Summary: Using an age-stratified allele frequency approach across adults aged 24 to 70, researchers tracked how genetic variants change in frequency across age brackets and identified 168 variants under active natural selection. Of these, 159 show evidence of purifying selection. Nearly 90% of the detected variants are extremely rare, including 71 listed as pathogenic in ClinVar.
The results reveal complex evolutionary dynamics: purifying selection acting on a rare BRCA1 haplotype carrying multiple deleterious changes coexists with signals of positive selection in nearby DNA repair regions. The study also maps widespread pleiotropic effects in genes such as ATG9A and FADS2 and identifies red blood cell–related adaptations likely tied to historical malaria exposure.
Key Facts
- Age-stratified selection tracking: By comparing allele frequencies across adult age cohorts (ages 24–70) in 72,635 individuals, the method detects ongoing natural selection in contemporary human populations without relying on pedigrees or multi-generational family trees.
- Rare-variant sensitivity: The analysis uncovered 168 variants that deviate from neutral expectations; 159 of them show signs of purifying selection. Approximately 90% are extremely rare alleles that conventional genome-wide selection scans, which focus on common variants, often overlook.
- Pathogenic variant identification: Seventy-one of the identified variants are recorded in ClinVar as pathogenic or likely pathogenic and are associated with inherited disorders, cancer, cardiovascular disease, kidney conditions, and neurological disorders.
- BRCA1 evolutionary paradox: A rare BRCA1 haplotype carrying 16 protein-altering variants appears to be under purifying selection, while neighboring regions near BRCA1, BRCA2, and MLH1 show signals consistent with positive selection, illustrating contrasting selective pressures within DNA repair loci.
- Pleiotropy and trade-offs: Strong evolutionary signals center on ATG9A and FADS2, genes with pleiotropic effects on lipid metabolism, bone density, liver and kidney function, and metabolic traits. Separately, about 150 variants influence red blood cell traits that may reflect adaptation to past infectious pressures like malaria.
Source: NYCU
Background: For more than a century, researchers have reconstructed human evolution using fossils, population genetic variation, and ancient DNA. Large population biobanks now enable a complementary approach: detecting how natural selection continues to shape genomes within living populations.
In the new study, investigators analyzed genomic data from over 72,000 Han Taiwanese participants in the Taiwan Biobank. By comparing allele frequencies across age groups, they identified genomic signatures of ongoing selection and revealed disease-associated variants that might otherwise remain undetected in conventional studies.
Published in The American Journal of Human Genetics, the work demonstrates that biobanks are valuable not only for precision medicine but also for studying contemporary human evolution. The authors suggest the same age-stratified approach can be applied to other population biobanks to discover medically relevant variants across diverse ancestries.
“One of the most exciting aspects of this study was seeing how age-stratified allele-frequency trajectories could reveal ongoing natural selection in a contemporary population,” said first author Jing-Lian Chen, formerly a master’s student in Dr. Wen-Ya Ko’s laboratory. “This approach complements existing methods and helps uncover disease-associated variants that might otherwise remain undetected.”
“Biobanks are usually viewed as resources for studying disease,” said corresponding author Dr. Wen-Ya Ko. “Our study shows that these resources can also reveal how ongoing natural selection shapes disease-related genetic variation, creating new opportunities to integrate evolutionary biology with precision medicine.”
Detecting rare disease variants often missed by conventional studies
The team evaluated 509,817 genome-wide variants from 72,635 Han Taiwanese individuals aged 24–70. Instead of focusing on preselected disease genes, they tested whether any inherited variants consistently rose or fell in frequency across adult age cohorts. This design flags variants that affect survival, reproductive success, or age-dependent disease risk.
Their analysis detected 168 variants that deviated from neutral expectations, with 159 showing declining frequencies across younger cohorts—consistent with purifying selection removing deleterious alleles. Most of these candidates are rare (allele frequency ≤ 0.1%), highlighting the study’s sensitivity to low-frequency, population-specific variants that typical selection scans miss.
Many identified variants have prior links to inherited disorders: 71 are classified as pathogenic or likely pathogenic in ClinVar, and others have been associated with cancer, neurological disorders, cardiovascular disease, kidney disease, and more. These findings illustrate how evolutionary analyses can prioritize medically relevant mutations for follow-up functional and clinical research.
Complex selection patterns at BRCA1 and other DNA repair genes
A striking discovery was a rare BRCA1 haplotype that carries 16 protein-altering variants—15 of which are already labeled pathogenic. This haplotype shows evidence of purifying selection and appears to be becoming less common across age cohorts. At the same time, nearby regions around BRCA1 and other DNA repair genes, including BRCA2 and MLH1, exhibit signatures of positive selection. Together these patterns indicate temporally fluctuating and locus-specific selective pressures within DNA repair pathways.
“Evolution rarely acts on genes in a straightforward manner,” said Prof. Yoko Satta. “A variant that increases disease risk today may once have provided a benefit under different environmental conditions. Recognizing these trade-offs helps us interpret disease-associated variation in modern populations.”
Pleiotropy: single genes with broad health effects
The study identified ATG9A and FADS2 as loci with significant pleiotropic effects. Variants in these regions are associated with traits spanning lipid metabolism, liver and kidney function, blood cell measures, diabetes-related markers, cardiovascular metrics, and bone density. Because one gene can influence many physiological systems, selection acting on such loci can produce broad and sometimes contrasting effects on health.
Red blood cell traits point to shared evolutionary pressures
Although candidate variants are distributed across many genes, about 150 of them consistently associate with red blood cell characteristics—specifically higher mean corpuscular volume and lower mean corpuscular hemoglobin concentration. The authors suggest these patterns may reflect historical adaptation to infectious diseases such as malaria, which influenced regional selective pressures in the past. Further work is needed to clarify mechanisms, but the finding underscores how multiple loci can converge to shape common physiological responses to environmental challenges.
Toward more representative precision medicine
Beyond individual discoveries, the study highlights a flexible analytical framework that can be applied to other large genomic datasets. Most global genomic reference panels disproportionately represent European ancestry. Applying age-stratified allele-frequency analysis to a large Han Taiwanese cohort shows how population-specific evolutionary histories can reveal medically important variants that European-focused studies might miss. As more countries build national biobanks, this approach can enhance understanding of how evolution continues to influence health and disease across diverse populations.
“Human evolution did not end thousands of years ago,” the researchers note. “Living populations still carry its genetic imprints. Combining large biobanks with modern genomic analysis offers a powerful way to study how evolution shapes health, disease, and human diversity today.”
Key Questions Answered:
A: By dividing biobank participants into age cohorts (for example, ages 24 to 70) and comparing allele frequencies across those groups. A genetic variant that steadily declines in frequency with increasing age suggests purifying selection reducing its prevalence among older adults.
A: The study uncovered a rare BRCA1 haplotype with many protein-altering, pathogenic variants under purifying selection, while nearby regions showed evidence of positive selection. This demonstrates that different variants within the same DNA repair genes can face opposing selective pressures over time.
A: Most genomic reference datasets overrepresent European ancestry. Applying age-stratified allele-frequency analysis to a large Han Taiwanese cohort reveals population-specific variants and disease mechanisms that may be missed by studies focused mainly on European populations.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by staff.
About this genetics and evolution research news
Author: Chien Wen Lo
Source: NYCU
Contact: Chien Wen Lo – NYCU
Image: Image credited to Neuroscience News
Original Research: Open access. “Allele-frequency trajectories across age groups reveal ongoing natural selection shaping disease susceptibility” by Jing-Lian Chen, Mei-Ling Kang, Cheng-Jui Lin, Yun-Hua Lo, Yann-Jang Chen, Hsiao-Hui Lee, Valis Tanapima, Chao-Kuang Lin, I-Hui Lee, Yoko Satta, Wen-Ya Ko. American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2026.07.002
Abstract
Allele-frequency trajectories across age groups reveal ongoing natural selection shaping disease susceptibility
Understanding how selection shapes disease risk remains challenging. Variants that influence complex traits, including common diseases, can also affect fitness and thus be constrained by purifying selection. As a result, genetic variation underlying disease susceptibility may be enriched for low-frequency, population-specific alleles.
The researchers analyzed 509,817 genome-wide variants from 72,635 Han Taiwanese individuals to identify loci exhibiting age-dependent allele-frequency shifts indicative of ongoing selection. After adjusting for potential age-related population structure, they detected 168 variants deviating from neutrality, most showing declining frequencies in younger generations—consistent with purifying selection on deleterious alleles that influence disease risk.
These candidates are enriched for rare alleles (≤0.1%) and for disease-associated variants. At BRCA1, the team identified 16 rare pathogenic variants in strong linkage disequilibrium undergoing purifying selection that coexist with a positively selected haplotype, revealing temporally fluctuating selection. Similar patterns at BRCA2 and MLH1 suggest recurrent trade-offs in DNA repair genes.
Phenome-wide association analyses across hematologic and cardiometabolic traits linked a subset of candidates to increased erythrocyte volume and reduced hemoglobin concentration, implying subclinical physiological effects. Collectively, the results demonstrate ongoing natural selection acting on disease-relevant variation—particularly affecting hematologic traits in the Han Taiwanese population—and highlight opportunities to refine risk models in precision medicine.