{"doi":"10.1186/s12863-020-0828-7","title":"Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon","abstract":"<h4>Background</h4>POLG, located on nuclear chromosome 15, encodes the DNA polymerase γ(Pol γ). Pol γ is responsible for the replication and repair of mitochondrial DNA (mtDNA). Pol γ is the only DNA polymerase found in mitochondria for most animal cells. Mutations in POLG are the most common single-gene cause of diseases of mitochondria and have been mapped over the coding region of the POLG ORF.<h4>Results</h4>Using PhyloCSF to survey alternative reading frames, we found a conserved coding signature in an alternative frame in exons 2 and 3 of POLG, herein referred to as ORF-Y that arose de novo in placental mammals. Using the synplot2 program, synonymous site conservation was found among mammals in the region of the POLG ORF that is overlapped by ORF-Y. Ribosome profiling data revealed that ORF-Y is translated and that initiation likely occurs at a CUG codon. Inspection of an alignment of mammalian sequences containing ORF-Y revealed that the CUG codon has a strong initiation context and that a well-conserved predicted RNA stem-loop begins 14 nucleotides downstream. Such features are associated with enhanced initiation at near-cognate non-AUG codons. Reanalysis of the Kim et al. (2014) draft human proteome dataset yielded two unique peptides that map unambiguously to ORF-Y. An additional conserved uORF, herein referred to as ORF-Z, was also found in exon 2 of POLG. Lastly, we surveyed Clinvar variants that are synonymous with respect to the POLG ORF and found that most of these variants cause amino acid changes in ORF-Y or ORF-Z.<h4>Conclusions</h4>We provide evidence for a novel coding sequence, ORF-Y, that overlaps the POLG ORF. Ribosome profiling and mass spectrometry data show that ORF-Y is expressed. PhyloCSF and synplot2 analysis show that ORF-Y is subject to strong purifying selection. An abundance of disease-correlated mutations that map to exons 2 and 3 of POLG but also affect ORF-Y provides potential clinical significance to this finding.","journal":"BMC Genetics","year":2020,"id":7695,"datarank":1.0715337227468174,"base_score":3.7376696182833684,"endowment":3.7376696182833684,"self_citation_contribution":0.5606504427425053,"citation_network_contribution":0.510883280004312,"self_endowment_contribution":0.5606504427425053,"citer_contribution":0.510883280004312,"corpus_percentile":null,"corpus_rank":null,"citation_count":41,"citer_count":24,"citers_with_citation_signal":22,"citers_with_endowment":22,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0541,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-03-06","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":292,"name":"Irwin Jungreis","orcid":"0000-0002-3197-5367","position":1,"is_corresponding":false},{"id":43288,"name":"James C. Wright","orcid":"0000-0001-6950-4328","position":2,"is_corresponding":false},{"id":24517,"name":"Shinichi Morishita","orcid":"0000-0002-6201-8885","position":3,"is_corresponding":false},{"id":17805,"name":"Jyoti Sharma Choudhary","orcid":"0000-0003-0881-5477","position":4,"is_corresponding":false},{"id":17822,"name":"Andrew E. Firth","orcid":"0000-0002-7986-9520","position":5,"is_corresponding":false},{"id":14693,"name":"Sharon L. R. Kardia","orcid":"0000-0002-9853-3379","position":6,"is_corresponding":false},{"id":59641,"name":"Yousuf A. Khan","orcid":"0000-0003-0201-2796","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}