搜索结果：Genes & genomics

Rare diseases are collectively common, affecting approximately one in twenty individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in DNA sequencing, development of new computational and experimental approaches to prioritize genes and genetic variants, and increased global exchange of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize, and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Further, all data generated, currently representing ~7500 individuals from ~3000 families, is rapidly made available to researchers worldwide via the Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) to catalyze global efforts to develop approaches for genetic diagnoses in rare diseases (https://gregorconsortium.org/data). The majority of these families have undergone prior clinical genetic testing

Long-range dependencies are critical for understanding genomic structure and function, yet most conventional methods struggle with them. Widely adopted transformer-based models, while excelling at short-context tasks, are limited by the attention module's quadratic computational complexity and inability to extrapolate to sequences longer than those seen in training. In this work, we explore State Space Models (SSMs) as a promising alternative by benchmarking two SSM-inspired architectures, Caduceus and Hawk, on long-range genomics modeling tasks under conditions parallel to a 50M parameter transformer baseline. We discover that SSMs match transformer performance and exhibit impressive zero-shot extrapolation across multiple tasks, handling contexts 10 to 100 times longer than those seen during training, indicating more generalizable representations better suited for modeling the long and complex human genome. Moreover, we demonstrate that these models can efficiently process sequences of 1M tokens on a single GPU, allowing for modeling entire genomic regions at once, even in labs with limited compute. Our findings establish SSMs as efficient and scalable for long-context genomic an

Recent advancements in single-cell genomics necessitate precision in gene panel selection to interpret complex biological data effectively. Those methods aim to streamline the analysis of scRNA-seq data by focusing on the most informative genes that contribute significantly to the specific analysis task. Traditional selection methods, which often rely on expert domain knowledge, embedded machine learning models, or heuristic-based iterative optimization, are prone to biases and inefficiencies that may obscure critical genomic signals. Recognizing the limitations of traditional methods, we aim to transcend these constraints with a refined strategy. In this study, we introduce an iterative gene panel selection strategy that is applicable to clustering tasks in single-cell genomics. Our method uniquely integrates results from other gene selection algorithms, providing valuable preliminary boundaries or prior knowledge as initial guides in the search space to enhance the efficiency of our framework. Furthermore, we incorporate the stochastic nature of the exploration process in reinforcement learning (RL) and its capability for continuous optimization through reward-based feedback. Thi

Understanding the mechanistic function of a gene is a critical starting point for biology. However, for much of the human proteome that knowledge is scattered across thousands of primary papers or remains poorly established, while the curated databases biologists rely on can lag years behind recent literature. Large language models can now read and synthesize that literature on demand, but doing so faithfully for many genes is an expensive, non-reproducible retrieval session that does not scale across users. Here, we present Affinage, an LLM pipeline that performs this retrieval and mechanistic reasoning once per gene--from the primary literature alone--and stores the result as a reusable, structured annotation. A biologist-designed reading pass extracts only direct experimental evidence, and a synthesis pass reasons over those findings alone. Applied across the genome, Affinage annotates 19,293 human protein-coding genes. This analysis provides mechanism for thousands of genes whose UniProt function is empty or a stub, beating the curated reference on 99.1% of head-to-head genes as scored by a cross-family LLM judge. Affinage also delineates the 10% of the proteome that remains me

Determining the full complement of protein-coding genes is a key goal of genome annotation. The most powerful approach for confirming protein coding potential is the detection of cellular protein expression through peptide mass spectrometry experiments. Here we map the peptides detected in 7 large-scale proteomics studies to almost 60% of the protein coding genes in the GENCODE annotation the human genome. We find that conservation across vertebrate species and the age of the gene family are key indicators of whether a peptide will be detected in proteomics experiments. We find peptides for most highly conserved genes and for practically all genes that evolved before bilateria. At the same time there is almost no evidence of protein expression for genes that have appeared since primates, or for genes that do not have any protein-like features or cross-species conservation. We identify 19 non-protein-like features such as weak conservation, no protein features or ambiguous annotations in major databases that are indicators of low peptide detection rates. We use these features to describe a set of 2,001 genes that are potentially non-coding, and show that many of these genes behave m

The neutral mutation rate is known to vary widely along human chromosomes, leading to mutational hot and cold regions. We provide evidence that categories of functionally-related genes reside preferentially in mutationally hot or cold regions, the size of which we have measured. Genes in hot regions are biased toward extra-cellular communication (surface receptors, cell adhesion, immune response, etc.) while those in cold regions are biased toward essential cellular processes (gene regulation, RNA processing, protein modification, etc.). From a selective perspective, this organization of genes could minimize the mutational load on genes that need to be conserved and allow fast evolution for genes that must frequently adapt. We also analyze the effect of gene duplication and chromosomal recombination, which contribute significantly to these biases for certain categories of hot genes. Overall, our results show that genes are located non-randomly with respect to hot and cold regions, offering the possibility that selection acts at the level of gene location in the human genome.

The COVID-19 crisis has demonstrated the potential of cutting-edge genomics research. However, privacy of these sensitive pieces of information is an area of significant concern for genomics researchers. The current security models makes it difficult to create flexible and automated data sharing frameworks. These models also increases the complexity of adding or revoking access without contacting the data publisher. In this work, we investigate an automated attribute-based access control (AABAC) model for genomics data over Named Data Networking (NDN). AABAC secures the data itself rather than the storage location or transmission channel, provides automated data invalidation, and automates key retrieval and data validation while maintaining the ability to control access. We show that AABC when combined with NDN provide a secure and flexible combination for work with genomics research.

Diatoms, a major group of microalgae, play a critical role in global carbon cycling and primary production. Despite their ecological significance, comprehensive genomic resources for diatoms are limited. To address this, we have annotated previously unannotated genome assemblies of 49 diatom species. Genome assemblies were obtained from NCBI Datasets and processed for repeat elements using RepeatModeler2 and RepeatMasker. For gene prediction, BRAKER2 was employed in the absence of transcriptomic data, while BRAKER3 was utilized when transcriptome short read data were available from the Sequence Read Archive. The quality of genome assemblies and predicted protein sets was evaluated using BUSCO, ensuring high-quality genomic resources. Functional annotation was performed using EnTAP, providing insights into the biological roles of the predicted proteins. Our study enhances the genomic toolkit available for diatoms, facilitating future research in diatom biology, ecology, and evolution.

The Global Alliance for Genomics and Health (GA4GH) Beacon protocol lets researchers ask whether a genomic variant has been observed in a participating cohort and receive aggregate variant-level counts. As Beacon networks grow, two privacy risks remain: host institutions can see plaintext queries, and repeated rare-variant queries can support membership-inference attacks. We present bioETH-Beacon, a smart-contract prototype that runs the Beacon "aggregate count" query over encrypted data on a fully homomorphic Ethereum Virtual Machine (fhEVM). Hospitals upload encrypted marker-count entries, authorized researchers submit encrypted marker queries, and the contract returns an encrypted answer that is released, via an off-chain key-management service, only to the requester named in the contract's on-chain ACL. The design is organized as a 3x4 tier-by-query-family grid spanning genotype, sex, age, and phenotype queries, with tiers that trade stronger confidentiality for lower query cost. For genotype paths, the prototype can add bounded on-chain noise to mitigate probing attacks. Experiments on synthetic panels derived from a Polygenic Score (PGS) catalog show the expected scaling beha

The emergence of telomere-to-telomere (T2T) genome assemblies has opened new avenues for comparative genomics, yet effective tokenization strategies for genomic sequences remain underexplored. In this pilot study, we apply Byte Pair Encoding (BPE) to nine T2T primate genomes including three human assemblies by training independent BPE tokenizers with a fixed vocabulary of 512,000 tokens using our custom tool, dnaBPE. Our analysis reveals that only 11,569 tokens are shared across all assemblies, while nearly 991,854 tokens are unique to a single genome, indicating a rapid decline in shared vocabulary with increasing assembly comparisons. Moreover, phylogenetic trees derived from token overlap failed to recapitulate established primate relationships, a discrepancy attributed to the disproportionate influence of species-specific high-copy repetitive elements. These findings underscore the dual nature of BPE tokenization: while it effectively compresses repetitive sequences, its sensitivity to high-copy elements limits its utility as a universal tool for comparative genomics. We discuss potential hybrid strategies and repeat-masking approaches to refine genomic tokenization, emphasizin

Genomic language models (gLMs) have transformed computational biology, achieving state-of-the-art performance across genomic tasks. Yet a fundamental question threatens the foundation of this success: do these models learn the mechanistic principles governing gene regulation, or do they merely exploit statistical shortcuts? We introduce the Mechanistic Invariance Test (MIT), a rigorous 650-sequence benchmark across 8 classes with scrambled controls that enables clean discrimination between compositional sensitivity and genuine positional understanding. We evaluate five gLMs spanning all major architectural paradigms (autoregressive, masked, and bidirectional state-space models) and uncover a universal failure mode. Through systematic mechanistic probing via AT titration, positional ablation, spacing perturbation, and strand orientation tests, we demonstrate that apparent compensation sensitivity is driven entirely by AT content correlation (r=0.78-0.96 across architectures), not positional regulatory logic. The failures are striking: Evo2-1B and Caduceus score regulatory elements at incorrect positions higher than correct positions, inverting biological reality. All models are stra

The article presents an application of Hidden Markov Models (HMMs) for pattern recognition on genome sequences. We apply HMM for identifying genes encoding the Variant Surface Glycoprotein (VSG) in the genomes of Trypanosoma brucei (T. brucei) and other African trypanosomes. These are parasitic protozoa causative agents of sleeping sickness and several diseases in domestic and wild animals. These parasites have a peculiar strategy to evade the host's immune system that consists in periodically changing their predominant cellular surface protein (VSG). The motivation for using patterns recognition methods to identify these genes, instead of traditional homology based ones, is that the levels of sequence identity (amino acid and DNA sequence) amongst these genes is often below of what is considered reliable in these methods. Among pattern recognition approaches, HMM are particularly suitable to tackle this problem because they can handle more naturally the determination of gene edges. We evaluate the performance of the model using different number of states in the Markov model, as well as several performance metrics. The model is applied using public genomic data. Our empirical resul

Gene enhancers control when and where genes switch on, yet their sequence diversity and tissue specificity make them hard to pinpoint in colorectal cancer. We take a sequence-only route and fine-tune DNABERT-2, a transformer genomic language model that uses byte-pair encoding to learn variable-length tokens from DNA. Using assays curated via the Johnston Cancer Research Centre at Queen's University Belfast, we assembled a balanced corpus of 2.34 million 1 kb enhancer sequences, applied summit-centered extraction and rigorous de-duplication including reverse-complement collapse, and split the data stratified by class. With a 4096-term vocabulary and a 232-token context chosen empirically, the DNABERT-2-117M classifier was trained with Optuna-tuned hyperparameters and evaluated on 350742 held-out sequences. The model reached PR-AUC 0.759, ROC-AUC 0.743, and best F1 0.704 at an optimized threshold (0.359), with recall 0.835 and precision 0.609. Against a CNN-based EnhancerNet trained on the same data, DNABERT-2 delivered stronger threshold-independent ranking and higher recall, although point accuracy was lower. To our knowledge, this is the first study to apply a second-generation ge

Analyzing a functional genomics experiment, such as ATAC-, ChIP- or RNA-sequencing, requires reference data including a genome assembly and gene annotation. These resources can generally be retrieved from different organizations and in different versions. Most bioinformatic workflows require the user to supply this genomic data manually, which can be a tedious and error-prone process. Here we present genomepy, which can search, download, and preprocess the right genomic data for your analysis. Genomepy can search genomic data on NCBI, Ensembl, UCSC and GENCODE, and compare available gene annotations to enable an informed decision. The selected genome and gene annotation can be downloaded and preprocessed with sensible, yet controllable, defaults. Additional supporting data can be automatically generated or downloaded, such as aligner indexes, genome metadata and blacklists. Genomepy is freely available at https://github.com/vanheeringen-lab/genomepy under the MIT license and can be installed through pip or bioconda.

The advent of rapid and inexpensive DNA sequencing has led to an explosion of data waiting to be transformed into knowledge about genome organization and function. Gene prediction is customarily the starting point for genome analysis. This paper presents a bioinformatics study of the oil palm genome, including comparative genomics analysis, database and tools development, and mining of biological data for genes of interest. We have annotated 26,059 oil palm genes integrated from two independent gene-prediction pipelines, Fgenesh++ and Seqping. This integrated annotation constitutes a significant improvement in comparison to the preliminary annotation published in 2013. We conducted a comprehensive analysis of intronless, resistance and fatty acid biosynthesis genes, and demonstrated that the high quality of the current genome annotation. 3,658 intronless genes were identified in the oil palm genome, an important resource for evolutionary study. Further analysis of the oil palm genes revealed 210 candidate resistance genes involved in pathogen defense. Fatty acids have diverse applications ranging from food to industrial feedstocks, and we identified 42 key genes involved in fatty a

Human genomic data carry unique information about an individual and offer unprecedented opportunities for healthcare. The clinical interpretations derived from large genomic datasets can greatly improve healthcare and pave the way for personalized medicine. Sharing genomic datasets, however, pose major challenges, as genomic data is different from traditional medical data, indirectly revealing information about descendants and relatives of the data owner and carrying valid information even after the owner passes away. Therefore, stringent data ownership and control measures are required when dealing with genomic data. In order to provide secure and accountable infrastructure, blockchain technologies offer a promising alternative to traditional distributed systems. Indeed, the research on blockchain-based infrastructures tailored to genomics is on the rise. However, there is a lack of a comprehensive literature review that summarizes the current state-of-the-art methods in the applications of blockchain in genomics. In this paper, we systematically look at the existing work both commercial and academic, and discuss the major opportunities and challenges. Our study is driven by five

Here, we provide revised gene models for D. ananassae, D. yakuba, and D. simulans, which include UTRs and empirically verified intron-exon boundaries, as well as ortholog groups identified using a fuzzy reciprocal-best-hit blast comparison. Using these revised annotations, we perform differential expression testing using the cufflinks suite to provide a broad overview of differential expression between reproductive tissues and the carcass. We identify thousands of genes that are differentially expressed across tissues in D. yakuba and D. simulans, with roughly 60% agreement in expression patterns of orthologs in D. yakuba and D. simulans. We identify several cases of putative polycistronic transcripts, pointing to a combination of transcriptional read-through in the genome as well as putative gene fusion and fission events across taxa. We furthermore identify hundreds of lineage specific genes in each species with no blast hits among transcripts of any other Drosophila species, which are candidates for neofunctionalized proteins and a potential source of genetic novelty.

Systematic characterization of biological effects to genetic perturbation is essential to the application of molecular biology and biomedicine. However, the experimental exhaustion of genetic perturbations on the genome-wide scale is challenging. Here, we show that TranscriptionNet, a deep learning model that integrates multiple biological networks to systematically predict transcriptional profiles to three types of genetic perturbations based on transcriptional profiles induced by genetic perturbations in the L1000 project: RNA interference (RNAi), clustered regularly interspaced short palindromic repeat (CRISPR) and overexpression (OE). TranscriptionNet performs better than existing approaches in predicting inducible gene expression changes for all three types of genetic perturbations. TranscriptionNet can predict transcriptional profiles for all genes in existing biological networks and increases perturbational gene expression changes for each type of genetic perturbation from a few thousand to 26,945 genes. TranscriptionNet demonstrates strong generalization ability when comparing predicted and true gene expression changes on different external tasks. Overall, TranscriptionNet

We have used the Monte Carlo based computer models to show that selection pressure could affect the distribution of recombination hotspots along the chromosome. Close to critical crossover rate, where genomes may switch between the Darwinian purifying selection or complementation of haplotypes, the distribution of recombination events and the force of selection exerted on genes affect the structure of chromosomes. The order of expression of gene s and their location on chromosome may decide about the extinction or survival of competing populations.