| The Human Proteome Project(HPP)of the Human Proteome Organization(HUPO)was established in 2010 as a global initiative.One scientific project of HPP is the Chromosome-Centric Human Proteome Project(C-HPP).The mission of the C-HPP is to map and annotate the entire predicted human protein set encoded by each chromosome.The initial steps of the project are focused on missing proteins,which lacked documented evidence for existence at protein level.MPs are those proteins that belong to PE2–4 in neXtProt,which lack confident MS evidence or any antibody-captured verification,but for which there can be either transcriptomic evidence in human,or any type of evidence in other species.Before the start of this research,there are still more than 10% of proteins which missing.Previous studies on missing proteins have shown that the potential solutions for such problems may be the development of advanced software for spectral search methods and the use of high-resolution mass spectrometry.Also,useing of RNA-Seq analysis can better guide tissue selection.In addition,previous studies have shown that evolution is closely related to the regulation of development,differentiation and tumorigenesis.Because missing-protein-encoding genes tend to located in some chromosomal gene clusters,regularity analysis combining chromosome location,chromosome evolution and gene expression and regulation is necessary for the identification and functional research of missing proteins.Here,we classified missing-protein-encoding genes into two groups,the genes encoding PE2 proteins(with transcript evidence)and the genes encoding PE3/4proteins(with no transcript evidence).We believe the extremely special physical-chemical properties of PE2 missing proteins affect their detectability by proteomic technologies.The PE3/4 genes may only express at extremely not common organs,tissues,cell types(OTCs),or special conditions,so they were considered to be extremely spatial-temporal specific genes.To define the spatial-temporal specificity of gene expression,we used a comprehensive transcriptome data set of 32 different human organs and tissues to count the number of organs or tissues in which the interest gene expressed.Ordinary spatial-temporal specific genes were the organ-,tissue-,or cell-type-specific genes(OTCFGs).Then we defined multispecies homologous synteny blocks(ms HSBs),and calculated the evolutionary rates of human proteins based on the ortholog pairs between H.sapiens and P.troglodytes.We also defined gene age by the most recent common ancestor(MRCA).Pairwise paralogy relationships were used to identify the paralogous gene groups(PGGs).The regularity analysis revealed that missing-protein-encoding genes distribute unevenly among different chromosomes,chromosomal regions,or gene clusters.In the view of evolutionary features,PE3/4 genes tend to be young,spreading at the non-homology chromosomal regions,evolving at higher rates.And interestingly,there is a higher proportion of singletons in PE3/4 genes than the proportion of singletons in all PCGs and OTCSGs(organ,tissue,cell type-specific genes).More importantly,most of the PE3/4 genes belong to the newly duplicated members of the paralogous gene groups,which mainly contribute to special biological functions,such as “smell perception”.These functions are heavily restricted into specific type of cells,tissues or specific developmental stages,acting as the new functional requirements which facilitated the emergence of the missing-protein-encoding genes during evolution.In addition,the criteria for the extremely special physical-chemical proteins were firstly set up based on the properties of PE2 proteins,and the evolutionary characteristics of those proteins were explored.In summary,we obtain the extremely spatio-temporal specific expression pattern and the evolutionary model of missing proteins,which provides new insights into the relationship between evolution and regulation,also expected to be highly instructive for proteomics and functional studies of MPs in the future. |
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