Naturally arising de novo open reading frames as potential zinc chelators in Drosophila melanogaster
A central open problem in the study of de novo gene origination is that the molecular mechanisms and functions driving the emergence of such evolutionarily young, de novo protein-coding genes remain poorly understood. Metal chelation, a simple, directly selectable activity that both requires no specific interaction partners and is also compatible with intrinsic disorder, is one possible function.…
A compelling open question in the investigation of newly created protein-coding genes is the molecular processes and purposes that drive their emergence. Metal binding, a straightforward, easily selectable trait that does not necessitate specific interaction partners and is also compatible with inherent disorder, is one potential function.
This hypothesis was examined using sequence markers in 7,849 transcriptionally supported and still present de novo open reading frames in the Drosophila melanogaster genome. Surprisingly, these newly generated open reading frames (neORFs) exhibit a higher frequency of bis-histidine motifs at the metal-binding coordinates H-x-H and H-x-x-x-H compared to repeat-masked intergenic ORFs.
Importantly, these neORFs also deviate from the C-x-x-C pattern characteristic of conventional metal-binding proteins.
The study reveals that the H-x-H bis-histidine signal is synthesized through the translation of (CA) microsatellites into His-Thr-His in Drosophila melanogaster. This is supported by a CAC-codon bias within the H-x-H motifs and a fourfold higher concentration of threonine at the central position. These findings suggest that recurrent microsatellite expansion offers Drosophila a dispersed, independently originated collection of potential metal-binding proteins originating from de novo peptides.
The authors then track one neORF (ZMEG) from its conserved non-coding ancestry to a transcribed, melanogaster-lineage open reading frame. The (CA)9-derived His run in ZMEG corresponds to a candidate His32-His36 bis-histidine site. This discovery implies that such de novo proteins may form a distinct group of molecules connected not by common ancestry but by their shared origin in evolvable repeat sequences. This highlights the significance of emergence bias in molecular evolution.
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