Noam Shtolz (Ben Gurion University of the Negev)

From mitochondrial genome evolution to ribosomal frameshifting as a new route to novel gene birth

Animal mitochondrial genomes are constrained throughout evolution, yet their regulation, architecture, and evolutionary dynamics are not well understood. My PhD studies address two aspects of the mitochondrial genetic system: how are nuclear and mitochondrial DNA genes (nDNA and mtDNA, respectively) co-regulated in response to environmental challenges, and what are the selective constraints that act on the mtDNA genetic information in terms of mtDNA genomic rarrangements and gene overlapping sequences, especially while considering dual-coding regions. First, we characterized the mito-nuclear gene expression response to hypoxia across 21 human cell lines, identifying c-JUN as a likely coordinator of OXPHOS genes across the mtDNA and nDNA, thus establishing a new axis of mito-nuclear communication (Shtolz et al., Communications Biology, 2026). On the evolutionary side, large-scale comparative analysis of ~8,000 metazoan mtDNAs quantified gene order conservation, genomic rearrangements, and lineage-specific gene content variation across phyla (Shtolz et al., Communications Biology 2023). Furthermore, analysis of dual coding regions across ~66,000 different human mtDNA sequences revealed simultaneous purifying selection on both reading frames, providing population-level selective constraints acting on translational dual-coding (Shtolz et al., PhiloB, 2026). Currently, we are investigating the molecular mechanism underlying such overlaps. Using an expanded version of the aforementioned database of metazoan mtDNA sequences, combined with RNA structure probing (DMS-MaPseq) and in-vivo mutagenesis experiments, we show that ribosomal frameshifting explains the translational transition between the overlapping ATP8 and ATP6 frames, with conserved but distinct sequence elements comparable to canonical viral programmed ribosomal frameshifting. I will close by presenting a prospective research framework proposing ribosomal frameshifting as a possible mechanism for de-novo gene birth via overprinting.