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dc.contributor.authorKhan, Yousuf A
dc.contributor.authorJungreis, Irwin
dc.contributor.authorWright, James C
dc.contributor.authorMudge, Jonathan M
dc.contributor.authorChoudhary, Jyoti S
dc.contributor.authorFirth, Andrew E
dc.contributor.authorKellis, Manolis
dc.date.accessioned2020-07-10T20:28:44Z
dc.date.available2020-07-10T20:28:44Z
dc.date.issued2020-03
dc.date.submitted2019-11
dc.identifier.issn1471-2156
dc.identifier.urihttps://hdl.handle.net/1721.1/126141
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. ©2020en_US
dc.description.sponsorshipNational Human Genome Research Institute of the NIH (Award no. U41HG007234)en_US
dc.description.sponsorshipR01 HG004037en_US
dc.description.sponsorshipWellcome Trust (grant 106207)en_US
dc.publisherBioMed Centralen_US
dc.relation.isversionofhttps://dx.doi.org/10.1186/s12863-020-0828-7en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.sourceBioMed Centralen_US
dc.titleEvidence for a novel overlapping coding sequence in POLG initiated at a CUG start codonen_US
dc.typeArticleen_US
dc.identifier.citationKhan, Yousuf A. et al., "Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon." BMC Genetics 21 (March 2020): no. 25 doi. 10.1186/s12863-020-0828-7 ©2020 Authorsen_US
dc.contributor.departmentMassachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratoryen_US
dc.contributor.departmentBroad Institute of MIT and Harvarden_US
dc.relation.journalBMC Geneticsen_US
dc.identifier.mitlicensePUBLISHER_CC
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2020-06-26T11:02:48Z
dc.language.rfc3066en
dc.rights.holderThe Author(s).
dspace.date.submission2020-06-26T11:02:47Z
mit.journal.volume21en_US
mit.licensePUBLISHER_CC


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