Translation and natural selection of micropeptides from long non-canonical RNAs

Patraquim, Pedro; Magny, Emile G.; Pueyo, José Ignacio; Platero, Ana Isabel; Couso, Juan Pablo

doi:10.1038/s41467-022-34094-y

Cited by 40 publications

(31 citation statements)

References 73 publications

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“…ORFs in Drosophila has been demonstrated using ribosomal profiling (Aspden et al, 2014;Patraquim et al, 2022), and pervasive transcription has also shown to evolve new functional protein (Ruiz-Orera et al, 2018). Overall, we observed all possible combinations of features to be involved in the creation of new ORFs, implying that there are many different paths giving rise to new ORFs.…”

Section: Enabling Mutationsmentioning

confidence: 59%

“…Furthermore, the here reported abundance of mainly short ORFs in non-coding DNA makes it likely that many are randomly translated (Ingolia et al, 2014). Indeed, the coding potential of thousands of small ORFs in Drosophila has been demonstrated using ribosomal profiling (Aspden et al, 2014; Patraquim et al, 2022), and pervasive transcription has also shown to evolve new functional protein (Ruiz-Orera et al, 2018). Overall, we observed all possible combinations of features to be involved in the creation of new ORFs, implying that there are many different paths giving rise to new ORFs.…”

Section: Discussionmentioning

confidence: 99%

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Population genomics reveals mechanisms and dynamics ofde novoproto-gene emergence inDrosophila melanogaster

Grandchamp

Kühl

Lebherz

et al. 2022

Preprint

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Novel genes are essential for evolutionary innovations and differ substantially even between closely related species. Recently, multiple studies across many taxa have suggested that some novel genes arise de novo, i.e. from previously non-coding DNA. In order to characterise the underlying mutations that allowed de novo gene emergence and their order of occurrence, homologous regions must be detected within non-coding sequences in closely related sister genomes. So far, most studies do not detect non-coding homologs of de novo genes due to inconsistent data and long evolutionary distances separating genomes. Here we overcome these issues by searching for proto-genes, the not-yet fixed precursors of de novo genes that emerged within a single species. We sequenced and assembled genomes with long-read technology and the corresponding transcriptomes from inbred lines of Drosophila melanogaster, derived from seven geographically diverse populations. We found line-specific proto-genes in abundance but few proto- genes shared by lines, suggesting a rapid turnover. Gain and loss of transcription is more frequent than the creation of Open Reading Frames (ORFs), e.g. by forming new START- and STOP-codons. Consequently, the gain of ORFs becomes rate limiting and is frequently the initial step in proto-gene emergence. Furthermore, Transposable Elements (TEs) are major drivers for intra genomic duplications of proto-genes, yet TE insertions are less important for the emergence of proto-genes. However, highly mutable genomic regions around TEs provide new features that enable gene birth. In conclusion, proto- genes have a high birth-death rate, are rapidly purged, but surviving proto-genes spread neutrally through populations and within genomes.

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Section: Enabling Mutationsmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Population genomics reveals mechanisms and dynamics ofde novoproto-gene emergence inDrosophila melanogaster

Grandchamp

Kühl

Lebherz

et al. 2022

Preprint

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“…However, up to 0.3 micropeptides might exist per transcribed lncRNA, which is significant for a molecular species characterized by its noncoding character. Up to 7000 micropeptides can be expected to be expressed in the human genome [ 52 ]. Currently, only 10% of these are already quantifiable, and most need to be functionally tested [ 53 ].…”

Section: New Concepts Of Long Noncoding Rnas Function With Potential ...mentioning

confidence: 99%

Long noncoding RNAs in cardiovascular disease

Kohlmaier

Holdt

Teupser

2023

Current Opinion in Cardiology

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Purpose of review Here, we review recent findings on the role of long noncoding RNAs (lncRNAs) in cardiovascular disease (CVD). In addition, we highlight some of the latest findings in lncRNA biology, providing an outlook for future avenues of lncRNA research in CVD. Recent findings Recent publications provide translational evidence from patient studies and animal models for the role of specific lncRNAs in CVD. The molecular effector mechanisms of these lncRNAs are diverse. Overall, cell-type selective modulation of gene expression is the largest common denominator. New methods, such as single-cell profiling and CRISPR/Cas9-screening, reveal additional novel mechanistic principles: For example, many lncRNAs establish RNA-based spatial compartments that concentrate effector proteins. Also, RNA modifications and splicing features can be determinants of lncRNA function. Summary lncRNA research is passing the stage of enumerating lncRNAs or recording simplified on-off expression switches. Mechanistic analyses are starting to reveal overarching principles of how lncRNAs can function. Exploring these principles with decisive genetic testing in vivo remains the ultimate test to discern how lncRNA loci, by RNA motifs or DNA elements, affect CVD pathophysiology.

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“…Comparative analyses of translation properties and molecular and evolutionary signatures of these translated smORFs have revealed the existence of distinct classes of smORFs which could represent different stages of smORF functionalization (Aspden et al, 2014;Couso and Patraquim, 2017;Patraquim et al, 2022). This classification suggested the existence of five different ORF classes, which displayed different size, conservation, organisation, translation, structure, and amino acid preference that each different class would represent a step in gene, protein and peptide evolution.…”

Section: Introductionmentioning

confidence: 98%

“…For instance, lncORFs and upstream ORFs (uORFs) both have a very similar median ORF size (22-24 codons), and they are found in polycistronic arrangements within the transcript. Generally, the conservation scores of these two ORF classes are low, their codon usages are not random but are different from canonical proteins, and despite being translated their translational efficiency is low in comparison with canonical proteins (Aspden et al, 2014;Couso and Patraquim, 2017;Patraquim et al, 2020;Patraquim et al, 2022). Although, several uORFs and lncORFs encode peptides with important cellular functions (Magny et al, 2013;Anderson Douglas et al, 2015;Matsumoto et al, 2017;Jayaram et al, 2021) the majority of uORF and lncORF classes appear to function as translational regulators of main ORFs and in a variety of non-coding regulatory functions respectively (Aspden et al, 2014;Couso and Patraquim, 2017;Patraquim et al, 2020;Patraquim et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Purriato is a conserved small open reading frame gene that interacts with the CASA pathway to regulate muscle homeostasis and epithelial tissue growth in Drosophila

Pueyo

Salazar²,

Grincho³

et al. 2023

Front. Cell Dev. Biol.

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Recent advances in proteogenomic techniques and bioinformatic pipelines have permitted the detection of thousands of translated small Open Reading Frames (smORFs), which contain less than 100 codons, in eukaryotic genomes. Hundreds of these actively translated smORFs display conserved sequence, structure and evolutionary signatures indicating that the translated peptides could fulfil important biological roles. Despite their abundance, only tens of smORF genes have been fully characterised; these act mainly as regulators of canonical proteins involved in essential cellular processes. Importantly, some of these smORFs display conserved functions with their mutations being associated with pathogenesis. Thus, investigating smORF roles in Drosophila will not only expand our understanding of their functions but it may have an impact in human health. Here we describe the function of a novel and essential Drosophila smORF gene named purriato (prto). prto belongs to an ancient gene family whose members have expanded throughout the Protostomia clade. prto encodes a transmembrane peptide which is localized in endo-lysosomes and perinuclear and plasma membranes. prto is dynamically expressed in mesodermal tissues and imaginal discs. Targeted prto knockdown (KD) in these organs results in changes in nuclear morphology and endo-lysosomal distributions correlating with the loss of sarcomeric homeostasis in muscles and reduction of mitosis in wing discs. Consequently, prto KD mutants display severe reduction of motility, and shorter wings. Finally, our genetic interaction experiments show that prto function is closely associated to the CASA pathway, a conserved mechanism involved in turnover of mis-folded proteins and linked to muscle dystrophies and neurodegenerative diseases. Thus, this study shows the relevance of smORFs in regulating important cellular functions and supports the systematic characterisation of this class of genes to understand their functions and evolution.

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Translation and natural selection of micropeptides from long non-canonical RNAs

Cited by 40 publications

References 73 publications

Population genomics reveals mechanisms and dynamics ofde novoproto-gene emergence inDrosophila melanogaster

Population genomics reveals mechanisms and dynamics ofde novoproto-gene emergence inDrosophila melanogaster

Long noncoding RNAs in cardiovascular disease

Purriato is a conserved small open reading frame gene that interacts with the CASA pathway to regulate muscle homeostasis and epithelial tissue growth in Drosophila

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