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.

生物性别差异的复杂性在人类生理学和病理学中表现得非常明显。尽管许多差异可以归因于性激素的表达，但造成性别差异的另一个因素在于性染色体，而不仅仅是其在性别决定中的作用。尽管人类性染色体在很大程度上是非同源的，但它表达十七对同源基因，称为“X-Y 对”。这些 Y 编码蛋白的 X 染色体编码同源物在多个细胞过程中发挥着至关重要的作用，它们的失调常常导致疾病的发生。许多与这些 X 编码同源物相关的疾病的发病率或严重程度存在性别偏见。相比之下，人们对 Y 连接同系物的差异功能知之甚少。在这里，我们总结并讨论了目前对这些 X-Y 配对蛋白中的五种的理解，以及差异功能和与疾病中的性别偏见存在潜在联系的最新证据，强调了氨基酸水平序列差异如何区分它们的功能和导致人类疾病中的性别偏见。