Sex as an evolutionary compatibility feedback signal: mechanistic predictors of synonymous-site constraint explain mammalian conservation beyond GC

Sexual reproduction repeatedly combines independently sampled genomes and therefore imposes a population-wide interoperability constraint: cis-regulatory and RNA-processing programs must remain executable when a large fraction of the genomic background is swapped each generation. We propose that this pressure selects a conserved compatibility layer—"genomic firmware”—that stabilizes core execution while permitting open-ended variation (“flexible determinism”). Using a mammalian compendium of fourfold-degenerate (4D) synonymous sites, we show that splicing- and regulation-linked annotations predict conservation (PhyloP) beyond a strengthened sequence-context baseline that includes 3‑mer context and codon identity, with held-out chromosome validation. A phylogenetic control in Drosophila melanogaster indicates that synonymous conservation beyond local context is also present, while motivating dedicated sexual–asexual sister-clade tests as a falsifiable next step.