In a new study published in Cell titled, “Dynamics of natural selection preceding human viral epidemics and pandemics,” researchers from University of California, San Diego (UCSD) report that most zoonotic viruses, including the cause of COVID-19, do not show evidence that acquiring adaptive mutations is required to sustain human-to-human transmission.
Joel Wertheim, PhD, senior author and professor of medicine in the Division of Infectious Diseases and Global Public Health at UCSD School of Medicine and co-corresponding author of the paper, says the work has direct relevance to answering questions around COVID-19 origins.
“From an evolutionary perspective, we find no evidence that SARS-CoV-2 was shaped by selection in a laboratory or prolonged evolution in an intermediate host prior to its emergence,” said Wertheim. “That absence of evidence is exactly what we would expect from a natural zoonotic event and it represents another nail in the coffin for theories invoking laboratory manipulation.”
The research team analyzed viral genomes from outbreaks caused by influenza A, Ebola, Marburg, mpox, SARS-CoV and SARS-CoV-2, and focused on the evolutionary period immediately preceding human outbreaks.
Across these diverse viruses, selection pressures before zoonotic emergence were indistinguishable from those acting during routine circulation in animal reservoirs. Instead, measurable changes in selection typically appeared only after sustained transmission began in humans.
“Rather than requiring rare, finely tuned adaptations in animals, many viruses may already possess the basic capacity to infect and transmit between humans. What matters most is human exposure to a diverse array of animal viruses,” Wertheim said.
The study used a phylogenetic framework that measured changes in the intensity of natural selection across entire viral genomes. By comparing rates of different types of mutations, the researchers detected whether natural selection was intensified, relaxed or unchanged across key evolutionary transitions. The team validated their approach using artificially selected viruses propagated in cell culture or in laboratory animals, which produced reproducible evolutionary signatures distinct from natural transmission.
Those controls proved critical when examining the reemergence of H1N1 influenza A virus in 1977. Unlike other zoonotic events, the 1977 H1N1 strain showed both unusually limited genetic divergence from 1950s viruses and a clear shift in selection consistent with viruses that propagated in cell culture or in laboratory animals.
“The 1977 influenza story is, in many ways, even more compelling than what we found for COVID-19,” Wertheim said. “Our results provide new molecular evidence supporting the long-suspected idea that the H1N1 pandemic was sparked by a laboratory strain, possibly in the context of a failed vaccine trial.”
Historical records and prior genetic analyses suggest that the 1977 H1N1 virus appeared almost unchanged after a 20-year absence, a pattern difficult to reconcile with natural evolution. The new findings also show that the virus also experienced selection similar to that seen in laboratory-adapted influenza strains and live-attenuated vaccines.
The authors argue that the work has implications for how scientists interpret future outbreaks. The framework provides a benchmark for distinguishing natural spillovers from scenarios involving laboratory handling or prolonged artificial selection.
Looking ahead, the researchers see potential applications in outbreak forensics, viral surveillance and pandemic preparedness. Wertheim says the goal is not just to understand the past, but to be better prepared for the future.
“By clarifying how pandemics actually begin, we can focus attention where it belongs, on surveillance, prevention and reducing the opportunities for the constant barrage of viral spillover,” he said.
