Alternative Reading Frames are an Underappreciated Source of Protein Sequence Novelty

Ardern, Zachary

doi:10.1007/s00239-023-10122-3

Cited by 4 publications

(2 citation statements)

References 128 publications

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“…Taken together, although the ORFs encoded by these de novo genes are young, their loci should be old enough to facilitate an accurate inference of their origin and evolution. Theoretically, these loci could be regions encoding long non-coding RNAs (lncRNAs), previously existing genes encoding other ORFs (Ardern, 2023;Keese & Gibbs, 1992), or even revitalized pseudogenes, to provide the backbones for new de novo proteins (Figure 2).…”

Section: The Definition Of De Novo Genesmentioning

confidence: 99%

Origin of functional de novo genes in humans from “hopeful monsters”

Liu,

Xiao,

et al. 2024

WIREs RNA

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For a long time, it was believed that new genes arise only from modifications of preexisting genes, but the discovery of de novo protein‐coding genes that originated from noncoding DNA regions demonstrates the existence of a “motherless” origination process for new genes. However, the features, distributions, expression profiles, and origin modes of these genes in humans seem to support the notion that their origin is not a purely “motherless” process; rather, these genes arise preferentially from genomic regions encoding preexisting precursors with gene‐like features. In such a case, the gene loci are typically not brand new. In this short review, we will summarize the definition and features of human de novo genes and clarify their process of origination from ancestral non‐coding genomic regions. In addition, we define the favored precursors, or “hopeful monsters,” for the origin of de novo genes and present a discussion of the functional significance of these young genes in brain development and tumorigenesis in humans.This article is categorized under: RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution

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Section: The Definition Of De Novo Genesmentioning

confidence: 99%

Origin of functional de novo genes in humans from “hopeful monsters”

Liu,

Xiao,

et al. 2024

WIREs RNA

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“…As for eukaryotic SSOGs, rapid coding sequence divergence, frameshifting mutations, rearrangements or a combination of the above could explain some of the genes lacking similarity, including entirely species-specific ones(Yu & Stoltzfus 2012; Lobb et al 2015). Additionally, SSOGs could emerge de novo either from non-genic regions or from already coding ones but on an alternative reading frame, the latter known as overprinting(Delaye et al 2008; Ardern 2023). As in eukaryotes, pervasive transcription and translation occurs in prokaryotes and may generate raw material that natural selection can shape into a functional protein(Smith et al 2022; Wade & Grainger 2014; Wacholder et al 2023).…”

Section: Introductionmentioning

confidence: 99%

Large-scale investigation of species-specific orphan genes in the human gut microbiome elucidates their evolutionary origins

Vakirlis

Kupczok

2023

Preprint

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Orphan genes, i.e., genes that lack homologs outside a given species, are ubiquitous in all domains of life. In prokaryotes, orphans can originate (i) in the native genome via de novo evolution from non-genic regions or alternative frames of existing genes, or by rapid divergence and remodeling, or (ii) in a foreign genome, including viruses, followed by horizontal transfer. However, strong quantitative evidence supporting either scenario is lacking. Here we performed a systematic, large-scale analysis of orphan genes from human gut prokaryotes. After exhaustive filtering, we identified more than 6 million orphans in 4,644 species, which lack similarity to other prokaryotes and have no known functional domains. We find that a given species pangenome contains on average 2.6% orphan genes, which are mostly rare within a species. Overall, orphan genes use optimal codons less frequently, and their proteins are more disordered than those of conserved (i.e., non-orphan) genes. Importantly, the GC content of orphan genes in a given genome closely matches that of conserved ones. In contrast, the 5% of orphans that share similarity to known viral sequences have distinct characteristics that set them apart from the rest of the orphans, including lower GC content. By identifying the genomic region from which they evolved in closely related species, we provide evidence for native origination for a small subset of orphan genes and find that these orphans also differ in their properties from the remaining orphans. Finally, predicting orphan function by examining functional annotations in operon-like arrangements suggests that some orphan genes are membrane-related and involved in spore germination. Our results support that orphans emerge due to multiple routes, challenging the notion that external elements such as phages and plasmids are the primary source of prokaryotic genetic novelty. Importantly, origination in the native genome might provide a constant influx of mostly transient genes into the cloud genome of prokaryotic pangenomes, where some orphans may prove adaptive, facilitating evolutionary innovation.

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Large-scale investigation of species-specific orphan genes in the human gut microbiome elucidates their evolutionary origins

Vakirlis,

Kupczok

2024

Genome Res.

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Species-specific genes, also known as orphans, are ubiquitous across life's domains. In prokaryotes, species-specific orphan genes (SSOGs) are mostly thought to originate in external elements such as viruses followed by horizontal gene transfer, whereas the scenario of native origination, through rapid divergence or de novo, is mostly dismissed. However, quantitative evidence supporting either scenario is lacking. Here, we systematically analyzed genomes from 4644 human gut microbiome species and identified more than 600,000 unique SSOGs, representing an average of 2.6% of a given species’ pangenome. These sequences are mostly rare within each species yet show signs of purifying selection. Overall, SSOGs use optimal codons less frequently, and their proteins are more disordered than those of conserved genes (i.e., non-SSOGs). Importantly, across species, the GC content of SSOGs closely matches that of conserved ones. In contrast, the ∼5% of SSOGs that share similarity to known viral sequences have distinct characteristics, including lower GC content. Thus, SSOGs with similarity to viruses differ from the remaining SSOGs, contrasting an external origination scenario for most of them. By examining the orthologous genomic region in closely related species, we show that a small subset of SSOGs likely evolved natively de novo and find that these genes also differ in their properties from the remaining SSOGs. Our results challenge the notion that external elements are the dominant source of prokaryotic genetic novelty and will enable future studies into the biological role and relevance of species-specific genes in the human gut.

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Alternative Reading Frames are an Underappreciated Source of Protein Sequence Novelty

Cited by 4 publications

References 128 publications

Origin of functional de novo genes in humans from “hopeful monsters”

Origin of functional de novo genes in humans from “hopeful monsters”

Large-scale investigation of species-specific orphan genes in the human gut microbiome elucidates their evolutionary origins

Large-scale investigation of species-specific orphan genes in the human gut microbiome elucidates their evolutionary origins

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