Most detailed map of human genetic mutations unveiled

Understanding how human DNA mutates over time is key to decoding the origins of disease and the path of evolution. But until now, some of the most change-prone regions of our genome have remained out of reach. That’s beginning to change.

A collaboration between researchers at the University of Utah Health, the University of Washington, PacBio, and other institutions has recently produced the most detailed map to date of how human genetic mutations pass from one generation to the next.

By combining multiple cutting-edge DNA sequencing methods, the researchers uncovered parts of the genome that mutate far faster than previously thought – findings that could reshape our understanding of both rare genetic conditions and the broader story of human evolution.

“It’s mutations that ultimately differentiate us from other species,” said study co-author Lynn Jorde, a geneticist at the University of Utah. “We’re getting at a very basic property of what makes us human.”

The hidden speed of DNA mutation

By directly comparing the DNA of parents to that of their children, the team calculated how often new mutations occur and are passed on. Jorde calls the human genetic mutation rate a biological constant, as vital as the speed of light in physics.

“This is something you really need to know – the speed at which variation comes into our species,” Jorde said. “All of the genetic variation that we see from individual to individual is a result of these mutations.” These changes, over time, have led to diverse traits such as eye color, lactose tolerance, and certain inherited diseases.

On average, every person inherits nearly 200 new mutations that are not present in either parent. While many of these are harmless or fall in regions of DNA that don’t code for genes, others can have profound biological consequences.

Mutable regions of the genome

Until now, the most mutable regions of the genome have remained largely unexamined. Aaron Quinlan, a professor and chair of human genetics at the University of Utah and co-author of the study, noted that the new research breaks that barrier.

Previous studies focused on the genome’s most stable sections. The new work, by contrast, highlights areas that mutate rapidly – regions that Quinlan describes as “previously untouchable.”

“We saw parts of our genome that are crazy mutable, almost a mutation every generation,” said Quinlan. In contrast, other DNA segments were remarkably stable.

New clues to disease

The findings could be highly useful for genetic counseling. As Jorde explains, knowing whether a human genetic mutation is new or inherited helps doctors and families assess the likelihood of disease reoccurring in siblings.

“If you have a child who’s affected with a disease, is it likely to be inherited from a parent, or is it likely to be a new mutation?” Jorde said.

If the mutation occurs in a so-called “hotspot,” it’s more likely to be unique to that child, and the chance of recurrence in another child is lower. But if the mutation is inherited, other children may be at higher risk.

Four generations of DNA

Central to the research was a remarkable Utah family that has worked with scientists since the 1980s as part of the Human Polymorphism Study Center, also contributing to the original Human Genome Project.

Four generations of this family donated DNA and consented to its analysis, creating an extraordinary dataset for studying how mutations appear and are passed down.

“A large family with this breadth and depth is an incredibly unique and valuable resource,” said co-author Deborah Neklason, a research associate professor of internal medicine at the University of Utah. “It helps us understand variation and changes to the genome over generations in incredible detail.”

Peeking into our genome

To capture a complete and accurate picture of genetic change, the team employed several DNA sequencing technologies.

Some tools detect tiny changes like single-nucleotide variants, while others scan broader genome regions to catch large-scale alterations or structural variations.

Sequencing each family member using multiple technologies allowed the researchers to achieve both fine detail and broad coverage. This multi-platform approach gave them the clearest view yet of how our genome shifts across generations.

Charting the future of DNA

The researchers now plan to apply their comprehensive sequencing approach to more families. “We saw really interesting stuff in this one family,” Quinlan said.

The next step is to ask: “How generalizable are those findings across families when trying to predict risk for disease or how genomes evolve?”

To encourage further discovery, the team is making its sequencing data freely available. By opening access to this unparalleled genetic atlas, the researchers hope others will continue to unravel the mysteries of human evolution, diversity, and inherited disease.

The study is published in the journal Nature.

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