scholarly journals A deep proteome and transcriptome abundance atlas of 29 healthy human tissues

2018 ◽  
Author(s):  
Dongxue Wang ◽  
Basak Eraslan ◽  
Thomas Wieland ◽  
Björn Hallström ◽  
Thomas Hopf ◽  
...  
Keyword(s):  
Protein Expression ◽  
Protein Level ◽  
Synthetic Peptides ◽  
Human Tissues ◽  
Healthy Human ◽  
Specific Expression ◽  
Human Genes ◽  
Mrna Variants ◽  
Human Protein Atlas ◽  
Human Proteins

AbstractGenome-, transcriptome- and proteome-wide measurements provide valuable insights into how biological systems are regulated. However, even fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we have generated a systematic, quantitative and deep proteome and transcriptome abundance atlas from 29 paired healthy human tissues from the Human Protein Atlas Project and representing human genes by 17,615 transcripts and 13,664 proteins. The analysis revealed that few proteins show truly tissue-specific expression, that vast differences between mRNA and protein quantities within and across tissues exist and that the expression levels of proteins are often more stable across tissues than those of transcripts. In addition, only ~2% of all exome and ~7% of all mRNA variants could be confidently detected at the protein level showing that proteogenomics remains challenging, requires rigorous validation using synthetic peptides and needs more sophisticated computational methods. Many uses of this resource can be envisaged ranging from the study of gene/protein expression regulation to protein biomarker specificity evaluation to name a few.

scholarly journals Humanization of yeast genes with multiple human orthologs reveals principles of functional divergence between paralogs

2019 ◽  
Author(s):  
Jon M. Laurent ◽  
Riddhiman K. Garge ◽  
Ashley I. Teufel ◽  
Claus O. Wilke ◽  
Aashiq H. Kachroo ◽  
...  
Keyword(s):  
Functional Divergence ◽  
Gene Families ◽  
Evolutionary Divergence ◽  
Orthologous Genes ◽  
Specific Expression ◽  
Human Genes ◽  
Human Orthologs ◽  
Human Proteins ◽  
Yeast Genes ◽  
Opening Up

AbstractDespite over a billion years of evolutionary divergence, several thousand human genes possess clearly identifiable orthologs in yeast, and many have undergone lineage-specific duplications in one or both lineages. The ortholog conjecture postulates that orthologous genes between species retain ancestral functions despite divergence over vast timescales, but duplicated genes will be free to diverge in function. However, the retention of ancestral functions among co-orthologs between species and within gene families has been difficult to test experimentally at scale. In order to investigate how ancestral functions are retained or lost post-duplication, we systematically replaced hundreds of essential yeast genes with their human orthologs from gene families that have undergone lineage-specific duplications, including those with single duplications (one yeast gene to two human genes, 1:2) or higher-order expansions (1:>2) in the human lineage. We observe a variable pattern of replaceability across different ortholog classes, with an obvious trend towards differential replaceability inside gene families, rarely observing replaceability by all members of a family. We quantify the ability of various properties of the orthologs to predict replaceability, showing that in the case of 1:2 orthologs, replaceability is predicted largely by the divergence and tissue-specific expression of the human co-orthologs, i.e. the human proteins that are less diverged from their yeast counterpart and more ubiquitously expressed across human tissues more often replace their single yeast ortholog. These trends were consistent with in silico simulations demonstrating that when only one ortholog is replaceable, it tends to be the least diverged of the pair. Replaceability of yeast genes having more than two human co-orthologs was marked by retention of orthologous interactions in functional or protein networks as well as by more ancestral subcellular localization. Overall, we performed >400 human gene replaceability assays revealing 56 new human-yeast complementation pairs, thus opening up avenues to further functionally characterize these human genes in a simplified organismal context.

scholarly journals Proteogenomics analysis of non-coding region encoded peptides in normal tissues and five cancer types

2020 ◽  
Author(s):  
Rong Xiang ◽  
Leyao Ma ◽  
Mingyu Yang ◽  
Zetian Zheng ◽  
Xiaofang Chen ◽  
...  
Keyword(s):  
Protein Level ◽  
Common Mechanism ◽  
Human Tissues ◽  
Proteomics Data ◽  
Coding Region ◽  
Healthy Human ◽  
Normal Tissues ◽  
Analysis Workflow ◽  
Cancer Types ◽  
Non Coding Rnas

AbstractPrevious proteogenomics studies have identified peptides encoded by non-coding sequences such as pseudogenes and long non-coding RNAs (lncRNAs) in healthy human tissues as well as in cancers. However, these studies are either limited to analyze only healthy or cancerous tissues, lacking direct comparison between them. In this study, we used an established proteogenomics analysis workflow to analyze proteomics data from 926 cancer samples of five cancer types and 31 different healthy human tissues. We observed the protein level expression of pseudogenes can be classified as ubiquitous or lineage expression. The ubiquitously translated pseudogenes are homologous to house-keeping genes. Our results suggest there is common mechanism underlying the translation of pseudogenes in both normal and tumors. Moreover, we discovered several translated non-coding genes such as DGCR5 and RHOXF1P3 that were up-regulated in tumors compared to normal. These translated pseudogenes imply the biological function of pseudogenes extends to protein level yet to be studied. Further, from the non-coding region encoded peptides specifically detected in tumors we have predicted a large number of potential neoantigens which can be developed as cancer vaccine.

scholarly journals Disrupting upstream translation in mRNAs is associated with human disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
David S. M. Lee ◽  
Joseph Park ◽  
Andrew Kromer ◽  
Aris Baras ◽  
Daniel J. Rader ◽  
...  
Keyword(s):  
Protein Expression ◽  
Biological Significance ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Protein Coding ◽  
Stop Codons ◽  
Human Genes ◽  
Strong Negative Selection ◽  
Disease Associations ◽  
Reading Frames

AbstractRibosome-profiling has uncovered pervasive translation in non-canonical open reading frames, however the biological significance of this phenomenon remains unclear. Using genetic variation from 71,702 human genomes, we assess patterns of selection in translated upstream open reading frames (uORFs) in 5’UTRs. We show that uORF variants introducing new stop codons, or strengthening existing stop codons, are under strong negative selection comparable to protein-coding missense variants. Using these variants, we map and validate gene-disease associations in two independent biobanks containing exome sequencing from 10,900 and 32,268 individuals, respectively, and elucidate their impact on protein expression in human cells. Our results suggest translation disrupting mechanisms relating uORF variation to reduced protein expression, and demonstrate that translation at uORFs is genetically constrained in 50% of human genes.

scholarly journals Annotation of snoRNA abundance across human tissues reveals complex snoRNA-host gene relationships

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Étienne Fafard-Couture ◽  
Danny Bergeron ◽  
Sonia Couture ◽  
Sherif Abou-Elela ◽  
Michelle S. Scott
Keyword(s):  
Housekeeping Genes ◽  
Host Gene ◽  
Rna Modification ◽  
Human Tissues ◽  
Rna Seq ◽  
Healthy Human ◽  
Protein Coding ◽  
Conservation Level ◽  
Nucleolar Rnas ◽  
Host Genes

Abstract Background Small nucleolar RNAs (snoRNAs) are mid-size non-coding RNAs required for ribosomal RNA modification, implying a ubiquitous tissue distribution linked to ribosome synthesis. However, increasing numbers of studies identify extra-ribosomal roles of snoRNAs in modulating gene expression, suggesting more complex snoRNA abundance patterns. Therefore, there is a great need for mapping the snoRNome in different human tissues as the blueprint for snoRNA functions. Results We used a low structure bias RNA-Seq approach to accurately quantify snoRNAs and compare them to the entire transcriptome in seven healthy human tissues (breast, ovary, prostate, testis, skeletal muscle, liver, and brain). We identify 475 expressed snoRNAs categorized in two abundance classes that differ significantly in their function, conservation level, and correlation with their host gene: 390 snoRNAs are uniformly expressed and 85 are enriched in the brain or reproductive tissues. Most tissue-enriched snoRNAs are embedded in lncRNAs and display strong correlation of abundance with them, whereas uniformly expressed snoRNAs are mostly embedded in protein-coding host genes and are mainly non- or anticorrelated with them. Fifty-nine percent of the non-correlated or anticorrelated protein-coding host gene/snoRNA pairs feature dual-initiation promoters, compared to only 16% of the correlated non-coding host gene/snoRNA pairs. Conclusions Our results demonstrate that snoRNAs are not a single homogeneous group of housekeeping genes but include highly regulated tissue-enriched RNAs. Indeed, our work indicates that the architecture of snoRNA host genes varies to uncouple the host and snoRNA expressions in order to meet the different snoRNA abundance levels and functional needs of human tissues.

Conditional Degrons for Controlling Protein Expression at the Protein Level

2017 ◽  
Vol 51 (1) ◽  
pp. 83-102 ◽  
Author(s):  
Toyoaki Natsume ◽  
Masato T. Kanemaki
Keyword(s):  
Protein Expression ◽  
Protein Level

scholarly journals Erythroid-Specific Expression of LIN28A Is Sufficient for Robust Gamma-Globin Gene and Protein Expression in Adult Erythroblasts

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0144977 ◽  
Author(s):  
Y. Terry Lee ◽  
Jaira F. de Vasconcellos ◽  
Colleen Byrnes ◽  
Megha Kaushal ◽  
Antoinette Rabel ◽  
...  
Keyword(s):  
Protein Expression ◽  
Globin Gene ◽  
Specific Expression ◽  
Gamma Globin ◽  
Gene And Protein Expression

scholarly journals Human Genes Escaping X-inactivation Revealed by Single Cell Expression Data

2018 ◽  
Author(s):  
Kerem Wainer Katsir ◽  
Michal Linial
Keyword(s):  
Single Cell ◽  
X Chromosome ◽  
Noncoding Rna ◽  
Phenotypic Variability ◽  
Cell Types ◽  
X Inactivation ◽  
Specific Expression ◽  
X Chromosomes ◽  
Human Genes ◽  
Cumulative Knowledge

AbstractBackgroundIn mammals, sex chromosomes pose an inherent imbalance of gene expression between sexes. In each female somatic cell, random inactivation of one of the X-chromosomes restores this balance. While most genes from the inactivated X-chromosome are silenced, 15-25% are known to escape X-inactivation (termed escapees). The expression levels of these genes are attributed to sex-dependent phenotypic variability.ResultsWe used single-cell RNA-Seq to detect escapees in somatic cells. As only one X-chromosome is inactivated in each cell, the origin of expression from the active or inactive chromosome can be determined from the variation of sequenced RNAs. We analyzed primary, healthy fibroblasts (n=104), and clonal lymphoblasts with sequenced parental genomes (n=25) by measuring the degree of allelic-specific expression (ASE) from heterozygous sites. We identified 24 and 49 candidate escapees, at varying degree of confidence, from the fibroblast and lymphoblast transcriptomes, respectively. We critically test the validity of escapee annotations by comparing our findings with a large collection of independent studies. We find that most genes (66%) from the unified set were previously reported as escapees. Furthermore, out of the overlooked escapees, 11 are long noncoding RNA (lncRNAs).ConclusionsX-chromosome inactivation and escaping from it are robust, permanent phenomena that are best studies at a single-cell resolution. The cumulative information from individual cells increases the potential of identifying escapees. Moreover, despite the use of a limited number of cells, clonal cells (i.e., same X-chromosomes are coordinately inhibited) with genomic phasing are valuable for detecting escapees at high confidence. Generalizing the method to uncharacterized genomic loci resulted in lncRNAs escapees which account for 20% of the listed candidates. By confirming genes as escapees and propose others as candidates from two different cell types, we contribute to the cumulative knowledge and reliability of human escapees.

scholarly journals Investigation of olfactory receptor family 51 subfamily j member 1 (OR51J1) gene susceptibility as a potential breast cancer-associated biomarker

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246752
Author(s):  
Maryam Asadi ◽  
Nahid Ahmadi ◽  
Simin Ahmadvand ◽  
Ali Akbar Jafari ◽  
Akbar Safaei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Statistical Analysis ◽  
Protein Expression ◽  
Olfactory Receptor ◽  
Mrna Level ◽  
Expression Level ◽  
Pcr Analysis ◽  
Normal Tissues ◽  
Qrt Pcr ◽  
Human Protein Atlas

Among cancer treatment methods, targeted therapy using cancer-associated biomarkers has minimum side effects. Recently olfactory receptor (OR) family attracts the researcher’s attention as a favorable biomarker of cancer. Here, a statistical approach using complete data from the human protein atlas database was used to evaluate the potential of OR51J1 gene as a cancer-associated biomarker. To confirm the findings of statistical analysis, the OR51J1 mRNA and protein expression levels in breast tumor and normal tissue were measured using quantitative Real Time PCR (qRT-PCR) and immunohistochemistry (IHC) techniques. The association with clinicopathological factors was analyzed. Statistical analysis revealed that OR51J1 has a high expression level in more than 20 types of cancer tissues without any expression in 44 normal tissues. In 15 cancer types, including breast cancer, expression score was more than 90%. The qRT-PCR analysis in breast cancer showed OR51J1 have significantly higher expression level in tumors than normal tissues (2.91 fold). The IHC results showed OR51J1 expression on other cellular subtypes than tumor and normal cells, including myoepithelium, fibroblast, and lymphocytes. OR51J1 protein expression in invasive cells, as well as its overall score, showed a significant correlation with ER and PR expression and breast cancer (BC) subtypes. Results revealed the potential of OR51J1 as a cancer-associated biomarker for the diagnosis of breast cancer at the mRNA level.

scholarly journals On the scope and limitations of baker's yeast as a model organism for studying human tissue-specific pathways

2014 ◽  
Author(s):  
Shahin Mohammadi ◽  
Baharak Saberidokht ◽  
Shankar Subramaniam ◽  
Ananth Grama
Keyword(s):  
Drug Targets ◽  
Model Organism ◽  
Functional Space ◽  
Computational Method ◽  
Therapeutic Interventions ◽  
Human Tissues ◽  
Human Interactome ◽  
Tissue Specific ◽  
Complex Disorders ◽  
Human Genes

Budding yeast, S. cerevisiae, has been used extensively as a model organism for studying cellular processes in evolutionarily distant species, including humans. However, different human tissues, while inheriting a similar genetic code, exhibit distinct anatomical and physiological properties. Specific biochemical processes and associated biomolecules that differentiate various tissues are not completely understood, neither is the extent to which a unicellular organism, such as yeast, can be used to model these processes within each tissue. We propose a novel computational and statistical framework to systematically quantify the suitability of yeast as a model organism for different human tissues. We develop a computational method for dissecting the human interactome into tissue-specific cellular networks. Using these networks, we simultaneously partition the functional space of human genes, and their corresponding pathways, based on their conservation both across species and among different tissues. We study these sub-spaces in detail, and relate them to the overall similarity of each tissue with yeast. Many complex disorders are driven by a coupling of housekeeping (universally expressed in all tissues) and tissue-selective (expressed only in specific tissues) dysregulated pathways. We show that human-specific subsets of tissue-selective genes are significantly associated with the onset and development of a number of pathologies. Consequently, they provide excellent candidates as drug targets for therapeutic interventions. We also present a novel tool that can be used to assess the suitability of the yeast model for studying tissue-specific physiology and pathophysiology in humans.

scholarly journals Functional human genes typically exhibit epigenetic conservation

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0253250
Author(s):  
Daniel Rud ◽  
Paul Marjoram ◽  
Kimberly Siegmund ◽  
Darryl Shibata
Keyword(s):  
Cell Lines ◽  
Drug Sensitivity ◽  
Single Gene ◽  
Functional Genes ◽  
Human Tissues ◽  
Gene Conservation ◽  
Individual Culture ◽  
Human Genes

Recent DepMap CRISPR-Cas9 single gene disruptions have identified genes more essential to proliferation in tissue culture. It would be valuable to translate these finding with measurements more practical for human tissues. Here we show that DepMap essential genes and other literature curated functional genes exhibit cell-specific preferential epigenetic conservation when DNA methylation measurements are compared between replicate cell lines and between intestinal crypts from the same individual. Culture experiments indicate that epigenetic drift accumulates through time with smaller differences in more functional genes. In NCI-60 cell lines, greater targeted gene conservation correlated with greater drug sensitivity. These studies indicate that two measurements separated in time allow normal or neoplastic cells to signal through conservation which human genes are more essential to their survival in vitro or in vivo.

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