Sci. Adv. | Huijun Yuan's Team at the Center for Archaeological Sciences, Sichuan University, Constructs Genetic Map of STRs in Highland Populations, Revealing Their Key Role in High-Altitude Adaptation

The diversity of the human genome is a profound imprint of our long evolutionary history, recording the survival wisdom and genetic trade-offs of our ancestors during migration, admixture, and adaptation. The Qinghai-Tibet Plateau, one of the most extreme environments on the planet, provides a natural dynamic laboratory for exploring the triangular relationship between evolution, genetics, and health with its conditions of low oxygen, low temperature, and strong ultraviolet radiation. Over the past decade, through studies of single nucleotide polymorphisms (SNPs) in genes such as EPAS1 and EGLN1, scientists have begun to unveil the classic genetic mechanisms of high-altitude adaptation in highland populations. However, these known genetic clues are far from painting a complete picture of human adaptation to extreme environments, especially in the realm of short tandem repeats (STRs), often referred to as the "dark matter" of the genome, whose role in high-altitude adaptation and human health has long remained a blind spot for exploration.

Recently, the team of Professor Huijun Yuan from the Center for Archaeological Sciences, Sichuan University, and the Rare Diseases Institute, West China Hospital, published a research paper in *Science Advances* titled "Short tandem repeats in populations of the Qinghai-Tibet Plateau and adjacent regions provide insights into high-altitude adaptation." This study, for the first time, systematically constructed a whole-genome map of short tandem repeat (STR) variations for populations in the Qinghai-Tibet Plateau and its adjacent regions. It reveals the multi-level regulatory functions of STRs in the adaptive evolution to high-altitude environments, offering a new perspective for understanding the genetic mechanisms of human adaptation to extreme environments. Dr. Yuguo Huang, a postdoctoral fellow at the Rare Diseases Institute, West China Hospital, Sichuan University, and Associate Professor Mengge Wang from the Department of Forensic Medicine, School of Basic Medical Sciences, Chongqing Medical University, are the co-first authors. Professor Huijun Yuan, Associate Researcher Guanglin He, and Associate Researcher Jing Cheng from the Center for Archaeological Sciences, Sichuan University, and the Rare Diseases Institute, West China Hospital; along with Associate Researcher Fengxiao Bu and Associate Researcher Yu Lu from West China Hospital, Sichuan University, are the co-corresponding authors.

The Qinghai-Tibet Plateau, as one of Earth's most extreme environments, offers a unique natural laboratory to study the genetic mechanisms of human environmental adaptation due to its low oxygen, low temperature, and high ultraviolet radiation conditions. Past research has primarily focused on single nucleotide polymorphisms (SNPs) in genes like EPAS1 and EGLN1, providing initial insights into the mechanisms of hypoxia adaptation in highland populations. However, the role of repetitive sequences, which constitute over half of the human genome, particularly short tandem repeats (STRs), in high-altitude adaptation has long been an under-researched area. Leveraging the highland population resources from the "Genome Sequencing of 100,000 Rare Disease Patients (GSRD-100KWCH)" project, Huijun Yuan's team integrated 7,876 whole-genome sequencing datasets, including 3,808 newly sequenced samples from Tibeto-Burman speaking and Han Chinese highland populations. Through advanced bioinformatics methods, the research team conducted a systematic analysis of over 1.1 million STR loci, constructing the world's first whole-genome STR variation map for highland populations and filling a critical gap in the genetic resources of high-altitude populations.

The study revealed a unique STR genetic structure in Tibeto-Burman speaking populations. It was found that populations such as Tibetans and Yi people possess STR variation patterns significantly different from those of low-altitude Han Chinese. These differences not only reflect population genetic structure and migration-admixture history but also show that a large number of highly differentiated STRs are concentrated in known high-altitude adaptation-related genes (e.g., SHISA8, MAPKAPK5) and their regulatory regions, suggesting they may be under natural selection (Figure 1). Concurrently, the work confirmed the regulatory function of STRs on gene expression. The study found that these differentiated STRs can be expression quantitative trait loci (eQTLs), where variations in their length can precisely regulate the expression levels of target genes, thereby enhancing the body's adaptability in extreme environments. The systematic study identified key STRs strongly associated with the highland environment. Through association analysis, the research screened over 17,000 STRs significantly correlated with environmental factors such as altitude, temperature, and solar radiation. These STRs function through various mechanisms: STRs in coding regions affect protein function by altering amino acid sequences; STRs in regulatory regions influence gene expression by changing enhancer activity. The genes regulated by these STRs are significantly enriched in pathways closely related to high-altitude adaptation, such as the lysosome, folate metabolism, and energy metabolism pathways (Figure 2). Furthermore, the study established an association between STRs and complex traits. It was found that these functional STRs are in significant linkage with genetic risk loci affecting complex traits like lung function and blood lipid levels, providing new clues to explain the "missing heritability" in GWAS studies (Figure 3).

This research broadens the perspective of human adaptive evolution studies from traditional SNPs to the more complex STR variations, demonstrating that this genetic "dark matter" plays an indispensable role in adaptation to high-altitude environments. The constructed STR variation map provides a valuable resource for subsequent functional genomics, medical genetics, and forensic science research. Its strategy of integrating multi-omics data also offers a new paradigm for studying the genetic mechanisms of other complex traits.

Professor Xu Shuhua, a population geneticist at Fudan University, pointed out that this study has constructed the first comprehensive, high-quality STR variation map for Tibeto-Burman speaking populations. By integrating population differentiation, environmental association, and eQTL analysis, it systematically identifies candidate STR loci that may be involved in high-altitude adaptation, providing a clear "roadmap" for future functional studies. Professor He Shunmin, an expert in medical genetics at the Institute of Biophysics, Chinese Academy of Sciences, believes that the established STR allele frequency database has significant clinical application value and will enhance the accuracy of interpreting genetic variations in Tibeto-Burman speaking populations. The study's finding of a close link between non-coding STRs and risk loci for complex diseases offers a new direction for understanding the problem of "missing heritability." In the future, the research team will further validate the biological effects of key STRs through functional experiments and use technologies like long-read sequencing to comprehensively analyze the role of complex structural variations in human evolution and disease. This research not only deepens our understanding of the mechanisms of human adaptation to extreme environments but also provides a new genetic basis for precision medicine and human health research.

Figure 1. Discovery and polymorphism patterns of whole-genome STR variations.

Figure 2. Genetic background and STR variation landscape of Tibeto-Burman speaking populations.

Figure 3. STR-mediated multi-level regulation of high-altitude adaptation.