Evaluating the roles of testosterone and sex-linked genes in territorial aggression of sex-reversed XY females in the African pygmy mouse
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Abstract
Sex differences in social aggression are widespread across the animal kingdom, with males typically displaying greater territoriality. While this dimorphism has traditionally been attributed to sex hormones, sex chromosomes can also contribute to it independently of hormonal influence. In the African pygmy mouse Mus minutoides, naturally occurring sex-reversed XY females (named X*Y due to a mutation on the X chromosome) are highly territorial in comparison to the other female genotypes present in the population (XX and XX*). However, the molecular basis of this phenotype remains unknown. Here, we evaluate molecular factors, known to correlate with aggressiveness, following a standardized behavioural assessment of aggression. We focus on i) the androgen pathway by quantifying testosterone serum levels and expression of its receptor in the brain; ii) the brain dopaminergic system through expression of dopamine-regulating genes, including the sex-determining Sry gene; and iii) neuroendocrine circuits, via vasopressin and oxytocin expression. These systems, although distinct, converge on hypothalamic-limbic circuits that regulate social behaviour and threat responses, providing an integrated framework for the modulation of aggression. Contrary to earlier reports, we found reduced level of aggression in X*Y females, likely to reflect a breeding facility effect. We also observe no correlations between aggressiveness and androgen levels or gene expression of the tested factors. However, our results support a stimulation of the dopaminergic system and of the oxytocin pathway following the agonistic assay suggesting their potential involvement in aggression-related responses. This further supports the idea that aggression is multifactorial. It is shaped by the interaction of several neuroendocrine and neurotransmitter pathways rather than a single determinant.
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In almost every mammal, chromosomal sex and gonadal sex come together, so it is very hard to tell whether a sex difference in behaviour comes from hormones or from the sex chromosomes themselves. The African pygmy mouse Mus minutoides is one of the rare exceptions. A modified X chromosome, called X*, turns XY individuals into fertile females, so a population contains three kinds of females: XX, XX* and X*Y. Earlier work reported that X*Y females are far more territorial than the other two. This study asks why: is it testosterone, or is it the chromosomes?
The authors had a simple but important design decision. Instead of only measuring gene expression in females that had just fought an intruder, the authors also measured a group of females that never took the test. Comparing the two tells whether a difference was already there before …
In almost every mammal, chromosomal sex and gonadal sex come together, so it is very hard to tell whether a sex difference in behaviour comes from hormones or from the sex chromosomes themselves. The African pygmy mouse Mus minutoides is one of the rare exceptions. A modified X chromosome, called X*, turns XY individuals into fertile females, so a population contains three kinds of females: XX, XX* and X*Y. Earlier work reported that X*Y females are far more territorial than the other two. This study asks why: is it testosterone, or is it the chromosomes?
The authors had a simple but important design decision. Instead of only measuring gene expression in females that had just fought an intruder, the authors also measured a group of females that never took the test. Comparing the two tells whether a difference was already there before the encounter, or whether it is triggered by the encounter. Many candidate-gene studies of aggression cannot make that distinction.
The findings are useful largely because they rule several factors out. Testosterone levels and androgen receptor expression were the same across genotypes, and neither tracked how aggressive a female was, so testosterone is unlikely to explain the behaviour. The product of the sex-determining Sry gene was barely detectable in the brain. What did stand out was that only X*Y females turned up Tyrosine hydroxylase, monoamine oxyase A enzyme (MaoA) and Oxytocin after meeting a male, and MaoA was lower in X*Y females throughout. Even so, none of these genes correlated with how aggressive an individual actually was. The authors draw the appropriately modest conclusion: dopamine and oxytocin activity may make aggression possible without making it happen, and the three female types may arrive at similar behaviour by different routes.
The study also failed to reproduce the original behavioural difference, and is open about it. The likely reason is that about eighteen generations of captive breeding has selected against the most aggressive females — some of which had killed males and were removed from the colony. That is reasonable and testable explanation, and a warning worth heeding by anyone running behavioural work on a long-established colony.
The limits are stated clearly: whole brains were used, which confounds the signals confined to small regions; sample sizes are small; and the data are correlational, from a single time point after the test. Data and analysis scripts are deposited.
I recommend this preprint for its unusual model system, for a design that improves on the standard approach, and for its clarity.
References
Louise D. Heitzmann, Julie Perez, Romann Charbonnier, Marc Fichter, Xavier Hautecoeur, Theo Deremarque, Agnes O. Martin, Frederic Veyrunes (2026) Evaluating the roles of testosterone and sex-linked genes in territorial aggression of sex-reversed XY females in the African pygmy mouse. bioRxiv, ver.3 peer-reviewed and recommended by PCI Evolutionary Biology https://doi.org/10.64898/2025.12.05.692630
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