For more than a century, scientists have been trying to reconstruct human evolution using a variety of evidence, including fossils, genetic variation between populations, and ancient DNA. Building on these approaches, researchers are increasingly using large population biobanks to investigate how natural selection continues to shape the genomes of living populations.
In the new study, researchers analyzed genomic data from more than 72,000 Han Taiwanese Taiwanese Biobank participants by comparing allele frequencies across adult age groups. This analytical framework allowed us to identify genomic hallmarks of ongoing natural selection and reveal disease-associated genetic variations that might otherwise go undetected.
Published in American Journal of Human Geneticsthis study shows that large-scale biobanks can serve not only as a tool for precision medicine but also as a platform for investigating modern human evolution. The researchers suggest that this framework could be used around the world, providing new opportunities to identify medically relevant genetic variants in different populations.
One of the most exciting aspects of this study was observing how age-group allele frequency trajectories can reveal ongoing natural selection in modern populations. This approach complements existing methods and helps discover disease-associated mutations that may go undetected using other techniques. ”
Jing-Lian Chen, first author, former master’s student in Dr. Wen-Ya Ko’s laboratory at National Yangming Jiaotong University, Taiwan
“Biobanks are typically viewed as resources for studying diseases,” said corresponding author Dr. Wen-Ya Ko. “Our research shows that these same resources can also help reveal how ongoing natural selection continues to shape disease-associated genetic variation. This creates new opportunities to integrate evolutionary biology and precision medicine.”
Discovery of rare disease variants that are often overlooked by conventional research
The researchers examined 509,817 genome-wide mutations in 72,635 Taiwanese people of Han descent between the ages of 24 and 70. Instead of targeting genes associated with specific diseases, they investigated whether the frequency of certain genetic variants was consistently increasing or decreasing across different adult age groups.
Their analysis revealed 168 mutations that deviated from neutral expectations, 159 of which showed signs of ongoing purifying selection, an evolutionary process that gradually eliminates deleterious genetic variations. Remarkably, approximately 90% of these variants are extremely rare, indicating that this approach can detect evolutionary signals that may have been missed by previous selection scans that focused primarily on common variants.
Many of these rare variants have previously been associated with genetic diseases. ClinVar classifies 71 cases as pathogenic or potentially pathogenic, and many others are associated with cancer, neurological conditions, cardiovascular disease, kidney disease, and other serious health problems. The identification of these medically relevant mutations indicates that evolutionary analysis may be beneficial in prioritizing disease-causing mutations in future studies.
Unexpected evolutionary patterns of BRCA1 and DNA repair genes
One of the most notable findings was an unexpected evolutionary pattern associated with BRCA1, a well-known cancer susceptibility gene. Researchers have identified a rare BRCA1 haplotype that carries 16 protein-altering variants, 15 of which are already classified as pathogenic. This haplotype appears to have undergone purifying selection and gradually became less common in the population.
Interestingly, regions close to BRCA1 as well as BRCA2 and MLH1 showed evidence of positive selection. This suggests that different variants within the same DNA repair gene have experienced different forms of natural selection during evolution. Rather than being contradictory, these results highlight the complex interplay between genetic variants that increase disease risk and genetic variants that may have conferred an advantage in past environments.
“Evolution rarely acts directly on genes,” says Yoko Sada, a professor at Sokendai (The Graduate University for Advanced Studies). “Variations that currently increase disease risk may have previously been beneficial in different environmental contexts. Understanding these evolutionary trade-offs will enhance the interpretation of disease-associated mutations in current populations.”
One gene provides many health benefits
The study also found evidence that natural selection can favor genes that influence various aspects of human biology. Two genes, ATG9A and FADS2, exhibited remarkable pleiotropy, with a single gene influencing a large number of seemingly unrelated traits. Variations in these genes were associated with blood cell properties, liver and kidney function, lipid metabolism, diabetes-related traits, cardiovascular indicators, and bone density. This widespread biological influence may explain why these regions are repeatedly influenced by natural selection. Changing one gene can affect many physiological systems at once. This discovery shows that evolutionary studies can help identify genes at the center of human biology and that they may be promising targets for future functional and clinical studies.
Red blood cells emerge as a common feature of evolution
Although candidate variants are spread throughout the genome and occur in genes with diverse biological functions, many converge on common physiological patterns. Approximately 150 mutations are consistently associated with red blood cell traits, specifically increased mean corpuscular volume and decreased mean corpuscular hemoglobin concentration. Researchers believe this pattern may be due to historical adaptation to infectious diseases such as malaria that were once prevalent in Taiwan. Although further research is needed to confirm the exact mechanism, the findings reveal how evolutionary pressures shape similar physiological traits through genetic variation across multiple genes, rather than affecting single mutants in isolation.
Aiming for more representative precision medicine
The researchers believe that going beyond individual discoveries and introducing new analytical frameworks that can be adapted to other large genomic datasets will have the greatest impact. Most existing genomic reference datasets are biased towards populations of European descent. Applying this framework to one of the world’s largest Han Taiwanese cohorts demonstrates how a population’s unique evolutionary history can uncover medically important mutations that may otherwise go unnoticed. As more countries develop national biobanks, this approach could be expanded globally to better understand the continuing impact of evolution on human health across diverse populations.
“Human evolution did not stop thousands of years ago,” the scientists said. “Living populations still retain their genetic footprints. The combination of large-scale biobanks and advanced genomic analysis provides a powerful new way to explore how evolution continues to shape health, disease, and human diversity.”
sauce:
National Yangming Jiaotong University
Reference magazines:
Chen, J.-L. others. (2026). Trajectories of allele frequencies across age groups reveal ongoing natural selection that shapes disease susceptibility. American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2026.07.002. https://www.cell.com/ajhg/fulltext/S0002-9297(26)00268-5
