Viral Evolution — Questions

Antigenic drift is the gradual accumulation of point mutations in the surface proteins, selected because they evade existing antibody. The change is small and incremental, drives seasonal epidemics, and is why the influenza vaccine is reformulated each year.

Antigenic shift is the abrupt acquisition of a new surface protein by reassortment when two strains co-infect one host. The change is large, produces a subtype the population has little immunity to, and can cause a pandemic.

Because viruses evolve fast enough to differ over short periods, their sequences carry information about how they are related and how they have spread.

• Reconstructing transmission. Genetically near-identical viruses from different patients suggest a recent common source or transmission chain, while greater genetic distance argues against a direct link; this is used to investigate nosocomial outbreaks and to map an epidemic’s spread.
• Dating and origin. Tip-dated phylogenies, using each sequence’s sampling date, estimate when the most recent common ancestor existed and where a lineage arose.
• Reading the tree. Branch support such as bootstrap values indicates how reliable a grouping is, and trees that disagree across the genome flag recombination.
• Tracking change. The same methods follow the emergence and spread of drug-resistance and immune-escape variants.

A complete answer separates the sources of new variation from the forces that shape it.

Sources of genetic variation

• Mutation. Error-prone polymerases, lacking proofreading in RNA viruses, generate about one mutation per genome per replication, the ultimate source of all variation.
• Recombination. Co-infection lets RNA-virus polymerases switch templates (copy-choice), combining changes from two genomes in a single step; it is frequent in retroviruses and coronaviruses.
• Reassortment. Segmented viruses such as influenza A exchange whole segments, producing abrupt change (the basis of antigenic shift).

Forces that shape variation

• Natural selection. Purifying selection removes the many deleterious mutations; positive selection fixes the few advantageous ones (immune escape, drug resistance, host adaptation), measurable as dN/dS.
• Genetic drift and bottlenecks. Within a host, vast populations make selection efficient; at transmission a severe bottleneck, sometimes a single particle, lets chance dominate.
• Constraints. The mutation rate is capped by an error threshold that limits genome size, and compact genomes with overlapping functions tolerate little change.

Consequences

The product is a fast-moving, diverse population (sometimes modelled as a quasispecies) that pre-contains immune-escape and resistance variants, evolves on a measurable molecular clock, and can adapt to new hosts. Evolution is therefore the engine of antigenic variation, drug resistance and emergence.

dN/dS above one signals positive selection, where amino-acid-changing mutations are favoured, as in the antibody-targeted surface proteins. A ratio below one indicates purifying selection, the usual state of compact RNA-virus genomes.

Transmission imposes a severe bottleneck, and a new HIV or influenza infection is frequently established by just one virus particle. This sharply reduces diversity and lets chance, not only fitness, decide which variants are passed on.

A molecular clock lets the timing of a most recent common ancestor be estimated and outbreaks be dated and traced, because sequences sampled even weeks apart already differ. RNA viruses are therefore called measurably evolving populations.

A proofreading exoribonuclease lowers the coronavirus error rate, lifting the usual ceiling on RNA-virus genome size. It is the exception to the rule that RNA polymerases lack proofreading, and it shapes how this emerging-virus family evolves.

The large majority of random mutations are deleterious or lethal (around 40% lethal in vesicular stomatitis virus), with only ~4% beneficial. This is why purifying selection is the dominant force on these genomes.

When different parts of a genome have different evolutionary histories, the trees disagree across the breakpoint, the signature of recombination. Comparing a virus tree with its host tree, by contrast, distinguishes codivergence from cross-species host jumping.

Pushing the virus past its error threshold, so that fit genomes can no longer be regenerated, collapses the population: lethal mutagenesis, also called error catastrophe. The experimental agents are 5-fluorouracil and ribavirin, and the principle underlies modern mutagenic antivirals.

Reassortment is the exchange of whole genome segments when two strains co-infect a cell, so it requires a segmented genome, as in influenza A. It is the molecular basis of antigenic shift.

In copy-choice recombination the polymerase switches from one template to another mid-synthesis, producing a hybrid genome, the dominant mechanism in RNA viruses. The other options describe segmented-genome or DNA-virus mechanisms.

Under a very high mutation rate, a cluster of variants with moderate but robust fitness can outcompete a population built around one high-fitness variant surrounded by poor neighbours. Selection acts on the whole quasispecies, not the single best genome.

The RNA-dependent RNA polymerase has no proofreading or repair function, so its errors are not corrected, giving about one mutation per genome per replication. DNA viruses use higher-fidelity polymerases and so evolve far more slowly.

The mutant cloud already contains rare drug-resistant variants before the drug is ever encountered, so a single agent simply selects them, often within days. Durable regimens therefore combine agents with independent resistance pathways.