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The code presented here was used to discover and characterize a novel overlapping ORF in the mRNA of POLG (ORF-Y) and a second, further upstream ORF (ORF-Z) that is likely regulatory in modulating translation between ORF-Y and the main ORF. The work is of interest for two main reasons
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Overlapping ORFs in the human genome of such length are extremely rare. ORF-Y in POLG may represent the longest bonafide overlapping ORF in the human genome.
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POLG is of significant clinical relevance. Many mutations have been mapped across its mRNA that link to mitochondrial disease. Given the extent of overlap with ORF-Y, it is possible that the mechanism of action of some of these mutations is a combined effect exerted on both the protein products of main ORF and ORF-Y.
The following will cogently run the readers through how the analysis of each of the figures was conducted with the accompanying code.
Panel a - Schematic of POLG mRNA: Generated in Powerpoint/Adobe Illustrator using https://uswest.ensembl.org/Homo_sapiens/Transcript/Summary?g=ENSG00000140521;r=15:89316305-89334795;t=ENST00000268124 as a guide
Panel b - PhyloCSF analysis of POLG: PhyloCSF is well documented and more information can be found at https://github.com/mlin/PhyloCSF/wiki
The video below gives a brief walkthrough how to recreate the Synplots in Figure 2 (click on the image).The accompanying code is available on the GitHub Page
Panel a - Global ribosome profiling for POLG was mined from GWIPSviz. A link to an in-browswer view of a similar region can be found here (https://gwips.ucc.ie/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr15%3A89333747%2D89333820&hgsid=101372_aEB2npsxOKHmIw45L71UMoAE5pnZ)
Panel b - Global ribosome profiling for POLG ORF-Y stop codon was mined from TRIPSviz.k A link to an in-browswer view of a similar region can be found here (https://trips.ucc.ie/homo_sapiens/Gencode_v25/interactive_plot/?files=&ribo_studies=18,20,21,23,24,27,28,29,31,32,33,34,35,38,39,42,43,44,45,56,58,60,62,63,64,67,89,90,99,101,102,103,107,113,122,124,130,134,138,141,144,150,152,153,165,171,172,176,177,178,179,181,183,190,191,192,201,204,212,216,217,222,225,229,234,&tran=ENST00000268124&minread=25&maxread=150&user_dir=fiveprime&ambig=F&cov=F&lg=T&nuc=T&rs=0&crd=F&short=qw0)
Panel c - See the video below