Abstract
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).
Highlights
In most eutherian mammals with an XX/XY chromosomal system, sex development hinges on the presence or absence of the Y-linked testis-determining gene Sry[1,2,3]
We sequenced the entire Sry coding region in M. minutoides and M. mattheyi (Fig. 1a), a close relative with a typical XX/XY system[15], and identified 5 and 7 Sry haplotypes from M. minutoides and M. mattheyi respectively (Supplementary Figs S1–4 and Table 1), consistent with previous reports of multiple non-identical Sry copies in these species[14,16]
Mouse SRY protein comprises an N-terminal high mobility group (HMG) domain responsible for DNA binding, a short bridge domain of unknown function, and a large C-terminal polyQ domain composed of 8 (Mus musculus domesticus; hereafter referred to as M. domesticus) to 20 (Mus musculus molossinus; hereafter referred to as M. musculus) blocks of 2–13 glutamine residues interspersed by a short histidine-rich spacer sequence[17,18]
Summary
In most eutherian mammals with an XX/XY chromosomal system, sex development hinges on the presence or absence of the Y-linked testis-determining gene Sry[1,2,3]. When expressed in fetal gonads, SRY protein, together with its partner SF1 ( known as NR5A1), bind to the testis-specific enhancer core element (TESCO) of the target effector gene Sox[9] and upregulate its expression[5]. We have demonstrated previously that the polyQ tract plays essential roles in male sex determination in laboratory mice (Mus musculus) by stabilizing SRY protein and transcriptionally inducing Sox[9] expression via activating TESCO10,11. An atypical sex determination system has been described in the African pygmy mouse Mus minutoides In this species, regular XX females and XY males exist, but in addition, individuals bearing a normal Y and a variant X (X*) develop as females, despite the presence of the Y chromosome and Sry[12,13]. We propose a model in which weakening of the SRY/TESCO nexus may have facilitated the rise and stabilization of an X*-based feminizing mechanism in M. minutoides
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