3.2 Genome structures and organization strategies

Viral genomes come in various shapes and sizes, each with unique strategies for replication and survival. From tiny RNA strands to massive DNA molecules, these genetic blueprints dictate how viruses infect and spread. Understanding their structure is key to grasping viral behavior and developing treatments.

Genome organization is a viral superpower. Through clever tricks like overlapping genes and alternative splicing, viruses squeeze maximum information into minimal space. This efficiency allows them to rapidly replicate and adapt, making them formidable foes in the microscopic world.

Viral Genome Structures

Linear, Circular, and Segmented Genomes

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• Viral genomes consist of DNA or RNA with diverse structural configurations adapted to replication strategies and host interactions
• Linear genomes occur in many viruses (herpesviruses, influenza viruses) often with terminal structures like telomeres or covalently attached proteins
• Circular genomes form covalently closed loops in viruses (papillomaviruses, polyomaviruses) facilitating replication and gene expression
• Segmented genomes comprise multiple discrete nucleic acid molecules, each encoding one or more genes (influenza viruses, reoviruses)
• Some viruses possess diploid genomes, carrying two copies of their genetic material (retroviruses)
• Viral genome sizes vary greatly, ranging from a few thousand nucleotides in small RNA viruses to hundreds of thousands of base pairs in large DNA viruses
  • Small RNA viruses (picornaviruses) typically have genomes around 7-8 kilobases
  • Large DNA viruses (poxviruses) can have genomes exceeding 200 kilobases

Genome Composition and Size Variations

• Nucleic acid composition affects viral replication strategies and host cell interactions
  • DNA viruses generally replicate in the nucleus, utilizing host cell machinery
  • RNA viruses often replicate in the cytoplasm, requiring their own replication enzymes
• Genome size influences viral complexity and replication kinetics
  • Smaller genomes (bacteriophages) allow for rapid replication cycles
  • Larger genomes (herpesviruses) enable more complex gene regulation and host interactions
• Terminal structures play crucial roles in genome replication and stability
  • Telomeres in linear genomes protect from degradation (adenoviruses)
  • Covalently attached proteins can serve as primers for replication (parvoviruses)

Single-stranded vs Double-stranded Genomes

Single-stranded Genome Characteristics

• Single-stranded (ss) genomes exist as positive-sense (+) or negative-sense (-), determining their immediate functionality upon host cell entry
• Positive-sense ssRNA genomes serve directly as mRNA for protein synthesis (picornaviruses, flaviviruses)
  • Allows for rapid initiation of viral protein production
  • Requires less packaged viral enzymes
• Negative-sense ssRNA genomes require complementary RNA synthesis before protein production (influenza viruses, rhabdoviruses)
  • Necessitates packaging of viral RNA-dependent RNA polymerase
  • Provides an additional layer of regulation in the viral life cycle
• ssDNA genomes typically require conversion to a double-stranded form for replication and gene expression (parvoviruses, circoviruses)
  • Often rely on host cell machinery for second strand synthesis
  • Can exploit host cell cycle phases for efficient replication

Double-stranded Genome Properties

• Double-stranded (ds) genomes, whether DNA or RNA, provide greater genetic stability but often require more complex replication mechanisms
• dsDNA genomes (herpesviruses, adenoviruses) often mimic host chromosomes in structure and replication
  • Utilize host DNA replication machinery
  • Can integrate into host genomes (retroviruses)
• dsRNA genomes (reoviruses) are less common and require specialized replication strategies
  • Often remain encapsidated during replication to avoid triggering host immune responses
  • Utilize segmented genome structures for efficient packaging and replication
• Genome structure influences susceptibility to host defense mechanisms
  • dsRNA acts as a potent trigger for innate immune responses (interferon production)
  • ssDNA and RNA can form secondary structures to evade host recognition

Genome Organization Strategies

Coding Capacity Maximization

• Overlapping genes allow multiple protein-coding sequences to share the same nucleotide sequence, maximizing coding capacity in size-constrained genomes
  • Hepatitis B virus uses this strategy extensively, with every nucleotide in its genome part of at least one open reading frame
  • Influenza A virus segment 8 encodes both NS1 and NEP proteins in overlapping reading frames
• Polyproteins are large precursor proteins cleaved into multiple functional proteins, efficiently encoding the proteome of many RNA viruses
  • Picornaviruses produce a single polyprotein that is cleaved into structural and non-structural proteins
  • Flaviviruses use a polyprotein strategy for both structural and non-structural proteins
• Alternative splicing of viral mRNAs produces multiple protein isoforms from a single gene, increasing genomic coding capacity
  • HIV-1 generates over 40 different mRNA species through complex splicing patterns
  • Adenoviruses use alternative splicing to produce different isoforms of their fiber protein

Gene Expression Regulation

• Frameshifting or ribosomal slippage produces different proteins from the same genomic region, expanding the viral protein repertoire
  • HIV-1 uses a -1 frameshift to produce the Gag-Pol polyprotein
  • Coronaviruses employ both -1 and -2 frameshifting in their replication strategy
• Strategic positioning of regulatory sequences (promoters, enhancers, terminators) controls gene expression and replication timing
  • Early and late promoters in adenoviruses orchestrate temporal gene expression
  • Hepatitis B virus uses enhancers to regulate transcription from four overlapping open reading frames
• Cis-acting elements within viral genomes play crucial roles in replication, packaging, and other life cycle aspects
  • Internal ribosome entry sites (IRES) in picornaviruses facilitate cap-independent translation
  • Packaging signals in retroviruses ensure specific encapsidation of genomic RNA

Genome Structure and Pathogenesis

Replication Mechanisms and Efficiency

• Genome structure directly impacts viral replication mechanism and efficiency
  • Circular genomes often allow for rolling circle replication (papillomaviruses)
  • Linear genomes may require terminal repeat sequences for efficient replication initiation (herpesviruses)
• Terminal repeats or specific sequences facilitate genome circularization or template switching during replication
  • Adenoviruses use inverted terminal repeats for replication initiation
  • Retroviruses employ template switching during reverse transcription to generate long terminal repeats (LTRs)
• Segmented genomes enable genetic reassortment between different viral strains, potentially leading to new pathogenic variants
  • Influenza viruses can undergo antigenic shift through genome segment reassortment
  • Bunyaviruses can exchange genome segments, altering their host range or virulence

Pathogenesis and Host Interactions

• Organization of early and late genes in complex viruses orchestrates a temporal program of gene expression crucial for efficient replication
  • Poxviruses have a cascade of early, intermediate, and late gene expression
  • Herpesviruses employ immediate-early, early, and late gene expression patterns
• Viral genome structure affects susceptibility to host restriction factors and ability to evade innate immune responses
  • RNA viruses with double-stranded replication intermediates must shield these from cellular sensors
  • DNA viruses often encode proteins to counteract host restriction factors (APOBEC3 proteins)
• Location and regulation of virulence genes within the genome directly influence pathogenesis and host range
  • Presence of certain genes in poxviruses determines their host specificity
  • Pathogenicity islands in bacterial viruses can alter the virulence of their bacterial hosts
• Genome organization strategies impact the rate of evolution and adaptation to new hosts or environments
  • Segmented genomes allow for rapid evolution through reassortment (influenza viruses)
  • Error-prone replication of RNA viruses facilitates rapid adaptation to selective pressures