Researchers at UC San Diego have found that several of the most dangerous zoonotic viruses, including SARS-CoV-2, Ebola, and mpox, jumped from animals to humans without first evolving special genetic adaptations. The finding, published in the journal Cell, challenges a widely held assumption that viruses need a period of mutation in an intermediate host before they can efficiently infect people. If the conclusion holds, it means the pool of animal viruses capable of triggering the next pandemic may be far larger than previously estimated, and current surveillance strategies may be looking for the wrong warning signs.
No Genetic Warm-Up Before Spillover
The study, titled “Dynamics of natural selection preceding human viral epidemics and pandemics,” applied phylogenetic and genome-wide natural-selection analyses across six major viral families and outbreaks: influenza A, Ebola, Marburg, mpox, SARS-CoV, and SARS-CoV-2. For each pathogen, the researchers compared selection pressures on three distinct branches of the evolutionary tree: the animal reservoir lineage, the pre-outbreak stem lineage leading up to human spillover, and the outbreak lineage circulating among people. The central question was whether viruses showed a detectable burst of adaptive evolution on that critical stem branch, the moment just before they crossed into humans.
They found no such signal. Across every virus examined, the Cell analysis reported no detectable change in selection intensity immediately prior to the host switch. The researchers used a statistical tool called RELAX, originally described in Molecular Biology and Evolution, which quantifies whether natural selection is relaxed or intensified on specified phylogenetic branches through a parameter known as k. When applied to pre-spillover branches, the k values showed no evidence of intensified positive selection, the kind of evolutionary pressure that would indicate a virus was actively adapting to a new host.
According to a summary from UC San Diego, the team concluded that extensive pre-zoonotic adaptation is not necessary for human-to-human transmission of zoonotic viruses. That conclusion runs directly counter to the prevailing model, which assumes that a virus circulating in bats or rodents needs time and genetic fine-tuning, often in a secondary animal host, before it can bind to human cells, evade human immune defenses, and spread person to person. Instead, the data suggest that some animal viruses already possess the intrinsic capacity to infect humans efficiently, even before any detectable evolutionary “warm-up” occurs.
Why the Conventional Model May Be Wrong
For decades, pandemic preparedness planning has been built around the idea that spillover is a stepwise process. A bat coronavirus, for instance, was thought to require passage through civets or pangolins, accumulating key mutations along the way, before it could infect a human airway. That model shaped how agencies designed surveillance: watch for mutations in animal viruses that look like they are trending toward human compatibility. The Cell study suggests this approach may miss the real threat entirely, because viruses can arrive ready to infect without any detectable genetic rehearsal.
This does not mean every animal virus is equally dangerous. A key distinction, outlined in a CDC synthesis on spillover, separates viruses that can infect individual humans from those that can sustain transmission between humans. Many zoonotic viruses cause dead-end infections: a person gets sick from contact with an animal but cannot pass the pathogen along. The new findings speak specifically to the subset of viruses that did achieve sustained human-to-human transmission and caused epidemics or pandemics. Even among that subset, the researchers found no pre-adaptation footprint on the evolutionary branches leading into humans, suggesting that the capacity for spread may often be a pre-existing trait rather than a newly evolved one.
One implication is that host range (the spectrum of species a virus can infect) may be broader and more flexible than previously assumed. If a virus circulating in bats already has molecular machinery compatible with human cells, then the barrier to spillover is ecological exposure rather than genetic innovation. Changes in land use, wildlife trade, and human encroachment into animal habitats could therefore play a larger role than subtle sequence shifts in determining when and where the next outbreak begins.
Mpox as a Case Study
The mpox virus offers a particularly instructive example of apparent “ready-made” human infectivity. When the 2022 outbreak began spreading globally, genomic data became available quickly. The NCBI announcement highlighted the first complete mpox genome from that outbreak in GenBank under accession number ON563414, designated MPXV_USA_2022_MA001. That genome showed strong similarity to sequences collected from animal reservoirs between 2017 and 2018, suggesting the virus had not undergone dramatic genetic changes before entering human populations.
Separate research published in Nature Communications examined the genomic epidemiology of mpox during the New York City outbreak, providing explicit evolutionary-rate estimates and detailed intra-host diversity data from multiple specimens per individual. The evolutionary rates observed during human transmission were consistent with what would be expected from genetic drift rather than strong adaptive selection. In other words, the virus was changing as it spread among people, but those changes looked random rather than directional. This pattern aligns with the broader Cell finding: mpox did not need to evolve special tricks before it could jump into and spread among humans.
Clinical and epidemiologic information compiled by the U.S. mpox resource underscores how quickly the virus established sustained human-to-human transmission once it gained a foothold in new social and sexual networks. The key drivers of spread were contact patterns and public awareness, not a sudden burst of viral evolution. Together, these lines of evidence reinforce the idea that some animal viruses may already be fully competent to move through human populations once ecological circumstances allow.
What This Means for Pandemic Surveillance
If viruses do not telegraph their intentions through a detectable period of pre-adaptation, the implications for public health monitoring are significant. Traditional genomic surveillance has focused heavily on identifying mutations of concern, specific changes in receptor-binding domains or polymerase genes that might signal a virus is becoming more dangerous to humans. The Cell study suggests that approach, while still valuable for tracking variants once an outbreak begins, may be insufficient for predicting which animal virus will spill over next.
A more effective strategy, based on these findings, would involve broader and more frequent sampling of viral diversity in animal reservoirs. Rather than waiting for a virus to show human-adaptive mutations, public health agencies would need to catalog the full range of viruses circulating in wildlife and domesticated animals. Resources such as the NCBI sequence databases already serve as global repositories for viral genomes, but the coverage of many high-risk regions and host species remains sparse. Expanding that coverage would allow researchers to estimate how many animal viruses already have the molecular hallmarks associated with human infection, even if they have never been observed in people.
Surveillance systems would also need to integrate ecological and behavioral data more tightly with genomics. Because the barrier to spillover may be exposure rather than adaptation, monitoring activities that bring humans into closer contact with wildlife, such as deforestation, bushmeat hunting, live animal markets, and intensive farming, could be just as important as sequencing itself. Early detection of unusual clusters of illness in communities that interface with animal reservoirs may provide a more reliable early-warning signal than waiting for a recognizable pattern of mutations to appear in viral genomes.
For policymakers, the message is twofold. First, the absence of detectable pre-adaptation means that the number of animal viruses capable of infecting and spreading among humans is likely larger than current risk lists suggest. Second, because these viruses may not advertise their potential through obvious genetic changes, investments in broad-based surveillance, rapid diagnostics, and flexible response infrastructure become even more critical. Preparedness cannot hinge on spotting a handful of “dangerous” mutations in advance; it must assume that the next pandemic virus could emerge from the existing viral landscape with little warning.
The UC San Diego team’s work does not close the book on viral evolution before spillover. There may be subtle or transient adaptive events that current methods cannot detect, and other pathogens might behave differently. But by showing that several recent high-impact viruses appear to have crossed into humans without a genetic dress rehearsal, the study shifts the burden of proof. Until evidence shows otherwise, it may be safer to assume that many animal viruses are already capable of infecting us, and to design surveillance and response systems that reflect that unsettling possibility.
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*This article was researched with the help of AI, with human editors creating the final content.
