What makes us human? A first atlas of functional DNA changes offers new clues
Researchers identify evolutionary DNA changes that shaped the human skeleton and may help explain degenerative skeletal diseases, such as osteoarthritis
A new genetic atlas is helping scientists trace the DNA changes that transformed a shared primate ancestor into modern humans.
For the first time, researchers can systematically test which genetic differences between humans and chimpanzees affect gene activity.
The study, published in Nature, grew out of a collaboration among researchers at McGill University, Kyoto University and the Weizmann Institute of Science.
“Human and chimpanzee genomes are more than 98 per cent identical, but until now we had no way to know which genetic differences had meaningful biological effects,” said first author Yizhi Yan, a PhD student in the Kyoto-McGill International Collaborative Program in Genomic Medicine.
Understanding those changes could reveal not only how humans evolved, but also why some diseases arise in the first place.
Insights into skeletal development and disease
As a first test of the atlas, researchers examined the effect of hundreds of thousands of DNA differences on gene expression in skeletal cells.
“We were surprised to find that thousands of genetic changes appeared to have meaningful effects. That opens up a wealth of new avenues for future research,” said co-author Guillaume Bourque, Professor in McGill's Department of Human Genetics and Distinguished Visiting Professor at Kyoto University.
Researchers then narrowed the field to genes linked to cartilage development.
Their analysis suggests humans evolved to have lower levels of molecules that help cartilage retain water and withstand pressure than do other great apes.
While this shift may have helped shape distinctive features of the human skeleton, it may also help explain why humans are particularly vulnerable to some skeletal disorders.
Evolutionary trade-off
The finding points to an evolutionary trade-off, the authors note.
“The genetic changes that gave humans new traits may also have created new vulnerabilities. Understanding those trade-offs can help us understand why some diseases exist today,” said Bourque.
In the case of the skeleton, that could mean a better understanding of conditions affecting cartilage and bone, including osteoarthritis and osteoporosis, he added.
The team is now looking to apply the same approach to cells from other parts of the body, notably the brain, where the atlas could shed new light on the evolution of human cognition.
About the study
“The gene-regulatory evolution of the human skeleton” by Yizhi Yan, Guillaume Bourque, Fumitaka Inoue and David Gokhman et al., was published in Nature. Funding for the study was provided by research agencies and foundations in Europe, Israel, Japan and Canada, including the European Research Council, Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Israel Science Foundation and the Leakey Foundation.
Journal
Nature
Method of Research
Computational simulation/modeling
Article Title
The gene-regulatory evolution of the human skeleton
Large-scale study advances detection of DNA mutations across the human genome
Mayo Clinic
ROCHESTER, Minn. — Researchers in a Mayo Clinic-led study have shown how to detect a broad range of DNA mutations in noncancerous human tissues and across the genome. The analysis, drawing on more than 90 trillion DNA letters of sequencing data, could help scientists study when these changes arise — from early development through aging — and how they contribute to cancer and other diseases.
Published in Cell, the study is the flagship paper in a package of roughly a dozen publications from the National Institutes of Health (NIH) Common Fund's Somatic Mosaicism across Human Tissues, or SMaHT, Network. The network includes more than 300 members from more than two dozen U.S. universities and hospitals. Researchers evaluated approaches for detecting somatic mutations ranging from single-letter DNA changes to large deletions, insertions and rearrangements.
Alexej Abyzov, Ph.D., a Mayo Clinic professor of biomedical informatics who leads the Somatic Mutations in Development and Aging Laboratory, is the corresponding author of the Cell study.
"We often think of the human genome as a single, fixed sequence, but every person is a mosaic of cells that acquire genetic changes over time," Dr. Abyzov says. "As we have increasingly recognized in recent years, these mutations are relevant not only to cancer but also to a broad range of age-related diseases."
Reading the cellular mosaic
Unlike inherited genetic changes, somatic mutations arise after conception and accumulate over a lifetime. As cells divide, they can pass those changes to new cells, creating genetic differences within the same person, known as somatic mosaicism. Some somatic mutations can alter how cells behave and contribute to cancer, aging, and neurodevelopmental, cardiovascular and autoimmune diseases.
These mutations can be difficult to detect when they are rare or occur in complex, repetitive regions of the genome. The SMaHT Network compared short- and long-read whole-genome sequencing, duplex sequencing, single-cell sequencing, and computational approaches.
One of the clearest findings came from long-read sequencing, which reads longer stretches of DNA at a time. Much like reading a full sentence instead of a few scattered words, the added context made large genetic changes easier to find. Long-read sequencing detected about twice as many large DNA changes as short-read sequencing. It also found insertions that shorter reads often missed.
Researchers improved detection in other hard-to-read parts of the genome too. In one benchmark, a more complete genome reference raised precision from 79% to 89%. Single-cell sequencing of 102 lung and colon cells revealed differences from cell to cell and helped trace their history back to early development.
Companion study maps rare mutations across tissues
Dr. Abyzov also co-led a companion SMaHT paper published in The American Journal of Human Genetics. Deep whole-genome sequencing accurately detected rare, single-letter DNA changes present at levels below 1% in a tissue sample.
Analyzing DNA from different organs also helped detect mutations that arose early in development and spread to multiple tissues. Combining lung and colon data uncovered 13 additional shared mutations, improving detection by 145% for these very rare mutations compared with analyzing either tissue alone.
SMaHT aims to catalog somatic mutations across 10 to 15 tissue types from 150 donors while improving the tools used to detect them. NIH is planning a second stage focused on understanding how these mutations influence biological processes and disease.
Dr. Abyzov says the research could eventually help identify people at higher cancer risk and track precancerous changes in tissues before developing symptoms.
The studies were supported by the NIH Common Fund through the Office of Strategic Coordination in the NIH Office of the Director. The companion study received additional NIH support for work conducted at Mayo Clinic. For complete author lists, disclosures and funding information, review the Cell study and the companion The American Journal of Human Genetics study.
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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.
Journal
Cell
Article Title
Comprehensive benchmarking of somatic mutation detection by the SMaHT Network
Article Publication Date
15-Oct-2026
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