Jump–Decline Evolution of Transcription Factor-Type Master Sex-Determining Genes

Master sex-determining genes (MSDGs) occupy the top of developmental hierarchies and act as molecular switches that initiate female or male differentiation. Despite their essential roles, MSDGs exhibit rapid evolutionary turnover across vertebrates. In this review, we examine the molecular evolutionary trajectories of three independently evolved vertebrate MSDGs—Sry in mammals, dmy in medaka fishes, and dm-W in Xenopus frogs—and assess the extent to which their evolutionary histories are consistent with initial functional innovation followed by relaxed functional constraint, possible tolerated functional decline, and potential replacement or loss. Regulatory rewiring, structural innovation, or key amino acid substitutions can generate a functional “Jump” that enables a newly arisen gene to cross the threshold required for sex determination and become established as a master regulator. Once the new sex-determining system is established, further increases in MSDG activity may provide little additional fitness advantage, allowing purifying selection to relax. Nearly neutral or mildly deleterious substitutions can then accumulate while residual activity remains sufficient for normal sex determination, producing a tolerated functional “Decline.” Importantly, replacement need not await a decline in ancestral MSDG activity below the functional threshold. A newly emerging MSDG may become established through competition within a population while the ancestral determinant still retains sufficient sex-determining activity, thereby rendering the ancestral MSDG dispensable and permitting its subsequent functional decay or loss. Together, these cases suggest that the switch-like, threshold-dependent architecture of sex determination can permit initial innovation followed by relaxed functional constraint and, in some lineages, turnover of upstream master regulators. We propose “Jump-Decline” evolution as a testable conceptual framework linking the birth, functional relaxation, and potential turnover of vertebrate MSDGs.