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dc.contributor.authorKhan, YA
dc.contributor.authorJungreis, I
dc.contributor.authorWright, JC
dc.contributor.authorMudge, JM
dc.contributor.authorChoudhary, JS
dc.contributor.authorFirth, AE
dc.contributor.authorKellis, M
dc.date.accessioned2020-04-09T13:31:09Z
dc.date.issued2020-03-06
dc.identifier.citationBMC genetics, 2020, 21 (1), pp. 25 - ?
dc.identifier.issn1471-2156
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3589
dc.identifier.eissn1471-2156
dc.identifier.doi10.1186/s12863-020-0828-7
dc.description.abstractBackground 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.formatElectronic
dc.format.extent25 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectMitochondria
dc.subjectRibosomes
dc.subjectHumans
dc.subjectDNA, Mitochondrial
dc.subjectCodon, Initiator
dc.subjectAmino Acid Sequence
dc.subjectNucleic Acid Conformation
dc.subjectOpen Reading Frames
dc.subjectExons
dc.subjectDNA Polymerase gamma
dc.titleEvidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon.
dc.typeJournal Article
dcterms.dateAccepted2020-02-19
rioxxterms.versionofrecord10.1186/s12863-020-0828-7
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-03-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBMC genetics
pubs.issue1
pubs.notesNo 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-statusPublished
pubs.volume21
pubs.embargo.termsNo embargo
icr.researchteamFunctional Proteomics Groupen_US
dc.contributor.icrauthorWright, Jamesen
dc.contributor.icrauthorChoudhary, Jyotien


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