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Biology subjects

Jehn, J.

Publications and source records attributed to Jehn, J..

5 recordsLinked to original sources

LOAM: A family of genomic language models trained on long-read soil metagenomes

Soil ecosystems represent a vast, largely uncharacterised reservoir of microbial diversity. Metagenomic assembly has unlocked access to this resource, and recent advances in long-read sequencing have improved the recovery and quality of microbial genomes from complex samples. While genomic language models have proven highly effective at capturing biological concepts from large sequence datasets, they have predominantly been trained on reference genomes or short-read assemblies. Here, we present LOAM, a family of decoder-only genomic language models ranging from 25 to 624 million parameters and trained exclusively on Oxford Nanopore long-read environmental metagenomes. LOAM model performance scales predictably with model size and training-token budget. Despite a relatively small training sequence corpus, LOAM models outperformed comparably sized models across biological benchmarks, and achieved performance competitive with substantially larger state-of-the-art models trained on much larger datasets. Context-intervention experiments further showed that LOAM models use genomic information over several kilobases, highlighting the potential value of increased contiguity provided by long-read metagenome-assembled genomes. For probe-based benchmark tasks, we systematically evaluated representations across hidden layers and revealed that task-relevant biological information was frequently more linearly accessible from intermediate than final model layers. Finally, we observed that variation in zero-shot variant-effect prediction was strongly associated with the presence of homologous target sequences in the pre-training corpus. Together, these results establish long-read environmental metagenomes as a viable foundation for training competitive genomic language models and demonstrate the importance of both model scale and training-corpus composition for biological generalisation.

genomics↗

TransfoRNA: Navigating the Uncertainties of Small RNA Annotation with an Adaptive Machine Learning Strategy

Small RNAs hold crucial biological information and have immense diagnostic and therapeutic value. While many established annotation tools focus on microRNAs, there are myriads of other small RNAs that are currently underutilized. These small RNAs can be difficult to annotate, as ground truth is limited and well-established mapping and mismatch rules are lacking. TransfoRNA is a machine learning framework based on Transformers that explores an alternative strategy. It uses common annotation tools to generate a small seed of high-confidence training labels, while then expanding upon those labels iteratively. TransfoRNA learns sequence-specific representations of all RNAs to construct a similarity network which can be interrogated as new RNAs are annotated, allowing to rank RNAs based on their familiarity. While models can be flexibly trained on any RNA dataset, we here present a version trained on TCGA (The Cancer Genome Atlas) small RNA sequences and demonstrate its ability to add annotation confidence to an unrelated dataset, where 21% of previously unannotated RNAs could be annotated. Relative to its training data, TransfoRNA could boost high-confidence annotations in TCGA by [~]50% while providing transparent explanations even for low-confidence ones. It could learn to annotate 97% of isomiRs from just single examples and confidently identify new members of other familiar classes with high accuracy, while reliably rejecting false RNAs. All source code is available at https://github.com/gitHBDX/TransfoRNA and can be executed at Code Ocean (https://codeocean.com/capsule/5415298/). An interactive website is available at www.transforna.com. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/599329v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@11bc3d9org.highwire.dtl.DTLVardef@1d6ff01org.highwire.dtl.DTLVardef@1ffac02org.highwire.dtl.DTLVardef@75ccd8_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

5’ tRNA halves are highly expressed in the primate hippocampus and sequence-specifically regulate gene expression

Fragments of mature tRNAs have long been considered as mere degradation products without physiological function. However, recent reports show that tRNA fragments (tRFs) play prominent roles in diverse cellular processes across a wide spectrum of species. Contrasting the situation in other small RNA pathways the mechanisms behind these effects appear more diverse, more complex and are generally less well understood. In addition, surprisingly little is known about the expression profiles of tRFs across different tissues and species. Here, we provide an initial overview of tRF expression in different species and tissues, revealing very high tRF-levels particularly in the primate hippocampus. We further modulated the regulation capacity of selected tRFs in human cells by transfecting synthetic tRF mimics (\"overexpression\") or antisense-RNAs (\"inhibition\") and identified differentially expressed transcripts based on RNAseq. We then used a novel k-mer mapping approach to dissect the underlying targeting rules, demonstrating that 5 tRNA halves (5 tRHs) silence genes in a sequence-specific manner, while the most efficient target sites align to the mid-region of the 5 tRH and are located within the CDS or 3 UTR of the target. This amends previous observations that tRFs guide Argonaut proteins to silence their targets via a miRNA-like 5 seed match and suggests a yet unknown mechanism of regulation. Finally, our data suggests that some 5 tRHs are also able to sequence-specifically stabilize mRNAs as upregulated mRNAs are also significantly enriched for 5 tRH target sites.

molecular biology↗

Widespread selection for high and low secondary structure in coding sequences across all domains of life

Codon composition, GC-content and local RNA secondary structures can have a profound effect on gene expression and mutations affecting these parameters, even though they do not alter the protein sequence, are not neutral in terms of selection. Although evidence exists that in some cases selection favors more stable RNA secondary structures, we currently lack a concrete idea of how many genes are affected within a species, and if this is a universal phenomenon in nature. We searched for signs of structural selection in a global manner, analyzing a set of one million coding sequences from 73 species representing all domains of life, as well as viruses, by means of our newly developed software PACKEIS. We show that codon composition and amino acid identity are main determinants of RNA secondary structure. In addition, we show that the arrangement of synonymous codons within coding sequences is non-random, yielding extremely high, but also extremely low secondary structures significantly more often than expected by chance. Together, we demonstrate that selection for high and low secondary structure is a widespread phenomenon. Our results provide another line of evidence that synonymous mutations are less neutral than commonly thought, which is of importance for many evolutionary models.

evolutionary biology↗

Conserved and ubiquitous expression of piRNAs and PIWI genes in mollusks antedates the origin of somatic PIWI/piRNA expression to the root of bilaterians

PIWI proteins and a specific class of small non-coding RNAs, termed Piwi interacting RNAs (piRNAs), suppress transposon activity in animals on the transcriptional and post-transcriptional level, thus protecting genomes from detrimental insertion mutagenesis. While in vertebrates the PIWI/piRNA system appears to be restricted to the germline, somatic expression of piRNAs directed against transposons is widespread in arthropods, likely representing the ancestral state for this phylum. Here, we show that somatic expression of PIWI genes and piRNAs directed against transposons is conserved in mollusks, suggesting that somatic PIWI/piRNA expression was already realized in an early bilaterian ancestor. We further describe lineage specific adaptations regarding transposon composition of piRNA clusters and show that different piRNA clusters are dynamically expressed during oyster development. Finally, bioinformatics analyses suggest that different populations of piRNAs participate in the ping-pong amplification loop in a tissue specific manner.

evolutionary biology↗