Researchers previously believed this condition developed mainly from a mix of genetic susceptibility and lifestyle or environmental influences. However, findings published in Hepatology show that in certain cases, a single inherited mutation can play a central role in triggering the disease.

The team traced the variant to the MET gene, which plays an important role in liver repair and how the body processes fat. When this gene does not function properly, fat begins to build up inside liver cells. This buildup can lead to inflammation. Over time, inflammation can progress to fibrosis and scarring that stiffens the liver. In more advanced stages, the condition can develop into cirrhosis, which may cause permanent liver damage or even liver cancer.

Metabolic dysfunction-associated steatotic liver disease affects roughly one-third of adults worldwide. Its more severe form, metabolic dysfunction-associated steatohepatitis, is expected to become the leading cause of cirrhosis and the primary reason for liver transplants in the near future.

“This discovery opens a window into how rare inherited genetic variants can drive common diseases,” says lead author Filippo Pinto e Vairo, M.D, Ph.D., medical director of the Program for Rare and Undiagnosed Diseases at Mayo Clinic’s Center for Individualized Medicine. “It provides new insights into this disease pathogenesis and potential therapeutic targets for future research.”

Family Case Reveals the Genetic Clue

The discovery began with genomic analysis of a woman and her father who both had metabolic dysfunction-associated steatohepatitis. Interestingly, neither of them had diabetes or high cholesterol, two of the most common risk factors associated with fat accumulation in the liver.

Because the usual explanations did not apply, researchers performed an extensive genetic analysis, examining DNA across more than 20,000 genes. During this search, they identified a small but potentially meaningful alteration in the MET gene.

Working together with scientists from the Medical College of Wisconsin’s John & Linda Mellowes Center for Genomic Sciences and Precision Medicine, led by Raul Urrutia, M.D., the research team confirmed that this mutation interfered with a critical biological process.

Genes are made up of chemical letters that carry instructions for how the body functions. In this case, a single swapped letter within the DNA sequence disrupted the message, preventing the liver from properly processing fat. This rare genetic variant found in the family has not previously been documented in scientific literature or public genetic databases.

“This study demonstrates that rare diseases are not rare but often hidden in the large pool of complex disorders, underscoring the immense power of individualized medicine in identifying them, and enabling the design of advanced diagnostics and targeted therapies,” Dr. Urrutia says.

Large Genomic Study Finds Similar Variants

To understand whether this mutation might appear in other patients, researchers analyzed data from Mayo Clinic’s Tapestry study. This large exome sequencing initiative aims to identify genetic factors that influence disease.

The Tapestry project has examined germline DNA from more than 100,000 participants across the United States, creating an extensive genomic database that supports research into both established and emerging health conditions.

Among nearly 4,000 adults in the Tapestry study who had metabolic dysfunction-associated steatotic liver disease, about 1% carried rare variants in the same MET gene that may contribute to the condition. Nearly 18% of these variants occurred in the same key region identified in the original family, strengthening the evidence that this gene plays a role in liver disease.

“This finding could potentially affect hundreds of thousands, if not millions, of people worldwide with or at risk for metabolic dysfunction-associated steatotic liver disease,” says Konstantinos Lazaridis, M.D., a lead author and the Carlson and Nelson Endowed Executive Director for the Center for Individualized Medicine.

Dr. Lazaridis also emphasized the importance of the Tapestry study in revealing hidden genetic factors behind disease.

“Once a pathogenic variant is discovered, interrogating our Tapestry data repository is giving us a clearer lens into the hidden layers of disease, and this discovery is one of the first to demonstrate its scientific significance,” Dr. Lazaridis says. “This finding highlights the profound value of studying familial diseases and the merit of large-scale genomic datasets, which can reveal rare genetic variations with broader implications for population health.”

Precision Genomics Helps Solve Medical Mysteries

The findings also highlight the growing role of genomic medicine in clinical care at Mayo Clinic. Researchers and clinicians are increasingly using advanced genetic technologies to help uncover the causes of complex diseases.

Since it launched in 2019, the Program for Rare and Undiagnosed Diseases has provided more than 3,200 patients with access to comprehensive genomic testing. The program works with nearly 300 clinicians across 14 divisions at Mayo Clinic to deliver precision diagnostics for patients with difficult-to-diagnose conditions, including rare liver diseases.

Researchers say future studies will examine how this discovery involving metabolic dysfunction-associated steatotic liver disease could guide the development of targeted treatments and improve how the disease is diagnosed and managed.

But the history of plague goes back even further. An earlier form of Y. pestis appeared about 5,000 years ago during the Bronze Age. This ancient strain infected people across Eurasia for nearly two millennia before disappearing. Unlike the medieval plague, however, this earlier version could not be transmitted by fleas. For years, scientists have struggled to understand how the disease managed to spread across such a vast region without that transmission pathway.

Ancient Sheep Provides a Critical Clue

Researchers have now uncovered an important piece of the puzzle. An international team that includes University of Arkansas archaeologist Taylor Hermes identified the first evidence of Bronze Age plague in a nonhuman host. The scientists detected Y. pestis DNA in the remains of a domesticated sheep that lived about 4,000 years ago.

The animal came from Arkaim, a fortified settlement in the Southern Ural Mountains of present day Russia near the border with Kazakhstan. The finding suggests that livestock may have played a role in the spread of plague during the Bronze Age, helping explain how the disease traveled so widely across Eurasia.

The research was published in Cell under the title “Bronze Age Yersinia pestis genome from sheep sheds light on hosts and evolution of a prehistoric plague lineage.” The international collaboration includes researchers from Harvard University and leading institutions in Germany, Russia and South Korea.

Searching Ancient DNA for Clues

Hermes co leads a major research project that studies ancient livestock DNA. By examining genetic material preserved in bones and teeth, his team is tracing how domesticated animals such as cattle, goats and sheep spread from the Fertile Crescent across Eurasia. These movements helped shape the rise of nomadic cultures and early empires.

“When we test livestock DNA in ancient samples, we get a complex genetic soup of contamination,” Hermes said. “This is a large barrier to getting a strong signal for the animal, but it also gives us an opportunity to look for pathogens that infected herds and their handlers.”

Working with ancient DNA is challenging and time consuming. Scientists must separate the DNA of the animal from many other sources found in the sample. Microorganisms living in the soil where bones were buried leave behind their own genetic traces. Researchers can also accidentally introduce DNA from their own skin cells or saliva.

The fragments recovered from ancient remains are extremely small. Many pieces measure only about 50 base pairs. For comparison, the full human genome contains more than 3 billion base pairs.

Animal remains also tend to be less well preserved than human remains, which are usually carefully buried. Animals were often cooked and eaten, and their bones discarded in waste piles where exposure to heat and weather gradually breaks down genetic material.

The Moment of Discovery

While studying livestock remains excavated from Arkaim in the 1980s and 1990s, Hermes and his colleagues noticed something unexpected. One sheep bone contained DNA belonging to Yersinia pestis.

“It was alarm bells for my team. This was the first time we had recovered the genome from Yersinia pestis in a non-human sample,” Hermes said. “We were extra excited because Arkaim is linked to the Sintashta culture, which is known for early horse riding, impressive bronze weaponry and substantial geneflow into Central Asia.”

How Did Bronze Age Plague Spread?

Researchers have previously found identical Bronze Age plague strains in human remains located thousands of kilometers apart. The question has been how the disease managed to travel such long distances.

“It had to be more than people moving. Our plague sheep gave us a breakthrough. We now see it as a dynamic between people, livestock and some still unidentified ‘natural reservoir’ for it, which could be rodents on the grasslands of the Eurasian steppe or migratory birds,” Hermes said.

A natural reservoir is an animal species that carries a pathogen without becoming sick. In the Middle Ages, rats served as the reservoir for Y. pestis, while fleas acted as the vector that spread the bacterium. Today, bats often fill this role for viruses such as Ebola and the Marburg virus.

Lessons From an Ancient Epidemic

Hermes recently received a five year grant from Germany’s Max Planck Society worth 100,000 Euros to continue excavations in the Southern Urals near Arkaim. His team will search for additional human and animal remains that may contain traces of Y. pestis.

The Bronze Age was a period when the Sintashta culture began managing larger livestock herds while also becoming skilled horse riders. Increased interaction with animals and expanding travel across the steppe may have exposed people to disease reservoirs in the environment.

Although these events happened thousands of years ago, Hermes believes the findings carry an important message today. Expanding economic activities into natural environments can disrupt ecosystems and increase the risk of disease spillover.

“We should appreciate the delicate inner workings of the ecosystems we might disturb and aim to preserve the balance,” Hermes said.

“It’s important to have a greater respect for the forces of nature,” he said.

For about fifty years, scientists have puzzled over another related mystery. Most large galaxies near our own, aside from Andromeda, appear to be moving away from us rather than being pulled inward by gravity. This seems surprising because these galaxies reside near the Local Group (the Milky Way, the Andromeda Galaxy and dozens of smaller galaxies), whose combined mass should exert a noticeable gravitational influence.

A Giant Cosmic Sheet Around the Local Group

An international research team led by PhD graduate Ewoud Wempe of the Kapteyn Institute in Groningen believes it has found the explanation. Using advanced computer simulations, the researchers discovered that the matter surrounding the Local Group is arranged in a broad, flattened structure that stretches tens of millions of light-years across. This structure includes not only ordinary matter but also the invisible dark matter that surrounds galaxies. Above and below this flattened region lie enormous empty areas known as cosmic voids.

The simulations show that this arrangement of matter can accurately reproduce both the positions and speeds of the galaxies observed around us. In other words, the computer model successfully recreates the same patterns astronomers see in the real universe.

Creating a Virtual Twin of Our Cosmic Neighborhood

To build their model, the scientists began with conditions from the early universe. They used measurements of the cosmic microwave background to estimate how matter was distributed shortly after the Big Bang. A powerful computer then evolved this early universe forward in time, eventually producing a system that matches the present day Local Group.

The resulting simulations replicate the masses, locations, and motions of the Milky Way and Andromeda, as well as the positions and velocities of 31 galaxies just outside the Local Group. Because the model so closely resembles our surroundings, researchers describe it as a “virtual twin” of our cosmic environment.

When the model includes the flat distribution of matter, the surrounding galaxies move away from us at speeds similar to those actually observed. Despite the gravitational pull of the Local Group, galaxies within the plane are influenced by additional mass spread throughout that same plane. This distant mass counterbalances the Local Group’s gravity. Meanwhile, regions outside the plane contain very few galaxies, which explains why we do not see objects falling toward us from those directions.

A Longstanding Puzzle Finally Explained

According to lead researcher Ewoud Wempe, the study represents the first detailed attempt to determine the distribution and motion of dark matter in the area around the Milky Way and Andromeda. “We are exploring all possible local configurations of the early universe that ultimately could lead to the Local Group. It is great that we now have a model that is consistent with the current cosmological model on the one hand, and with the dynamics of our local environment on the other.”

Astronomer Amina Helmi also welcomed the findings, noting that the problem has challenged researchers for decades. “I am excited to see that, based purely on the motions of galaxies, we can determine a mass distribution that corresponds to the positions of galaxies within and just outside the Local Group.”