Year: 2026
Type: preprint
Abstract: Male sex determination in mammals depends on sex-determining region Y (SRY), a transcription factor whose high-mobility group box (HMG box) binds and bends DNA to activate SOX9. The divergent N- and C-terminal domains lack sequence homology and have been dismissed as passive linkers, yet alignment-based homology cannot reveal whether they retain a hidden compositional grammar. We applied quantitative genomics to 65 full-length mammalian SRY proteins and 38 HMG-box subsequences across 75 mammals, integrating amino acid and dipeptide compositions, Shannon entropy, dominant-residue profiles, hydropathy-based n-gram spectra, longest hydropathy stretches, and cumulative proximity. The HMG box is tightly constrained: basic residues dominated, cysteine was nearly absent, entropy clustered near 4.0, polar content averaged 58.44%, and 25 of 38 HMG boxes shared 57.97% polar residues, whereas full-length SRY varied more, with rodents showing high polar and glutamine-rich profiles and cetaceans low polar content. Proximity-based clustering was more taxonomically consistent at the HMG level, while terminal regions blurred domain-level signals. Across 65 SRY proteins and 38 HMG domains, intrinsic disorder was the dominant predicted state, and a polyQ-rich rodent SRY illustrated how low-complexity repeats can produce misleading ordered predictions, underscoring the need for consensus disorder analysis in rapidly evolving intrinsically disordered regions. Cumulative proximity analysis identified Bos taurus and Bos grunniens as the only pair proximally clustered at both the full-length SRY and SRY-HMG levels, establishing multivariate proximity as a stringent criterion of compositional similarity satisfied by a single mammalian pair. These results suggest that SRY and its HMG box each carry a distinct compositional grammar, quantifiable only through alignment-independent signatures, with compositional individuality being the rule rather than the exception. These quantitative signatures provide a framework for interpreting SRY variation, assessing clinical mutations, and understanding evolutionary pressures shaping sex determination. Denser taxon sampling, structural modeling, and experimental tests are needed to clarify whether HMG-box drift and terminal-region variation affect DNA binding, bending, or reproductive function.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223560317