Menage a trois: a third, feminising sex chromosome. Evolutionary consequences and relevance to mammalian sex determination genetics – SEXREV

Sexual dimorphism imposes the challenge to produce from a single genome two distinct phenotypes (male and female) with different adaptive optima. How sex chromosomes help solving this antagonism has been the subject of intense research, but remains incompletely demonstrated and controversial. One main factor that hinders our understanding is that most studies have concerned extremely conserved sex determination systems (e.g. XY in mammals) that have been established long ago with no variation, blurring the evolutionary forces at play. Luckily, we have recently identified a mammalian exception to the XY rule. The species of African pygmy mouse Mus minutoides that harbours a third sex chromosome: a feminising variant of the X, named X*, that produces X*Y fertile females, found at high frequencies in natural populations. Thus, females can be either XX, XX* or X*Y, and all males are XY. We will characterise the evolutionary changes associated with this novel polygenic sex determination system by studying genome, transcriptome and phenotype differences between the four sex genotypes.

In this unique model, the gonadal sex and chromosomal sex are dissociated (XX vs. X*Y females, and XY males vs. X*Y females), and we showed previously that the X* has opposite effects in sex determination and sex differentiation, with feminisation of the gonad, but partial masculinisation of the brain. Our first objective is thus to use this fantastic framework to provide answers to longstanding but fundamental questions pertaining to the genetic basis of sex differences in brain and behaviour. We will extend the description of phenotypes associated with sex reversal to uncover how brain sexualisation may be determined by sex chromosomes independently of gonadal sex.

Mus minutoides is also an exceptional model to understand the evolutionary forces driving the birth, building and spread of a new sex chromosome architecture, and the resulting evolutionary opportunities and constraints. When the X* evolved more than 1 MYA, the complex set of evolutionary forces acting on sex chromosomes was disturbed: the X* acquired an exclusively female-transmission and stopped to recombine, the X now spends more time in male than female context, and the Y has become bisexually transmitted. Our second objective is thus to test theories of the role of sexual antagonism (evolution of gene content and sex-linked expression) in the evolution of genetic sex determination and sex chromosome transmission, a hotly debated topic. This will be the first study on a model with such variety of transmission modes of sex chromosomes in a single species.

Finally, M. minutoides, phylogenetically very close to the laboratory mouse, provides an invaluable model to decipher the yet largely ununderstood molecular mechanisms involved in the mammalian sex determination cascade. Our third objective is thus to characterise the genetic basis of this novel sex determining program and hence identify new genes involved in the mammalian sex determining pathway. A crucial development of such a study concerns its possible application to human’s Disorders of Sex Development where to date, the causative mutations remain unknown in more than 50% of the patients.

The partners represent a combination of expertise in several fields of biology (comparative genomics, evolutionary genomics, life-history traits evolution, neurobiology and molecular genetics), around an exceptional model (for which we are running the only breeding program in the world). Altogether, this provides a strong opportunity to answer longstanding but fundamental questions on the genetic basis of sex differences in brain and behaviour, and on the role of sexual antagonism in the evolution of sex chromosomes. It also places us in a better position than ever to identify new players in the yet largely ununderstood molecular basis of the mammalian sex determination pathway, with a strong potential impact on clinical research.