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In most eutherian mammals, sex determination is governed by the Y-linked gene  Sry,  but in African pygmy mice  Mus minutoides, Sry  action is overridden by a variant X chromosome (X*), yielding X*Y females. We hypothesized that X*Y sex reversal may be underpinned not only by neomorphic X chromosome functionality, but also by a compromised  Sry  pathway. Here, we show that neither  M. minutoides  SRY nor its target, the  Sox9- TESCO enhancer, had appreciable transcriptional activity in  in vitro  assays, correlating with sequence degradation compared to  Mus musculus  counterparts. However,  M. minutoides  SRY activated its cognate TESCO to a moderate degree, and can clearly engage the male pathway in  M. minutoides  in the wild, indicating that SRY and TESCO may have co-evolved in  M. minutoides  to retain function above a threshold level. We suggest that weakening of the SRY/TESCO nexus may have facilitated the rise and spread of a variant X* chromosome carrying female-inducing modifier gene(s).

Reduced Activity of SRY and its Target Enhancer Sox9-TESCO in a Mouse Species with X*Y Sex Reversal