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Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling

View Article: PubMed Central - PubMed

ABSTRACT

Accurate annotation of protein coding regions is essential for understanding how genetic information is translated into function. We describe riboHMM, a new method that uses ribosome footprint data to accurately infer translated sequences. Applying riboHMM to human lymphoblastoid cell lines, we identified 7273 novel coding sequences, including 2442 translated upstream open reading frames. We observed an enrichment of footprints at inferred initiation sites after drug-induced arrest of translation initiation, validating many of the novel coding sequences. The novel proteins exhibit significant selective constraint in the inferred reading frames, suggesting that many are functional. Moreover, ~40% of bicistronic transcripts showed negative correlation in the translation levels of their two coding sequences, suggesting a potential regulatory role for these novel regions. Despite known limitations of mass spectrometry to detect protein expressed at low level, we estimated a 14% validation rate. Our work significantly expands the set of known coding regions in humans.

Doi:: http://dx.doi.org/10.7554/eLife.13328.001

No MeSH data available.


Related in: MedlinePlus

Decision rules to identify matches and mismatches of mCDS to annotation.Illustrating the decisions by which mCDS inferred on each transcript are identified as an exact match, a frame match) or a mismatch to annotated coding sequences. Matches and mismatches are only defined when the transcript is annotated by GENCODE as coding and the classification depends on agreement with the annotated CDS. A gene is considered to have an exact (or frame) match if at least one of its isoforms is labeled an exact (or frame) match. In all other cases, the inference for the coding gene is considered a mismatch.DOI:http://dx.doi.org/10.7554/eLife.13328.005
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fig1s3: Decision rules to identify matches and mismatches of mCDS to annotation.Illustrating the decisions by which mCDS inferred on each transcript are identified as an exact match, a frame match) or a mismatch to annotated coding sequences. Matches and mismatches are only defined when the transcript is annotated by GENCODE as coding and the classification depends on agreement with the annotated CDS. A gene is considered to have an exact (or frame) match if at least one of its isoforms is labeled an exact (or frame) match. In all other cases, the inference for the coding gene is considered a mismatch.DOI:http://dx.doi.org/10.7554/eLife.13328.005

Mentions: Among 7801 GENCODE annotated coding genes for which we could infer a high posterior mCDS, we recovered the annotated reading frame for at least one transcript isoform in 7491 genes (96%); of these, we recovered the exact annotated CDS in 4500 genes. In the remaining 310 genes, among all isoforms where we inferred an mCDS, the mCDS had a distinct reading frame from the annotated CDS (Figure 1—figure supplement 3 details the rules that decide how our inference agrees with GENCODE). Of all GENCODE coding genes, we identified 814 GENCODE isoforms where our method identified an mCDS with a distinct reading frame from the annotated CDS. This set of 814 includes both isoforms within the 310 genes and additional isoforms within the 7491 genes (i.e., excluding the isoforms where the mCDS matched the frame of the annotated CDS).


Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling
Decision rules to identify matches and mismatches of mCDS to annotation.Illustrating the decisions by which mCDS inferred on each transcript are identified as an exact match, a frame match) or a mismatch to annotated coding sequences. Matches and mismatches are only defined when the transcript is annotated by GENCODE as coding and the classification depends on agreement with the annotated CDS. A gene is considered to have an exact (or frame) match if at least one of its isoforms is labeled an exact (or frame) match. In all other cases, the inference for the coding gene is considered a mismatch.DOI:http://dx.doi.org/10.7554/eLife.13328.005
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940163&req=5

fig1s3: Decision rules to identify matches and mismatches of mCDS to annotation.Illustrating the decisions by which mCDS inferred on each transcript are identified as an exact match, a frame match) or a mismatch to annotated coding sequences. Matches and mismatches are only defined when the transcript is annotated by GENCODE as coding and the classification depends on agreement with the annotated CDS. A gene is considered to have an exact (or frame) match if at least one of its isoforms is labeled an exact (or frame) match. In all other cases, the inference for the coding gene is considered a mismatch.DOI:http://dx.doi.org/10.7554/eLife.13328.005
Mentions: Among 7801 GENCODE annotated coding genes for which we could infer a high posterior mCDS, we recovered the annotated reading frame for at least one transcript isoform in 7491 genes (96%); of these, we recovered the exact annotated CDS in 4500 genes. In the remaining 310 genes, among all isoforms where we inferred an mCDS, the mCDS had a distinct reading frame from the annotated CDS (Figure 1—figure supplement 3 details the rules that decide how our inference agrees with GENCODE). Of all GENCODE coding genes, we identified 814 GENCODE isoforms where our method identified an mCDS with a distinct reading frame from the annotated CDS. This set of 814 includes both isoforms within the 310 genes and additional isoforms within the 7491 genes (i.e., excluding the isoforms where the mCDS matched the frame of the annotated CDS).

View Article: PubMed Central - PubMed

ABSTRACT

Accurate annotation of protein coding regions is essential for understanding how genetic information is translated into function. We describe riboHMM, a new method that uses ribosome footprint data to accurately infer translated sequences. Applying riboHMM to human lymphoblastoid cell lines, we identified 7273 novel coding sequences, including 2442 translated upstream open reading frames. We observed an enrichment of footprints at inferred initiation sites after drug-induced arrest of translation initiation, validating many of the novel coding sequences. The novel proteins exhibit significant selective constraint in the inferred reading frames, suggesting that many are functional. Moreover, ~40% of bicistronic transcripts showed negative correlation in the translation levels of their two coding sequences, suggesting a potential regulatory role for these novel regions. Despite known limitations of mass spectrometry to detect protein expressed at low level, we estimated a 14% validation rate. Our work significantly expands the set of known coding regions in humans.

Doi:: http://dx.doi.org/10.7554/eLife.13328.001

No MeSH data available.


Related in: MedlinePlus