A new genome-wide study of the virus that causes Marek’s disease in chickens has identified 10 regions in the virus genome that are associated with an increase in virulence — how severe the disease is and whether it can break through vaccine protection. The study could inform the development of next-generation vaccines that are more effective at preventing future breakthroughs.
Photo Credit: Heidi-Ann Fourkiller
Scientific Frontline: Extended "At a Glance" Summary: Marek's Disease Virus Evolution
The Core Concept: A highly contagious avian herpesvirus that causes Marek's disease, which manifests as tumors and paralysis in poultry, and has progressively evolved to evade multiple generations of vaccines.
Key Distinction/Mechanism: Unlike typical viral models where vaccines provide sterilizing immunity, Marek's disease vaccines delay symptoms rather than preventing transmission, which allows the virus to continuously circulate and mutate. A genome-wide association study (GWAS) identified ten specific genomic variants—most notably a tandem repeat DNA sequence—that statistically correlate with the virus's ability to break through vaccine-induced protection and achieve high virulence.
Origin/History: The virus has caused significant agricultural losses for decades, with widespread commercial vaccination protocols beginning in the 1970s. For this study, researchers sequenced the entire genomes of 65 viral strains, which were originally collected by the United States Department of Agriculture between 1962 and 2016.
Major Frameworks/Components:
- Pathotyping: The classification of viral strains into four specific disease categories, or "pathotypes," based on symptom severity and the pathogen's capacity to bypass vaccine defenses.
- Genome-Wide Association Study (GWAS): A computational analysis utilized to identify statistical correlations between specific DNA variants, such as single-nucleotide polymorphisms, insertions, or deletions, and observable disease severity.
- Phylogenetic Mapping: The construction of a viral evolutionary tree revealing that the most highly virulent strains share a common ancestor, which helps isolate the search for key mutational variants.
- Tandem Repeats: A specific structural DNA mutation where a genetic segment is duplicated, identified as the strongest genomic correlate with hypervirulence.
Branch of Science: Virology, Evolutionary Biology, Genomics, and Agricultural Science.
Future Application: The identification of these ten genomic variants provides the foundational genetic mapping required to design vaccines that are "future-proof," which can successfully block viral evasion and prevent infection entirely.
Why It Matters: With current third-generation vaccines showing vulnerability to newly emerging hypervirulent strains, understanding the biological mechanisms of viral evolution is critical for protecting animal health, preventing severe agricultural losses, and securing global food production systems.
A new genome-wide study of the Marek’s disease virus identified 10 regions in the genome associated with what makes certain strains more virulent and could inform next-generation vaccines.
A highly contagious herpesvirus causes Marek’s disease, a deadly illness that mainly infects chickens. While it does not make people sick, the virus causes tumors and paralysis in chickens and, if unchecked, can spread rapidly through entire flocks.
Beginning in the 1970s, widespread vaccination for the virus greatly reduced its impact on the poultry industry, but over the years, some strains of the virus have increased in virulence, causing more severe disease and evolving ways to break through and evade vaccine protection. A massive new study by researchers at Penn State and the US Department of Agriculture (USDA) has now identified 10 regions in the virus’s genome that likely played a role in the increases in virulence. The findings could inform the development of next-generation vaccines that are more effective at preventing future breakthroughs, according to the research team.
“Even with nearly universal vaccination, Marek’s disease virus still circulates on poultry farms, causing losses around the world, across the US, and here in Pennsylvania,” said Moriah L. Szpara, professor of biology and of biochemistry and molecular biology in the Eberly College of Science at Penn State and leader of the research team. “We hope that our new study could help inform the design of next-generation vaccines that could potentially stop the virus from evading their protection.”
Coauthor Andrew Read, Penn State’s senior vice president for research, started studying the virus on Pennsylvania farms more than a decade ago to try to understand the complex relationship between vaccination, virus transmission, and increases in virulence.
“This work shows the importance of sustained, collaborative research,” Read said. “By following this virus over many years and combining expertise in virology, evolution, genomics, and agriculture, we are now beginning to understand the biological mechanisms driving changes in virulence. That foundational knowledge is what ultimately will enable us to develop better tools to protect animal health and food production.”
In the current study, the team took a genome-wide approach to try to find the genetic changes that could have led to increases in virulence, using a large collection of different strains of the virus, said Szpara, who is also a co-hire of Penn State’s Huck Institutes of the Life Sciences.
The team sequenced the entire genomes of 65 strains of the Marek’s disease virus from a large collection maintained by the USDA. These strains were collected between 1962 and 2016, and each was classified using USDA-standardized tests into one of four disease categories. The categories, or pathotypes, are based on the severity of symptoms caused by a strain and its ability to break through the protection of vaccines, ranging from mild to highly virulent. While most Marek's disease virus strains can cause tumors in infected chickens, strains of high virulence can break through the earliest developed vaccines, and those of the highest virulence can break through second-generation vaccines.
The research team first aligned the genome sequences of all 65 virus strains to find any differences. They found nearly 800 sites where a single letter in the DNA alphabet differed among virus strains, and several sites where segments of DNA were inserted or deleted. They then built a family tree of the virus strains based on these similarities and differences to see how strains of different virulence were related to each other.
“We found that all of the highest-virulence strains in our sample shared a common ancestor,” said Alejandro Ortigas-Vasquez, a graduate student in biology at Penn State and first author of the paper. “So, somewhere in this grouping of strains, a mutation or set of mutations must have occurred to allow them to break through vaccine protection. This narrows the search for DNA variants responsible for the most virulent strains.”
The team then performed a genome-wide association study—or GWAS—to look for statistical correlations that show whether particular DNA variants are more likely to be found in strains that cause the most severe disease. These associations can potentially lead to identifying genes or other functional elements in the genome that are responsible for changes in virulence.
“We found 10 genomic variants that were statistically associated with virulence,” Ortigas-Vasquez said. “Several of the sites we found had been seen in previous studies, but we also found new ones. The strongest of these associations was with a type of DNA variant called a tandem repeat, where a segment of DNA gets duplicated. The next step will be to test the function of these variants.”
Understanding the genetic changes in Marek’s disease virus that led to differences in virulence could aid in the design of new, more future-proof vaccines, the researchers said.
“The current vaccines delay symptoms rather than being completely preventative,” Szpara said. “The third-generation vaccine is the most effective and can protect flocks against even the most virulent strains, but there are reports of so-called hypervirulent strains emerging that can evade even these vaccines.”
Funding: This work was funded by the Ecology and Evolution of Infectious Diseases (EEID) program—a multi-agency effort supported by the US National Science Foundation (NSF), the National Institutes of Health (NIH), and the US Department of Agriculture (USDA)—under award number R01GM105244; the NSF-NIH EEID program under award number R01GM140459; and the Pennsylvania Department of Health Commonwealth Universal Research Enhancement (CURE) Program. The Penn State Center for Infectious Disease Dynamics and Huck Institutes of the Life Sciences provided additional support.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NSF or the NIH.
Published in journal: Science Advances
Authors: Alejandro Ortigas-Vasquez, Utsav Pandey, Andrew S. Bell, Daniel W. Renner, Matthew J. Jones, Hans H. Cheng, John R. Dunn, Andrew F. Read, Maciej F. Boni, David A. Kennedy, and Moriah L. Szpara
Source/Credit: Pennsylvania State University | Sam Sholtis
Edited by: Scientific Frontline
Reference Number: vi080326_01