The Protein‐Coding Human Genome: Annotating High‐Hanging Fruits

Hatje, Klas; Mühlhausen, Stefanie; Simm, Dominic; Kollmar, Martin

doi:10.1002/bies.201900066

Cited by 18 publications

(12 citation statements)

References 151 publications

(134 reference statements)

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“…Setting aside the controversy in cell type definition ( 110 ), our work already provides tools and best practices to achieve better reference annotations and to share the gene signatures that capture the knowledge about how they were derived, which is novel compared to most current studies. As the human reference genome, which does not ultimately reflect a human genome consensus ( 111 ), but serves many practical purposes ( 112 ), accelerated genomic research, such reference cell type annotations will accelerate our understanding of biological systems even though they reflect only a subset of a cell's characteristics.…”

Section: Discussionmentioning

confidence: 99%

Besca, a single-cell transcriptomics analysis toolkit to accelerate translational research

Mädler

Julien-Laferrière

Wyss

et al. 2021

NAR Genomics and Bioinformatics

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Single-cell RNA sequencing (scRNA-seq) revolutionized our understanding of disease biology. The promise it presents to also transform translational research requires highly standardized and robust software workflows. Here, we present the toolkit Besca, which streamlines scRNA-seq analyses and their use to deconvolute bulk RNA-seq data according to current best practices. Beyond a standard workflow covering quality control, filtering, and clustering, two complementary Besca modules, utilizing hierarchical cell signatures and supervised machine learning, automate cell annotation and provide harmonized nomenclatures. Subsequently, the gene expression profiles can be employed to estimate cell type proportions in bulk transcriptomics data. Using multiple, diverse scRNA-seq datasets, some stemming from highly heterogeneous tumor tissue, we show how Besca aids acceleration, interoperability, reusability and interpretability of scRNA-seq data analyses, meeting crucial demands in translational research and beyond.

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Section: Discussionmentioning

confidence: 99%

Besca, a single-cell transcriptomics analysis toolkit to accelerate translational research

Mädler

Julien-Laferrière

Wyss

et al. 2021

NAR Genomics and Bioinformatics

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“…However, using the GENCODE transcript set as a reference increased the sensitivity, with the sensitivity of coding transcripts of some samples going above 60% and the noncoding sensitivity of some samples reaching 43%. Previous studies have reported that some genuine transcripts are missing in the GENCODE annotation [25,42,47,48]. Therefore, we repeated the analyses using the hPSC filtered transcript set [42].…”

Section: Impacts Of Sequencing Depth On Human Pluripotent Stem Cell Transcript Assemblymentioning

confidence: 99%

The effects of sequencing depth on the assembly of coding and noncoding transcripts in the human genome

Babarinde

Hutchins

2022

Preprint

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Background: Investigating the functions and activities of genes requires proper annotation of the transcribed units. However, transcript assembly efforts have produced a surprisingly large variation in the number of transcripts, and especially so for noncoding transcripts. The heterogeneity of the assembled transcript sets might be partially explained by sequencing depth. Results: Here, we used real and simulated short-read sequencing data as well as long-read data to systematically investigate the impact of sequencing depths on the accuracy of assembled transcripts. We assembled and analyzed transcripts from 671 human short-read data sets and four long-read data sets. At the first level, there is a positive correlation between the number of reads and the number of recovered transcripts. However, the effect of the sequencing depth varied based on cell or tissue type, the type of read considered and the nature and expression levels of the transcripts. The detection of coding transcripts saturated rapidly for both short-read and long-reads, however, there was no sign of saturation for noncoding transcripts at any sequencing depth. Increasing long-read sequencing depth specifically benefited transcripts containing transposable elements. Finally, we show how single-cell RNA-seq can be guided by transcripts assembled from bulk long-read samples, and demonstrate that noncoding transcripts are expressed at similar levels to coding transcripts but are expressed in fewer cells. Conclusions: This study shows the impact of sequencing depth on transcript assembly. Sequencing read depth has a relatively minor impact on coding transcript assembly, but a major effect on the assembly of noncoding transcripts. This study highlights important factors to consider when deciding the sequencing read depths to be used for transcript assembly.

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“…The sequencing of the human genome and that of other species has made great strides in cataloguing and annotating protein-coding genes. Systematic proteomic approaches have validated the existence of proteins for almost 20,000 protein-coding genes 1 . Notwithstanding, nearly 10% of these genes still lack functional annotation 2 .…”

Section: Introductionmentioning

confidence: 99%

Loss of C2orf69 defines a fatal auto-inflammatory mitochondriopathy in Humans and Zebrafish

Maier

et al. 2021

Preprint

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Human C2orf69 is an evolutionary-conserved gene whose function is unknown. Here, we report 9 children from 5 unrelated families with a fatal syndrome consisting of severe auto-inflammation, progredient leukoencephalopathy with recurrent seizures that segregate homozygous loss-of-function C2orf69 variants. C2ORF69 orthologues, which can be found in most eukaryotic genomes including that of unicellular phytoplanktons, bear homology to esterase enzymes. We find that human C2ORF69 is loosely bound to the mitochondrion and its depletion affects mitochondrial membrane potential in human fibroblasts and neurons. Moreover, we show that CRISPR/Cas9-inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures which is accompanied by persistent brain inflammation. Collectively, our results delineate a novel auto-inflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems as demonstrated in patients and in a zebrafish model of the disease.

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The Protein‐Coding Human Genome: Annotating High‐Hanging Fruits

Cited by 18 publications

References 151 publications

Besca, a single-cell transcriptomics analysis toolkit to accelerate translational research

Besca, a single-cell transcriptomics analysis toolkit to accelerate translational research

The effects of sequencing depth on the assembly of coding and noncoding transcripts in the human genome

Loss of C2orf69 defines a fatal auto-inflammatory mitochondriopathy in Humans and Zebrafish

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