Background - giffordlabcvr/Hepadnaviridae-GLUE GitHub Wiki

Overview

Hepadnaviruses (family Hepadnaviridae) are a family of small, enveloped DNA viruses. They are unique among DNA viruses due to their replication process, which involves reverse transcription, a step more commonly associated with retroviruses. The most well-known member of this family is the hepatitis B virus (HBV), which causes hepatitis B in humans. HBV is estimated to infect ~300 million people worldwide, causing substantial morbidity and mortality. Recent studies have revealed that hepadnaviruses infect a diverse range of vertebrate species, ranging from fish to mammals. They are associated with disease in many of these species.

Comparative genomics plays a crucial role in hepadnavirus research by enabling scientists to investigate genetic variation across different hepadnavirus strains and species. The GLUE software framework provides an extensible platform for implementing comparative genomic analysis of viruses in an efficient, standardised and reproducible way. It supports the dvelopment of "projects" not only integrate key data items such as sequences, alignments, and genome feature annotations, but also establish complex semantic links between these data items using a relational database. This foundation prepares virus sequences and their associated data for computational analysis, minimizing the need for labor-intensive pre-processing and enabling streamlined workflows.

Hepadnavirus-GLUE is a dedicated resource built within this framework, designed to facilitate comparative analysis of hepadnavirus genomes. It aims to provide researchers with tools to explore genetic diversity and functional genomics in a standardized, extensible environment.

Comparative Genomics and Hepadnavirus Research

Comparative genomics is a powerful tool for advancing hepadnavirus research by revealing evolutionary relationships, identifying functional genomic elements, and uncovering mechanisms of pathogenicity. Key areas where comparative genomics informs hepadnavirus studies include:

  1. Virus Evolution and Host Adaptation:

    • Phylogenetic Relationships: Comparative genome analysis reveals evolutionary links between different hepadnavirus species and strains, highlighting host-specific adaptations and divergence over time.
    • Host Specificity: Comparing human (HBV) and non-human hepadnaviruses (e.g., from ducks or woodchucks) helps identify mutations influencing host range and infectivity.

  2. Identifying Functional Genomic Elements:

    • Conserved Regions: Highly conserved genomic regions critical for viral replication and host interaction can serve as targets for antiviral therapies.
    • Regulatory Elements: Comparative genomics uncovers conserved promoters, enhancers, and RNA elements essential for viral replication and gene expression.

  3. Mechanisms of Pathogenicity:

    • Virulence Factors: Genomic differences between pathogenic and less virulent strains, such as mutations in the X gene, help explain variations in disease severity.
    • Immune Evasion: Identifying mutations that alter antigenicity or disrupt immune signaling provides insights into viral immune evasion strategies.

  4. Virus Evolution During Infection:

    • Population Dynamics: Tracking viral variants in HBV-infected individuals helps monitor evolution, drug resistance, and disease progression.
    • Viral Integration: Analysis of integrated viral sequences sheds light on HBV DNA integration into host genomes and its role in liver disease and cancer.

  5. Antiviral and Vaccine Development:

    • Drug Resistance: Comparative studies identify mutations linked to antiviral resistance, aiding the design of more effective treatments.
    • Vaccine Design: Understanding genetic diversity and conserved epitopes informs vaccine development targeting key viral antigens.

  6. Endogenous Viral Elements (EVEs):

    • Studying endogenous viral elements in host genomes uncovers ancient hepadnavirus infections and provides insights into virus-host co-evolution.

  7. Zoonotic Potential:

    • Comparative genomics helps assess the risk of cross-species transmission, revealing genetic factors that enable hepadnaviruses to jump between species and pose zoonotic risks.

Hepadnavirus-GLUE and Comparative Genomics

Hepadnavirus-GLUE is designed to facilitate comprehensive comparative genomic analyses of hepadnaviruses, offering standardized datasets and robust analytical tools. Researchers can leverage these features to explore hepadnavirus diversity, evolution, and pathogenicity across various species and strains. Key features include:

  1. Phylogenetic Analysis: Integration with RAXML enables users to construct detailed phylogenetic trees from hepadnavirus genomic data. Pre-configured alignments and reference sequences allow for precise control over alignment partitions, while the use of GLUE command files simplifies complex phylogenetic workflows, making advanced analyses more accessible.

  2. Host Range, Tropism & Pathogenesis: Hepadnavirus-GLUE supports investigations into host specificity, tissue tropism, and pathogenicity using standardized reference genomes. By facilitating comparative analysis across multiple strains, this resource can help researchers to identify genetic factors driving these traits, enhancing understanding of virus-host interactions.

  3. Immune Evasion & Vaccine Development: Users can explore mutation hotspots and conserved regions critical for immune evasion and antigenic variation. This information is vital for designing effective vaccines or therapeutics targeting essential viral regions and for monitoring the evolutionary response of hepadnaviruses to immune pressures.

  4. Genetic Variation Exploration: Hepadnavirus-GLUE provides a flexible system for defining genome feature coordinates, allowing for high-resolution exploration of genetic variation. Commands for querying amino acid frequencies can be combined with genome feature coordinates, enabling stratified analyses using 'where' clauses to filter and organize sequence data effectively.

  5. Functional Genomics: The platform provides tools and data for examining genetic variation in relation to evolutionary history, protein structure, and host immune responses. Hepadnavirus-GLUE thus facilitates the identification and analysis of functional elements, shedding light on how specific mutations impact viral replication and pathogenicity.

  6. Variation Scanning: Hepadnavirus-GLUE enables researchers to define sequence variations using regular expressions (REGEX) and scan extensive datasets for these variations. This feature is particularly useful for identifying mutations across consensus or reference sequences and for analyzing deep sequencing data.

  7. Epidemiology & Outbreak Tracking: The tool supports real-time tracking of hepadnavirus spread and the emergence of new strains by comparing outbreak genomes with reference data. Such comparisons can inform epidemiological studies, assist in outbreak management, and guide the development of updated vaccines.

  8. Customizable Analysis Pipelines: Researchers can tailor datasets and analysis workflows for specific hepadnavirus species or strains. Hepadnavirus-GLUE allows the scripting of multi-step processes, including alignment, feature annotation, and phylogeny construction, ensuring reproducibility and streamlining future analyses.

By providing these features, Hepadnavirus-GLUE equips researchers with the necessary tools to tackle a diverse range of comparative genomics questions, from evolutionary investigations to epidemiological tracking, all within a cohesive and adaptable framework.