For more than a century, the plague bacterium Yersinia pestis has haunted public health history. Best known for causing the Black Death in medieval Europe, this deadly pathogen is still found today in wildlife and occasional human cases across parts of Africa, Asia, and the Americas. While outbreaks are now rare, Y. pestis remains a major concern for global health security—and a potential biothreat agent.
Now, researchers have uncovered a surprising twist in this bacterium’s evolutionary story. According to a new study published in Emerging Microbes & Infections, a single-letter change in the DNA code of Y. pestis helped it become more competitive in its microbial environment—even though it weakened the bacterium’s ability to survive certain types of stress.
This new research, led by scientists from China’s Academy of Military Medical Sciences in collaboration with the Institut Pasteur de Lille, examined more than 1,000 ancient and modern Y. pestis genomes to understand a peculiar hotspot of genetic change in a gene called aspA. Their findings shed light on how this microscopic killer adapted to changing environments over thousands of years—and how it might continue to evolve in ways that impact both science and public health.
The Genetic Twist That Changed the Game
The study zeroes in on a tiny segment of DNA known as codon 363 in the aspA gene. This gene helps produce an enzyme called aspartate ammonia-lyase (or AspA), which plays a role in breaking down a common amino acid, aspartate, for energy and other cellular functions.
But not all versions of Y. pestis use this gene the same way. The researchers discovered that most modern strains carry a version of the gene with a specific mutation—changing one DNA letter to another—that effectively shuts the gene down. This “off” version (called TTG) prevents the bacteria from producing a working AspA enzyme.
So why would a pathogen lose a useful metabolic function? It turns out that this mutation may have given Y. pestis a competitive edge. The researchers found that strains with the TTG mutation were better at producing a weapon called pesticin—a kind of bacterial toxin used to kill other microbes competing for the same ecological niche. In other words, the mutation made Y. pestis a more effective microbial predator, allowing it to dominate environments full of rival bacteria like Escherichia coli or Yersinia pseudotuberculosis, its evolutionary cousin.
Evolutionary Trade-offs: Win Some, Lose Some
The benefits of this mutation didn’t come without costs. While TTG strains outcompeted other bacteria, they performed worse under certain stress conditions—such as cold temperatures and low oxygen environments—that are commonly encountered by Y. pestis outside of a host, like in soil or inside flea vectors. By contrast, strains with the older version of the gene (called GTG), which still make functional AspA, survived better in these challenging environments.
Using lab-grown bacteria, mice models, and a range of stress tests, the team showed that the TTG mutation conferred a situational advantage. When grown alone or in competition with others, TTG strains often thrived. But when exposed to environmental extremes, their performance lagged behind the GTG strains.
This suggests an evolutionary balancing act. As the bacterium adapted to new environments—particularly those where microbial competition was fierce—the TTG mutation helped it win the microbial arms race. Later, as the environment changed or stressors increased, some strains reverted back to making functional AspA, restoring the GTG allele or other similar forms.
Why This Matters for Public Health and National Security
Understanding how Y. pestis adapts and persists in the environment is more than an academic exercise—it’s vital to global health security. While modern medicine can treat plague if caught early, the bacterium’s ability to survive in wildlife and natural reservoirs means it’s never fully gone. Moreover, Y. pestis is classified as a Tier 1 select agent due to its potential use in bioterrorism.
This study offers new insight into how subtle genetic shifts can dramatically impact pathogen fitness, survival, and competition. For public health officials, these findings underscore the importance of monitoring bacterial evolution—not just for what it tells us about the past, but for what it could mean in the future.
For example, strains that excel at surviving in environmental reservoirs may influence the timing and location of outbreaks. Those better at outcompeting microbial rivals might be more likely to reemerge after periods of dormancy. And mutations that increase pesticin production could affect how Y. pestis interacts with other microbes in rodents, fleas, and even decomposing carcasses—all key parts of its complex transmission cycle.
From a national interest standpoint, this research contributes to the broader effort to anticipate how dangerous pathogens adapt to changing ecological and social conditions. It supports ongoing biosurveillance, risk modeling, and early-warning systems, especially as climate change and urbanization alter the dynamics of zoonotic diseases.
A Timeline of Plague’s Genetic Gamble
The researchers also speculate that the TTG mutation may have emerged roughly 4,000–5,000 years ago—around the same time Y. pestis developed the ability to be transmitted by fleas. This shift enabled the bacterium to spread more efficiently among rodents and, eventually, humans. It’s possible that the TTG mutation “hitchhiked” on this evolutionary leap, allowing it to quickly dominate plague populations through a founder effect.
Over time, as the bacterium encountered different ecological challenges—like cooler environments or nutrient-limited niches—other versions of the aspA gene re-emerged, restoring enzymatic activity. This cycle of gene inactivation and reactivation is rare but offers a compelling example of how bacteria fine-tune their survival strategies across time and space.
What Comes Next
The study’s authors emphasize that more research is needed, especially on modern strains with the TTG mutation that remain potentially dangerous. Due to biosafety concerns, it’s currently difficult to experimentally mutate these strains in the lab. However, tracking new mutations in the aspA gene—and understanding how they affect bacterial fitness—could help anticipate shifts in Y. pestis behavior over time.
There’s also growing interest in how environmental factors like temperature, microbial competition, and host availability drive evolutionary pressures on pathogens. As sequencing technology and environmental surveillance tools improve, scientists will be better equipped to detect early signs of such changes—offering a critical head start in managing the risks posed by ancient but ever-evolving microbes like Y. pestis.
Song K, Lv R, Shen L, et al., Retracing the Path of Evolution: Polymorphisms of aspA Codon 363 Shape the Fitness of Yersinia pestis. Emerging Microbes & Infections. 10 July 2025.