Abstract
In 2004, when the protein estimate from the finished human genome was only 24,000, the surprise was compounded as reviewed estimates fell to 19,000 by 2014. However, variability in the total canonical protein counts (i.e. excluding alternative splice forms) of open reading frames (ORFs) in different annotation portals persists. This work assesses these differences and possible causes. A 16-year analysis of Ensembl and UniProtKB/Swiss-Prot shows convergence to a protein number of ~20,000. The former had shown some yo-yoing, but both have now plateaued. Nine major annotation portals, reviewed at the beginning of 2017, gave a spread of counts from 21,819 down to 18,891. The 4-way cross-reference concordance (within UniProt) between Ensembl, Swiss-Prot, Entrez Gene and the Human Gene Nomenclature Committee (HGNC) drops to 18,690, indicating methodological differences in protein definitions and experimental existence support between sources. The Swiss-Prot and neXtProt evidence criteria include mass spectrometry peptide verification and also cross-references for antibody detection from the Human Protein Atlas. Notwithstanding, hundreds of Swiss-Prot entries are classified as non-coding biotypes by HGNC. The only inference that protein numbers might still rise comes from numerous reports of small ORF (smORF) discovery. However, while there have been recent cases of protein verifications from previous miss-annotation of non-coding RNA, very few have passed the Swiss-Prot curation and genome annotation thresholds. The post-genomic era has seen both advances in data generation and improvements in the human reference assembly. Notwithstanding, current numbers, while persistently discordant, show that the earlier yo-yoing has largely ceased. Given the importance to biology and biomedicine of defining the canonical human proteome, the task will need more collaborative inter-source curation combined with broader and deeper experimental confirmation in vivo and in vitro of proteins predicted in silico. The eventual closure could be well be below ~19,000.
Highlights
While hypothesis-neutral scientific endeavours are sometimes referred to in derogatory terms as “stamp collecting”, the collation of molecular part lists remains a crucially important exercise, for many aspects of basic biology, and for application to the biomedical sciences and drug discovery
The alpha-2B adrenergic receptor, ADRA2B (P18089) is solidly supported, but in this was Conclusions Despite over 16 years having elapsed since the first draft human genome, the diversity of current counts indicates that progress towards what the community might consider a gold-standard set of canonical protein sequences, remains frustratingly slow
The wider bioscience community could be forgiven being puzzled that major global efforts continue to produce different sets of canonical proteins at roughly the same time from the same primary data
Summary
While saying that the longest mRNA strategy has data support, it would be worth mentioning the exception of read-through transcripts which can confuse this strategy significantly. "the choice was made here to exemplify just four identifiers, Swiss-Prot accession numbers, HGNC IDs (directly, or via the current gene symbols) Ensembl gene IDs and NCBI Entrez Gene IDs These were chosen for their global prominence and methodological complementarity. The reason for the increase in mappings to HGNC IDs is more likely the inclusion of mappings to loci that HGNC do not regard as protein-coding, such as immunoglobulin light chain segments, than it is due to Swiss-Prot having more than one HGNC ID in any given record This explanation is discussed in the paragraph where the types of loci enriched in specific segments are discussed, such as immunoglobulin light chain segments and endogenous retroviruses (note again the NCBI pipeline is referred to as "automation" which I do not think is a fair representation).
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