Multiple sex chromosome drivers in a mammal with three sex chromosomes

Eukaryotes with separate males and females display a great diversity in the way they determine sex, but it is still unclear what evolutionary forces cause transitions between sex-determining systems. Rather that the lack of hypotheses, the problem is the scarcity of adequate biological systems to test them. Here, we take advantage of the recent evolution of a feminizing X chromosome (called X∗) in the African pygmy mouse Mus minutoides to investigate one of the evolutionary forces hypothesized to cause such transitions, namely sex chromosome drive (i.e., biased transmission of sex chromosomes to the next generation). Through extensive molecular sexing of pups at weaning, we reveal the existence of a remarkable male sex chromosome drive system in this species, whereby direction and strength of drive are conditional upon the genotype of males’ partners: males transmit their Y at a rate close to 80% when mating with XX or XX∗ females and only 36% when mating with X∗Y females. Using mathematical modeling, we explore the joint evolution of these unusual sex-determining and drive systems, revealing that different sequences of events could have led to the evolution of this bizarre system and that the “conditional” nature of sex chromosome drive plays a crucial role in the short- and long-term maintenance of the three sex chromosomes. •The African pygmy mouse Mus minutoides is a rodent with three sex chromosomes•In this species, transmission of male sex chromosomes (X and Y) is non-Mendelian•The X:Y transmission rate varies depending on genetic variants carried by females•Models show this played a key role in the evolution of the third sex chromosome Sex chromosome drive (non-Mendelian transmission) has been theorized to cause transitions in sex-determining systems. Saunders et al. present new data and formal models supporting this claim. In Mus minutoides, an uncommon type of male sex chromosome drive is shown to be crucial for the spread and maintenance of a newly evolved sex chromosome.