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X chromosome agents of sexual differentiation

Abstract

Understanding sex differences in physiology and disease requires the identification of the molecular agents that cause phenotypic sex differences. Two groups of such agents are genes located on the sex chromosomes, and gonadal hormones. The former have coherent linkage to chromosomes that form differently in the two sexes under the influence of genomic forces that are not related to reproductive function, whereas the latter have a direct or indirect relationship to reproduction. Evidence published in the past 5 years supports the identification of several agents of sexual differentiation encoded by the X chromosome in mice, including Kdm5c, Kdm6a, Ogt and Xist. These X chromosome agents have wide pleiotropic effects, potentially influencing sex differences in many different tissues, a characteristic shared with the gonadal hormones. The identification of X chromosome agents of sexual differentiation will facilitate understanding of complex intersecting gene pathways underlying sex differences in disease.

Key points

  • Phenotypic sex differences arise because of the different expression levels of genes on the sex chromosomes, including unequal downstream effects of gonadal hormones.

  • Evidence in the past 5 years implicates specific X chromosome genes as agents causing sex differences in a wide variety of tissues, which is relevant to many diseases.

  • Two major groups of agents of sexual differentiation, sex chromosome genes and gonadal hormones, might differ in their relevance to reproduction because of their different evolutionary history and chromosomal linkage.

  • Sex-biasing effects of sex chromosome genes and gonadal hormones might be favoured because they produce a de novo adaptive effect or offset another disadvantageous sex difference.

  • Because gonadal hormonal and sex chromosomal agents of sexual differentiation both have pleiotropic effects, they probably produce diverse sex differences that are not all equally advantageous.

  • Sex differences in disease might occur even in tissues that function equally in healthy individuals, if the sex difference is based on different compensatory mechanisms in the two sexes.

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Fig. 1: Classes of X chromosome genes that contribute more or less to sexual differentiation.
Fig. 2: Examples of diverse sex differences caused in part by Kdm6a dose in mice.
Fig. 3: Side effects of pleiotropic agents of sexual differentiation.

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Acknowledgements

The author thanks his many generous collaborators, who have inspired him and educated him concerning concepts discussed here. The author is supported by NIH grants OD030496, OD026560, HD100298, HD076125, DK083561 and HL131182.

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Correspondence to Arthur P. Arnold.

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Arnold, A.P. X chromosome agents of sexual differentiation. Nat Rev Endocrinol 18, 574–583 (2022). https://doi.org/10.1038/s41574-022-00697-0

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