dc.contributor.author | Khan, YA | |
dc.contributor.author | Jungreis, I | |
dc.contributor.author | Wright, JC | |
dc.contributor.author | Mudge, JM | |
dc.contributor.author | Choudhary, JS | |
dc.contributor.author | Firth, AE | |
dc.contributor.author | Kellis, M | |
dc.date.accessioned | 2020-04-09T13:31:09Z | |
dc.date.issued | 2020-03-06 | |
dc.identifier.citation | BMC genetics, 2020, 21 (1), pp. 25 - ? | |
dc.identifier.issn | 1471-2156 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3589 | |
dc.identifier.eissn | 1471-2156 | |
dc.identifier.doi | 10.1186/s12863-020-0828-7 | |
dc.description.abstract | BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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. | |
dc.format | Electronic | |
dc.format.extent | 25 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | BMC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Mitochondria | |
dc.subject | Ribosomes | |
dc.subject | Humans | |
dc.subject | DNA, Mitochondrial | |
dc.subject | Codon, Initiator | |
dc.subject | Amino Acid Sequence | |
dc.subject | Nucleic Acid Conformation | |
dc.subject | Open Reading Frames | |
dc.subject | Exons | |
dc.subject | DNA Polymerase gamma | |
dc.title | Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-02-19 | |
rioxxterms.versionofrecord | 10.1186/s12863-020-0828-7 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-03-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | BMC genetics | |
pubs.issue | 1 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Functional Proteomics Group | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Functional Proteomics Group | |
pubs.publication-status | Published | |
pubs.volume | 21 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Functional Proteomics Group | |
dc.contributor.icrauthor | Wright, James | |
dc.contributor.icrauthor | Choudhary, Jyoti | |