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Gephyrin is a highly-conserved gene that is vital for the organization of proteins at inhibitory receptors, molybdenum cofactor biosynthesis, and other diverse functions. Its specific function is intricately regulated and its aberrant activities have been observed for a number of human diseases. Here we report a remarkable yin-yang haplotype pattern encompassing gephyrin. Yin-yang haplotypes arise when a stretch of DNA evolves to present two disparate forms that bear differing states for nucleotide variations along their lengths. The gephyrin yin-yang pair consists of 284 divergent nucleotide states and both variants vary drastically from their mutual ancestral haplotype, suggesting rapid evolution. Several independent lines of evidence indicate strong positive selection on the region and suggest these high-frequency haplotypes represent two distinct functional mechanisms. This discovery holds potential to deepen our understanding of variable human-specific regulation of gephyrin while providing clues for rapid evolutionary events and allelic migrations buried within human history.

Human gephyrin is encompassed within giant functional noncoding yin–yang sequences