.C.O. and A.Y. wrote the manuscript and created the figures. M.C.O., A.Y. and K.F.L. participated in discussion of the manuscript and edited the manuscript.

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Owens, M.C., Yanas, A. & Liu, K.F. Sex chromosome-encoded protein homologs: current progress and open questions. Nat Struct Mol Biol 31, 1156–1166 (2024). https://doi.org/10.1038/s41594-024-01362-y

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