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PubMed2026

Wildlife Trade and Genetic Basis of Disease Susceptibility: A Review.

The surge in the trade of wildlife and wildlife products drives several species to extinction while coinciding with the increase in several zoonotic diseases. It is therefore essential to explore the roles of wildlife trade in disease transmission, and how the knowledge of genetics and immunogenetics can help in alleviating the attending challenges. Pathogen-driven selection plays a fundamental role in maintaining immune gene diversity, as individuals with alleles conferring resistance to endemic diseases have higher survival rate. However, anthropogenic disturbances, such as wildlife exploitation, can disrupt these evolutionary processes, leading to reduced genetic diversity and increased disease vulnerability. Advanced genomic tools, such as next-generation sequencing (NGS), whole-genome sequencing (WGS), CRISPR-Cas9 gene editing, genome-wide association studies (GWAS), epigenetics and transcriptomic analysis, can help identify immune gene variations and predict disease susceptibility in both wild and captive populations. Massive research targeting wildlife markets and the interface between the wild and the market players is necessary. It would be interesting to understand dynamics of pathogens and disease susceptibility, through the application of genetics and immunogenetics, thereby enhancing efforts to address the challenges posed by wildlife trade and zoonotic disease emergence.

Animals↗

PubMed2005

Design, engineering, and characterization of zinc finger nucleases.

Zinc finger nuclease (ZFN)-mediated gene targeting is rapidly becoming a powerful tool for "gene editing" and "directed mutagenesis" of plant and mammalian genomes including the human genome. ZFN-mediated gene targeting provides molecular biologists with the ability to site-specifically manipulate and permanently modify plant and mammalian genomes. Facile production of ZFNs and rapid characterization of their in vitro sequence-specific cleavage properties are a pre-requisite before ZFN-mediated gene targeting can become an efficient and effective practical tool for widespread use in biotechnology. Here, we report the design, engineering, and rapid in vitro characterization of ZFNs that target specific endogenous sequences within two mouse genes (mTYR and mCFTR), and two human genes (hCCR5 and hDMPK), respectively. These engineered ZFNs recognize their respective cognate DNA sites encoded in a plasmid substrate in a sequence-specific manner and, as expected, they induce a double-strand break at the chosen target site.

Amino Acid Motifs↗

PubMed2005

Zinc finger nucleases: custom-designed molecular scissors for genome engineering of plant and mammalian cells.

Custom-designed zinc finger nucleases (ZFNs), proteins designed to cut at specific DNA sequences, are becoming powerful tools in gene targeting--the process of replacing a gene within a genome by homologous recombination (HR). ZFNs that combine the non-specific cleavage domain (N) of FokI endonuclease with zinc finger proteins (ZFPs) offer a general way to deliver a site-specific double-strand break (DSB) to the genome. The development of ZFN-mediated gene targeting provides molecular biologists with the ability to site-specifically and permanently modify plant and mammalian genomes including the human genome via homology-directed repair of a targeted genomic DSB. The creation of designer ZFNs that cleave DNA at a pre-determined site depends on the reliable creation of ZFPs that can specifically recognize the chosen target site within a genome. The (Cys2His2) ZFPs offer the best framework for developing custom ZFN molecules with new sequence-specificities. Here, we explore the different approaches for generating the desired custom ZFNs with high sequence-specificity and affinity. We also discuss the potential of ZFN-mediated gene targeting for 'directed mutagenesis' and targeted 'gene editing' of the plant and mammalian genome as well as the potential of ZFN-based strategies as a form of gene therapy for human therapeutics in the future.

Animals↗

PubMed2006

ApoE gene therapy to treat hyperlipidemia and atherosclerosis.

Atherosclerosis is the leading cause of death in industrialized countries and is becoming an increasingly worldwide risk to health. Apolipoprotein E (ApoE) is a blood circulating protein with pleiotropic atheroprotective properties that has emerged as a strong candidate for treating hypercholesterolemia and cardiovascular disease. In this review, we discuss the major developments in both viral and non-viral vectors aimed at achieving efficient delivery and sustained expression of an ApoE transgene. The technological advances in engineering viruses include cross-packaging to generate different serotypes of recombinant adeno-associated virus, and the use of multiple-deleted and helper-dependent recombinant adenovirus vectors to minimize immune responses and to package genomic loci. Non-viral ApoE delivery systems, including plasmids and cell-based therapy are also described in this review. Finally, a radical alternative to gene addition that has the potential for permanent cure in many genetic diseases--'targeted gene editing'--is reviewed. This technology uses synthetic oligonucleotides to correct underlying point mutations in situ and has been evaluated for repairing dysfunctional APOE genes.

Animals↗

PubMed2026

Spatially guided in vivo single-cell functional genomics of postnatal heart.

Understanding how spatial organization and cell-cell interactions shape gene regulatory programs is central to decoding tissue development and function. The transition at birth, marked by increased circulatory demands and rapid tissue growth, requires precise spatiotemporal coordination of cardiac maturation. In this study, we generated a high-resolution spatial and temporal atlas of the postnatal mouse heart by integrating single-nucleus RNA sequencing with image-based spatial transcriptomics. This framework revealed dynamic cellular interactions, niche-specific signaling and transcriptional programs guiding cardiomyocyte maturation. To functionally test prioritized regulators in vivo and at scale, we developed PIP-seq (probe-based indel-detectable Perturb-seq), a high-throughput platform that detects single guide RNA identity, infers gene editing and profiles transcription from fixed nuclei. Applying PIP-seq to the developing postnatal heart, we identified 21 previously uncharacterized regulators of cardiomyocyte maturation, including genes essential for sarcomere assembly, metabolic reprogramming and electrophysiological transitions. Together, our findings define how microenvironmental signals and intrinsic gene programs cooperate to guide heart maturation and establish a broadly applicable framework for functional genomics in complex tissues.

Animals↗

PubMed1999

Identifying the precursors of Hodgkin and Reed-Sternberg cells in Hodgkin's disease: role of the germinal center in B-cell lymphomagenesis.

In the course of T-cell-dependent immune responses, germinal centers (GCs) are established within secondary lymphoid organs. In these structures, B lymphocytes clonally expand and modify their immunoglobulin (Ig) V genes by somatic hypermutation. In a process called affinity maturation, GC B cells expressing antigen receptor with increased affinity to the cognate antigen are selected, whereas B cells acquiring unfavorable mutations die by apoptosis. By molecular single cell analysis of Hodgkin and Reed-Sternberg (HRS) cells in Hodgkin's disease (HD), it could be shown that the HRS cells in classical as well as lymphocyte predominant (LP) HD represent clonal populations of mature B cells. Whereas HRS cells in classical HD appear to derive from crippled GC B cells that lost the capacity to express antigen receptor, the precursors of the HRS cells in LP HD are mutating, antigen-selected GC B cells. It is likely that chromosomal translocations resulting from mistakes in class switch recombination or somatic hypermutation (and potentially V gene editing) play an important role in the pathogenesis of GC B-cell-derived lymphomas.

Cell Differentiation↗

PubMed2000

Molecular characterization of guinea pig-adapted variants of Ebola virus.

Serial passage of initially nonlethal Ebola virus (EBOV) in outbred guinea pigs resulted in the selection of variants with high pathogenicity. Nucleotide sequence analysis of the complete genome of the guinea pig-adapted variant 8mc revealed that it differed from wild-type virus by eight mutations. No mutations were identified in nontranscribed regions, including leader, trailer, and intragenic sequences. Among noncoding regions the only base change was found in the VP30 gene. Two silent base changes were found in the open reading frame (ORF) encoding NP protein. Nucleotide changes resulting in single-amino-acid exchanges were identified in both NP and L genes. Three other mutations found in VP24 caused amino acid substitutions, which are responsible for larger structural changes of this protein, as indicated by an alteration in electrophoretic mobility. A highly pathogenic EBOV variant K5 from another passaging series showed an amino acid substitution at nearly the same location in the VP24 gene, suggesting the importance of this protein in the adaptation process. In addition, sequence variability of the GP gene was found when plaque-purified clones of EBOV-8mc were analyzed. Three of five viral clones showed insertion of one uridine residue at the GP gene-editing site, which led to a significant change in the expression of virus glycoproteins. This observation suggests that the editing site is a hot spot for insertion and deletion of nucleotides, not only at the level of transcription but also of genome replication. Irrespective of the number of uridine residues at the editing site, all plaque-purified clones of EBOV variant 8mc resembled each other in their pathogenicity for guinea pigs, indicating either the absence or only supportive role of mutations in the GP gene on the adaptation process.

Amino Acid Substitution↗

PubMed2026

Maize ZmMYB59 inhibits post-germinative shoot and root elongation through ZmGA2ox3/10-mediated gibberellin catabolism.

Gibberellin (GA) promotes seed germination, but sustained or excessive GA signaling after germination can lead to aberrant root and shoot elongation. How GA homeostasis is transcriptionally restrained during post-germinative seedling development remains unclear. Using overexpression and gene-edited maize materials, we demonstrate that ZmMYB59 inhibits root and shoot elongation during post-germinative growth. Integrated RNA-Seq and CUT&Tag analyses identified the GA catabolism genes ZmGA2ox3 and ZmGA2ox10 as candidate direct targets of ZmMYB59. Hormone profiling analysis showed elevated bioactive GA1 and GA4 levels in the scutellum and aleurone layer cells of zmmyb59 mutants. Dual-luciferase assays, electrophoretic mobility shift assays, and ChIP-qPCR further confirmed that ZmMYB59 directly binds AC8 cis-elements in the ZmGA2ox3/10 promoters and activates their transcription. The zmga2ox3/10 double mutant, but neither single mutant, exhibited enhanced root and shoot elongation, accompanied by GA4 accumulation. This phenotype was suppressed by exogenous application of the GA biosynthesis inhibitor uniconazole. Transcriptomic and biochemical analyses further revealed enhanced starch degradation, reduced starch content, and increased soluble sugar accumulation in the double mutant. Taken together, these findings reveal that the ZmMYB59-ZmGA2ox3/10 module restrains GA accumulation and starch mobilization after germination, thereby coordinating reserve utilization with post-germinative root and shoot growth in maize.

Gibberellins↗

PubMed2024

PRC1 and CTCF-Mediated Transition from Poised to Active Chromatin Loops Drives Bivalent Gene Activation.

Polycomb Repressive Complex 1 (PRC1) and CCCTC-binding factor (CTCF) are critical regulators of 3D chromatin architecture that influence cellular transcriptional programs. Spatial chromatin structures comprise conserved compartments, topologically associating domains (TADs), and dynamic, cell-type-specific chromatin loops. Although the role of CTCF in chromatin organization is well-known, the involvement of PRC1 is less understood. In this study, we identified an unexpected, essential role for the canonical Pcgf2-containing PRC1 complex (cPRC1.2), a known transcriptional repressor, in activating bivalent genes during differentiation. Our Hi-C analysis revealed that cPRC1.2 forms chromatin loops at bivalent promoters, rendering them silent yet poised for activation. Using mouse embryonic stem cells (ESCs) with CRISPR/Cas9-mediated gene editing, we found that the loss of Pcgf2, though not affecting the global level of H2AK119ub1, disrupts these cPRC1.2 loops in ESCs and impairs the transcriptional induction of crucial target genes necessary for neuronal differentiation. Furthermore, we identified CTCF enrichment at cPRC1.2 loop anchors and at Polycomb group (PcG) bodies, nuclear foci with concentrated PRC1 and its tethered chromatin domains, suggesting that PRC1 and CTCF cooperatively shape chromatin loop structures. Through virtual 4C and other genomic analyses, we discovered that establishing neuronal progenitor cell (NPC) identity involves a switch from cPRC1.2-mediated chromatin loops to CTCF-mediated active loops, enabling the expression of critical lineage-specific factors. This study uncovers a novel mechanism by which pre-formed PRC1 and CTCF loops at lineage-specific genes maintain a poised state for subsequent gene activation, advancing our understanding of the role of chromatin architecture in controlling cell fate transitions.

Journal Article↗

PubMed2005

Search for testicular cancer gene hits dead-end.

Testicular germ cell tumors (TGCTs) are the first tumors where the cell of origin, and the time of transformation were precisely defined. TGCTs in mice originate from primordial germ cells (PGCs) and develop within the testis during fetal development. TGCTs occur at an appreciable frequency (5%) only in the 129 family of inbred strains of laboratory mice, suggesting strong genetic control. These developmental and genetic properties make the 129 strains an exceptional model system to dissect TGCT pathogenesis. Ter is one of the most potent cancer modifiers genes known; it is a single gene mutation that causes progressive loss of PGCs on all inbred strain backgrounds and dramatically increased susceptibility to spontaneous TGCTs only on the 129 background. We recently showed that inactivation of the Dead end gene causes the Ter phenotype. Sequence analysis of Dead end encoded protein indicates it is homologous to factors involved in gene editing. The identity of Ter as Dead end and its function in PGCs will help clarify the role of editing in PGC biology and elucidate the causes of TGCTs in mice and humans.

Animals↗

PubMed2025

Generation of C9orf72 repeat knock-in iPSC lines for modelling ALS and FTD.

Induced pluripotent stem cell (iPSC) models are powerful tools for neurodegenerative disease modelling, as they allow mechanistic studies in a human genetic environment and they can be differentiated into a range of neuronal and non-neuronal cells. However, these models come with inherent challenges due to line-to-line and clonal variability. To combat this issue, the iPSC Neurodegenerative Disease Initiative (iNDI) has generated an iPSC repository using a single clonal reference line, KOLF2.1J, into which disease-causing mutations and revertants are introduced via gene editing. Here we describe the generation and validation of lines carrying the most common causative mutation for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a repeat expansion in the C9orf72 gene, for the iNDI collection of neurodegenerative iPSC models. We demonstrate that these C9orf72 knock-in lines differentiate efficiently into neurons and display characteristic C9orf72-associated pathologies, including reduced C9orf72 levels and the presence of dipeptide repeat proteins (DPRs) and RNA foci, which increase in abundance over time in culture. These pathologies are not present in revertant cells lacking the repeat expansion. These repeat expansion and revertant cell lines are now available to academic and for-profit institutions through the JAX iPS cell repository and will help to facilitate and standardise iPSC-based ALS/FTD research.

Journal Article↗

PubMed2026

The novel transcriptional activator Bhr1 combining NTPase and Zn(II)2Cys6 DNA-binding domains controls (hemi-)cellulase response to mannose-rich substrates in the white-rot fungus Dichomitus squalens.

The regulatory landscape responsible for lignocellulose degradation in white-rot basidiomycete fungi remains largely unexplored. In this study, we characterize a novel transcriptional activator, Bhr1, in the white-rot fungus Dichomitus squalens. Bhr1 exhibits an unusual domain architecture that combines a septin-like P-loop NTPase fold with Zn(II)2Cys6 DNA-binding domains and plays a critical role in activating (hemi-)cellulase enzyme production when D. squalens is exposed to mannose-rich substrates. Using CRISPR/Cas9-mediated gene editing, we generated a bhr1 disruption mutant that displayed distinct phenotypes and enzyme activity profiles on mannose and guar gum compared to the wild type. RNA sequencing data indicate that Bhr1 induces specific (hemi-)cellulase-encoding genes without altering the expression of genes encoding sugar transporters or sugar metabolic enzymes. Phylogenetic analyses show that Bhr1 is basidiomycete specific and largely restricted to saprotrophic and plant-associated Agaricomycetes fungi. Based on the domain architecture of Bhr1 and the effects of its disruption in D. squalens, our findings reveal a lineage-specific regulatory innovation in basidiomycetes that is distinct from those described in ascomycetes. Elucidating the function and evolutionary conservation of Bhr1 advances our understanding of lignocellulose degradation at the molecular level in basidiomycete fungi and may inform studies of their ecological adaptation and the development of biotechnological applications.IMPORTANCEUnderstanding the transcriptional regulatory mechanisms in white-rot fungi, such as Dichomitus squalens, is crucial for advancing our knowledge of lignocellulose degradation. This study identifies D. squalens Bhr1 as a key regulator of (hemi-)cellulase production on mannose-rich substrates and further distinguishes basidiomycete transcription factors involved in plant biomass degradation from their ascomycete counterparts. Our findings highlight the significance of lineage-specific regulators in facilitating adaptive enzyme production for efficient biomass utilization, which is critical to carbon cycling in terrestrial ecosystems. This work establishes a foundation for exploring novel regulatory strategies among wood-degrading fungi, potentially enabling targeted strain engineering in biotechnological applications.

Mannose↗

PubMed2025

Large-scale analysis of MYB genes in Cucurbitaceae identifies a novel gene regulating plant height.

The MYB transcription factor (TF) family, which is involved in plant growth and development, is large and diverse. Previous studies on MYB family in Cucurbitaceae were mostly based on a single genome or focused on the R2R3 subfamily. Here, we analyzed 91 genomes of 11 Cucurbitaceae species and identified a total of 15 858 MYB genes. According to phylogenetic relationships, these genes were divided into 27 subgroups. The identified MYB genes were further classified into 121 MYB orthologous gene groups (OGGs), including 25 core, 57 softcore, 19 shell and 20 line-specific/cloud groups. Whole-genome duplication was the most common mechanism of MYB genes expansion. In core group, the higher proportions of MYB genes were found to be in the coexpression network constructed by the RNA-seq data. Through the comprehensive analysis including phylogeny and gene expression profile of cucumber MYB genes, as well as genetic variations in 103 cucumber germplasms, we identified a MYB gene CsRAX5, which may be related to cucumber plant height. We used gene editing technology to knockout and overexpress CsRAX5. In the knockout lines, Csrax5, the height was significantly increased compared with wild type (WT), whereas after overexpression the height of CsRAX5-OE plants was significantly decreased compared with WT. These results indicated that MYB gene CsRAX5 negatively regulated cucumber plant height. The large-scale analysis of MYB genes in Cucurbitaceae in this study provides insights for further investigating the evolution and function of MYB genes in Cucurbitaceae crops.

Journal Article↗

PubMed1998

Porcine rubulavirus LPMV RNA persists in the central nervous system of pigs after recovery from acute infection.

In order to study persistence of the porcine rubulavirus LPMV, we examined tissue samples collected from pigs 53 days after experimental infection. These pigs survived the initial infection and could clinically be considered to have recovered from the infection. Two of the pigs used in this study were chemically immunosuppressed during the last 4 days before necropsy. No infectious virus or viral antigen could be detected in any tissue using standard methods for virus isolation and detection. However, the presence of viral genomic RNA and mRNA could be demonstrated in the mid brain of the convalescent pig using an optimised RT-nested PCR. Mid brain, forebrain and lung were all shown to contain LPMV RNA in the immunosuppressed convalescent pigs. In addition we examined the P-gene editing in the recovered pigs and conclude that the viral genome is transcriptionally active in these pigs. The relevance of the persistence of LPMV for maintenance and spread within and/or between pig populations is discussed.

Acute Disease↗

PubMed2003

Molecular characterisation of three avian paramyxovirus type 1 isolated from pigeons in France.

Three avian Paramyxovirus type 1 (aPMV-1) isolated from pigeons duringpigeon paramyxovirosis outbreaks were molecularly characterised by sequencing parts of the six genes (NP, P, M, F, HN and L) of each strain. Virulent 99143 isolate was found to be very closely related to non-pathogenic vaccine strains of aPMV-1, even for its F protein cleavage site motif. Strains 99299 and 99106, typical pigeon paramyxovirus type 1 (pPMV-1) variants, exhibited between 10% and 20% difference with aPMV-1 at the nucleotide level. The aPMV-1 specific pattern of eight amino acids in the intracellular domain of HN protein was found different by one residue for these two isolates, and might represent a specific pattern for pPMV-1. The unique sequence of the polycistronic P gene editing site of 99299 and 99106 was characterised by four instead of three cytosine residues, and might so have an influence on the expression level of the three proteins encoded by P. This work is also the first to provide molecular data on NP, P and L genes of typical pPMV-1.

Amino Acid Sequence↗

PubMed2026

Development of an Efficient Regeneration and Agrobacterium-Mediated Transformation Protocol for Hosta 'Light Star' Using the RUBY Reporter Gene.

Hosta plantaginea is a perennial shade-tolerant herb of the Liliaceae family, with high ornamental and urban greening value. Hosta 'Light Star' is a newly developed ornamental cultivar with yellow-margined leaves and lilac flowers, but no efficient in vitro regeneration or genetic transformation system has been established for this cultivar to date. In this study, we established a highly efficient in vitro regeneration system for Hosta 'Light Star,' and developed an Agrobacterium-mediated genetic transformation protocol using the RUBY visual reporter gene for non-invasive screening of positive transformants. The optimal callus induction medium was MS + 2 mg/L 6-BA + 0.3 mg/L NAA + 0.05 mg/L 2, 4-D, with a callus induction rate of 53.33% for leaf explants (the optimal explant for sterile seedlings). The optimal adventitious bud proliferation medium was MS + 2 mg/L 6-BA + 0.1 mg/L NAA, with a proliferation coefficient of 5.87. The optimal rooting medium was 1/2 MS + 0.5 mg/L NAA + 0.5 mg/L IBA, with a 100% rooting rate. The optimal transplant substrate was perlite:vermiculite = 2:1, with a 100% transplant survival rate after acclimatization. For Agrobacterium-mediated transformation, the optimal infection parameters were as follows: Agrobacterium suspension OD600 = 0.6, infection time of 10 min, and 200 μM acetosyringone; the optimal selection conditions were 300 mg/L cefotaxime for bacteriostasis and 30 mg/L hygromycin for transformant screening. The final stable transformation efficiency was 2.50% (95% CI 1.23-3.77%), with an escape rate of 16.13%. Transgenic plants showed distinct purplish-red coloration in roots, stems, and leaves, with significantly higher betacyanin accumulation than wild-type plants (p < 0.05). Stable integration and expression of the RUBY gene were confirmed by PCR, RT-PCR, and RT-qPCR. This study establishes the first efficient regeneration and Agrobacterium-mediated transformation system for Hosta 'Light Star,' and validates the feasibility of the RUBY reporter gene as a visual marker for Hosta transformation. This system provides a solid technical platform for functional genomic studies, CRISPR/Cas9-mediated gene editing, and molecular breeding of ornamental traits in Hosta.

Transformation, Genetic↗

PubMed2025

Fluorinated Ionizable Lipids for Efficient Spleen-Targeted mRNA Delivery in Cancer Immunotherapy.

Efficient and selective mRNA delivery to immune-related organs, particularly the spleen, remains a major barrier to the broader clinical translation of mRNA therapeutics. Here, leveraging the clinically approved SM-102/ALC-0315 ionizable lipid scaffold, we rationally designed a combinatorial library of fluorinated ionizable lipids (FILs) by systematically modulating hydrophobic tails and fluorine stoichiometry. Through synthesis and evaluation of 74 candidate FILs, we identify SSC6F5 lipid nanoparticles (LNPs) as a lead formulation with exceptional spleen-targeting specificity (>90%) across intravenous, intramuscular, and subcutaneous administrations. Compared to clinically approved SM102 LNPs and spleen-tropic SM102/18PA (SORT) LNPs, intravenously administered SSC6F5 LNPs achieve 10.6-fold and 63.1-fold higher splenic mRNA transfection, respectively. Proteomic analysis of protein corona on SSC6F5 LNPs reveals significant enrichment of apolipoprotein D (Apod) and reduction in apolipoprotein H (Apoh), implicating a novel endogenous recognition pathway driving enhanced spleen targeting. Functionally, SSC6F5 LNPs enable efficient genome editing in splenic macrophages, dendritic cells, T cells, and B cells in Ai9 mice, and elicit potent CD8+ T cell and humoral responses in a B16-OVA murine melanoma model, resulting in significant tumor growth inhibition. These findings establish fluorinated lipids as a mechanistically distinct and translationally versatile platform for precision spleen-targeted mRNA delivery in gene editing and cancer immunotherapy.

Animals↗

PubMed2024

Proteome-scale prediction of molecular mechanisms underlying dominant genetic diseases.

Many dominant genetic disorders result from protein-altering mutations, acting primarily through dominant-negative (DN), gain-of-function (GOF), and loss-of-function (LOF) mechanisms. Deciphering the mechanisms by which dominant diseases exert their effects is often experimentally challenging and resource intensive, but is essential for developing appropriate therapeutic approaches. Diseases that arise via a LOF mechanism are more amenable to be treated by conventional gene therapy, whereas DN and GOF mechanisms may require gene editing or targeting by small molecules. Moreover, pathogenic missense mutations that act via DN and GOF mechanisms are more difficult to identify than those that act via LOF using nearly all currently available variant effect predictors. Here, we introduce a tripartite statistical model made up of support vector machine binary classifiers trained to predict whether human protein coding genes are likely to be associated with DN, GOF, or LOF molecular disease mechanisms. We test the utility of the predictions by examining biologically and clinically meaningful properties known to be associated with the mechanisms. Our results strongly support that the models are able to generalise on unseen data and offer insight into the functional attributes of proteins associated with different mechanisms. We hope that our predictions will serve as a springboard for researchers studying novel variants and those of uncertain clinical significance, guiding variant interpretation strategies and experimental characterisation. Predictions for the human UniProt reference proteome are available at https://osf.io/z4dcp/.

Humans↗