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Ramadasan, H.

Publications and source records attributed to Ramadasan, H..

4 recordsLinked to original sources

OmicsFM brings proteomics into the foundation model era

While foundation models have been shown to learn biological representations from large transcriptomic atlases, it remained unknown whether proteomics data allow the same. We here therefore introduce OmicsFM, a modality-agnostic transformer pretrained through masked abundance reconstruction on an unprecedented proteomics data corpus of 48,837 quality-filtered proteomics profiles from 1,397 reprocessed PRIDE projects. Interestingly, despite training on 14- to 93-fold fewer profiles than matched bulk- and single-cell transcriptomic models, respectively, our proteomics model rivals both. On held-out projects, OmicsFM attention networks recovered more molecular relationships than co-expression methods and existing single-cell foundation models across nine reference databases that reveal pathway-level organization. Sample-level embeddings preserved biological structure across independent studies, and its representations transferred successfully to cell-type classification, gene-essentiality prediction, and perturbation-response prediction, while consistently outperforming task-specific models. Moreover, our results show that proteomics and transcriptomics representations capture complementary biology. OmicsFM thus firmly establishes the possibility of training highly performant proteomics-based foundation models, and their importance in modelling and uncovering fundamental biology.

bioinformatics↗

Amino acid repeat mosaics shape protein functional landscape

How combinations of functional units such as repeats and motifs within disordered regions influence protein functions remains poorly understood. Here, we investigate how co-occurring amino acid homorepeats of different types within the same protein (HR-mosaics) shape molecular outcomes. Using a novel evolutionary co-occurrence metric, human HR-mosaics were classified as segregated (each HR independently influences distinct outcomes), concerted-disjunct (both HRs jointly shape protein functionality without modulating each other), or concerted-conjunct (both HRs affect functionality through mutual influence). Molecular studies of naturally occurring polyGly-polyPro mosaic in DDX17 and chimeric mosaics of polyAla and polyHis demonstrate that HR-mosaics influence protein abundance, localisation, mobility and interaction landscape. Segregated HR-mosaics expand functional space, concerted-disjunct additionally confer biological context, and concerted-conjunct mosaics further enable rheostatic regulation between HRs. These design principles underscore amino acid type, length and relative positioning of HRs as central architects of HR-mosaic functionality, with implications in protein design and engineering and understanding repeat-associated pathologies.

Systems Biology↗

Molecular attributes of intrinsically disordered regions in secretomes influence fungal pathogenesis

Secretory proteins are crucial for establishing fungal infection through biomolecular interactions with the host. Accumulating evidence suggest that intrinsically disordered regions (IDRs) in proteins facilitate molecular interactions. How do IDRs of secretory proteins influence fungal pathogenesis? By analyzing 195,359 secretory proteins of 73 fungal species, we find that IDRs in plant pathogen extracellular non-effectors are enriched for weak polyampholytes and polyelectrolytes. These could adopt beads-on-string conformation effectively promoting assembly of diverse enzymes aiding swift degradation of host cell wall. Both animal pathogen secretory proteins and intracellular plant pathogen effectors show enrichment for strong polyampholytes, potentially aiding phase-separation and organizing intracellular biological matter to hijack or suppress host machinery. Importantly, IDRs of plant pathogen effectors which mimic host IDRs could have emerged through convergent evolution, while those of non-effectors might have evolved de novo. Thus, specific molecular attributes of fungal secretome IDRs can influence initiation, establishment and long-term persistence of infection.

systems biology↗

Proteins with amino acid repeats constitute rapidly evolvable and human-specific essentialome

Protein products of essential genes, indispensable for organismal survival, are highly conserved and bring about fundamental functions. Interestingly, proteins that contain amino acid homorepeats that tend to evolve rapidly are enriched in eukaryotic essentialomes. Why are proteins with hypermutable homorepeats enriched in conserved and functionally vital essential proteins? We solve this function versus evolutionary paradox by demonstrating that human essential proteins with homorepeats bring about cross-talk across biological processes through high interactability and have distinct regulatory functions affecting expansive global regulation. Importantly, essential proteins with homorepeats rapidly diverge with the amino acid substitutions frequently affecting functional sites, likely facilitating rapid adaptability. Strikingly, essential proteins with homorepeats influence human-specific embryonic and brain development, implying that the presence of homorepeats could contribute to the emergence of human-specific processes. Thus, we propose that homorepeat containing essential proteins affecting species-specific traits can be potential intervention targets across pathologies including cancers and neurological disorders.

systems biology↗