International Business Department           Liu Bojia           November 06, 2023

  From the different body sizes and weights of the two sexes to the developmental characteristics of different organs (e.g., antlers in bucks), in mammals, in addition to the reproductive organs, we can see obvious sex-differentiated features, and this difference is called sexual dimorphism. In fact, in addition to these features visible to the naked eye, there are also sex differences in the size, function and cellular composition of internal organs.

  In recent years, these gender dimorphisms have become the focus of a whole new level of research as scientists have realised the importance of gender differences in disease and drug research. It has been known for some time that these traits result from the activation of corresponding gene expression programmes, but it has not been clear at what stage these programmes function, how they differ between males and females, and how these differences affect organ function and cellular composition in adult mammals.

  In the latest issue of Science, a joint team of researchers from the Centre for Molecular Biology at the University of Heidelberg and the Francis Crick Institute decode, for the first time, the programs responsible for the sex-specific development of major organs in humans, mice, rats, rabbits, and opossums, and trace the evolution of sex-specific organ traits by comparison. The study systematically answers a series of questions about sex differences in different animals and refutes the hypothesis that sex differences originate early in development. These findings have important implications for understanding the evolution of sex differences and predicting the sex-specific efficacy of human diseases.

  Sexual dimorphism can be quantified by the number of sex-biased genes, i.e., genes that are differentially expressed in the two sexes and predominantly active in one sex. The latest study analysed gene expression activity over time in humans, mammals (mice, rats, rabbits, and opossums), and chickens of both sexes, covering gene expression datasets of five organs - brain, cerebellum, heart, kidney, and liver - at different stages of development.

  On the basis of these data, the team used bioinformatics analyses to identify the starting point of sex-biased gene expression in all mammals in the study: sex-biased gene expression is low during embryonic development, but increases dramatically around sexual maturity. This surprising pattern implies that the gene expression programme responsible for the development of sex-differentiated organ traits is triggered by either female or male hormones and is switched on mainly at later stages of organ development.

  In order to understand the evolution of these gene expression programmes, the researchers compared their results in different mammals in detail. The researchers found that sex differences in different organs differed between species. For example, in rats and mice, the liver and kidneys have more pronounced sexual dimorphism; while in rabbits, the heart is the most sexually dimorphic organ.

  "In most of the species we studied, the liver and kidney exhibit numerous differences in gene expression between the sexes, which in turn leads to sex-specific differences in the function of these organs," said Dr Margarida Cardoso-Moreira of the Francis Crick Institute, who co-led the study.

  Although sex-specific genes differ between species, the team found that the same sexually dimorphic cell types are shared across species. For example, in mice and rats, different genes were sex-biased in the liver, but in both cases, the sex-biased genes were active in hepatocytes. This could explain why there are sex differences in the efficacy of liver drugs.

  The team further revealed the evolutionary signature of sex-specific traits. Sex dimorphism does not have the same genetic basis in different species. Only a very small number of sex-biased genes are shared between species, suggesting that sex differences evolve rapidly and may stem from challenges during species formation. The study suggests that these rapid evolutions may be due to random genetic drift or positive selection triggered by conflicting evolutionary interests of the sexes.

  One exception is the small number of genes found on the X and Y sex chromosomes that exhibit intersex differences in all mammalian species. This may serve as an underlying genetic trigger for the development of sex-specific traits in all mammals.

  Taken together, this study not only lays the foundation for understanding the development and evolution of sex dimorphism, but also provides important knowledge for drug development. For example, most sex-biased genes are species-specific, and the expression trajectories of thousands of genes (including disease-associated genes) differ between humans and other mammals during development. This suggests that scientists may not be able to directly use knowledge of sex bias found in preclinical animal studies to predict sex bias in clinical trials.