Conservation, acquisition, and functional impact of sex-biased gene expression in mammalian tissues

Sex differences are widespread in human health and disease, which are frequently modeled in other mammalian species. However, the extent to which molecular sex differences are conserved across both tissues and species remains unclear. We conducted a 12-tissue, five-species survey of sex differences in gene expression using both publicly available (human) and newly generated (cynomolgus macaque, mouse, rat, and dog) RNA sequencing data. In each of the tissues assessed, we identified between 128 and 805 genes with conserved sex-biased expression. However, most sex bias in gene expression (~77%) - both female and male - has arisen since the last common ancestor of boroeutherian mammals, likely facilitated by reduced selective constraint. Evolutionary gains and losses of regulation by sex-biased transcription factors drove a significant fraction (~27%) of lineage-specific changes in sex bias. Our study suggests caution in the use of other species as models of human sex differences, and that similar selective pressures have driven sex-biased gene expression both within and outside the reproductive tract. Tissue transcriptomes from 12 tissues and 4 species, 3 males and 3 females per species (before removal of outliers) were sequenced and compared for sex differences人类健康与疾病领域广泛存在性别差异，此类差异常以其他哺乳动物为模型开展研究。然而，分子层面的性别差异在不同组织与物种间的保守程度仍未明确。为此，本研究针对基因表达中的性别差异开展了涵盖12种组织、5个物种的系统性调研，所用数据既包含公开获取的人类样本转录组数据，也包含新生成的食蟹猕猴（cynomolgus macaque）、小鼠、大鼠与犬的RNA测序数据。在所评估的每一种组织中，本研究均鉴定出128至805个具有保守性性别偏向表达的基因。然而，约77%的基因表达性别偏向（涵盖雌性偏向与雄性偏向）均起源于北方真兽类哺乳动物的最近共同祖先之后，其形成可能受选择约束减弱的推动。性别偏向转录因子调控的进化得失，推动了约27%的谱系特异性性别偏向变化。本研究提示，将其他物种作为人类性别差异模型时需保持谨慎；同时，类似的选择压力同时驱动了生殖道内外的性别偏向基因表达。本研究对来自12种组织、4个物种的组织转录组进行了测序，每个物种包含3只雄性与3只雌性个体（剔除异常值前），并针对性别差异开展了比较分析。