Center for Archaeological Science, Sichuan University, in collaboration with Academician Chao Liu's team, unveils the genetic and evolutionary secrets of Silk Road populations.
Recently, Science China Life Sciences (English Edition) published online a research paper titled "Pilot work of the 10K Chinese People Genomic Diversity Project along the Silk Road suggests a complex east-west admixture landscape and biological adaptations", co-authored by Academician Chao Liu, Associate Researcher Guanglin He of the Center for Archaeological Science, Sichuan University/West China Institute of Rare Diseases, Sichuan University, and Associate Professor Mengge Wang of the Department of Forensic Medicine, School of Basic Medical Sciences, Chongqing Medical University. This study delves into the fine-scale genetic structure and complex evolutionary history of populations along the Silk Road, as well as the genetic connections between ancient and modern populations in the region within the context of ancient and modern genomic resources. It reveals a complex history of population exchange and integration and systematically demonstrates the evolutionary genetic mechanisms of human population evolution events, particularly migration and admixture history, and biological adaptation in relation to human diseases and health.
Currently, large-scale population genomics studies are concentrated on individuals with European genetic backgrounds, such as the UK Biobank (UK100K), TOPMed, and All of Us in North America. This not only limits our comprehensive understanding of human genetic diversity but also exacerbates health inequalities in precision medicine. As one of the most populous countries in the world, China's research on the genetic history and evolutionary processes of its ancient and modern populations is crucial for global genetics and precision medicine. The Silk Road, as a network of ancient Eurasian trade routes, is a key location for understanding the genetic integration and cross-cultural exchange between western Eurasian populations and inland Chinese populations. This study focuses on Chinese populations along the Silk Road, aiming to reveal the genetic admixture and adaptive history of these populations.
In order to comprehensively capture the genomic diversity of populations along the Silk Road, the researchers reported the pilot study results of the sub-project "Genetic Evolution and Genetic Basis of Diseases and Health in Populations along the Silk Road" within the 10K Chinese People Genomic Diversity Project (10K_CPGDP). The project aims to detect under-represented populations in human genetics research along the Silk Road through whole-genome sequencing, integrate large-scale ancient and modern genomic resources, and combine computational biology methods to elucidate the genetic formation process, biological adaptations, and the map of medically relevant variations in populations along the Silk Road. The study revealed close genetic relationships between Chinese populations along the Silk Road and East Asian populations, especially modern Mongolian, Tungusic, and Tibeto-Burman-speaking populations in China, as well as ancient individuals from the Yellow River Basin, Qinghai-Tibet Plateau, Tibetan-Yi Corridor, and West Liao River Basin. Although these Silk Road populations cluster with the above-mentioned modern/ancient East Asian populations, there exists fine-scale genetic substructure within them, which can be divided into two genetic clusters: one including the Salar and Tu groups, and the other including the Dongxiang, Tibetan, and Yugur groups. In addition, the study found a closer genetic relationship between Han Chinese in Northwest China and neighboring Northern Han Chinese and Central/Southwestern Han Chinese and Mongolian-speaking Mongolians, rather than with geographically neighboring Northwest ethnic minority populations. This indicates the unique genetic background of the ethnically and linguistically diverse populations along the Silk Road and the complex admixture history among different populations.
This study's detailed modeling of population admixture history reveals that four major ancestral components have significantly contributed to the genetic structure of Chinese ethnic minorities along the Silk Road, including ancestral components related to high-altitude Tibetans, southern East Asians, ancient Northeast Asians, and western Eurasians. The qpAdm modeling analysis reveals that the ethnic minority populations along the Silk Road can be modeled as a mixture of ancestry related to the ancient population of the Shimao site in the Late Neolithic period (Shimao_LN: 87.2% to 94.4%) and the Andronovo culture nomadic population (Andronovo, 5.6% to 12.8%), further demonstrating that the interaction mode of populations along the Silk Road in the historical period was mainly cultural diffusion and supplemented by population diffusion. Based on the Multiple Sequentially Markovian Coalescent (MSMC2) method to estimate the effective population size and complex divergence time, the results reveal that the effective population size of the study population has experienced significant growth since anatomically modern humans first entered East Asia, but there are significant differences within ten thousand years. The study found significant sex-biased admixture in the Dongxiang, Tibetan, and Yugur populations, that is, more Eastern Eurasian females and Western Eurasian males have made differential contributions to the gene pools of these groups.
Figure 1. Geographic locations and genetic structure of populations along the Silk Road and modern and ancient Eurasian reference populations
In the long historical evolution of human populations, they have experienced complex natural selection pressures. These pressures include adaptation to complex and extreme environments, changes in dietary habits during the Neolithic agricultural innovation period, and the exacerbation and adaptation of pathogen exposure during the formation of primitive tribes and early states. Based on whole-genome sequencing data and complex biological adaptation detection strategies, this study identified seven genes (PRIM2, NBPFs 9/20/25P, PDE4DIP, NOTCH2, DDAH1, GALNT2, and MLIP) that showed strong signals of natural selection in populations along the Silk Road. Among them, PRIM2 and PDE4DIP are closely related to the occurrence of cardiovascular diseases. In addition, the NOTCH2 gene is related to the development of blood vessels, kidneys, and liver and shows obvious selective signals in Northwest Tibetan and Yugur populations; the DDAH1 gene is related to cardiovascular system diseases and pulmonary hypertension and shows adaptive selection signals in Dongxiang, Northwest Tibetan, and Yugur populations; the GALNT2 gene mainly plays a role in regulating triglyceride levels and type 2 diabetes and exhibits high statistical significance in the Northwest Tibetan population; the MLIP gene is related to stress response and negative regulation of myocardial hypertrophy and was identified as a significant selection signal in the Salar and Tu populations.
Figure 2. Natural selection signals and allelic frequency distributions of related genetic variations identified in populations along the Silk Road
The complex evolutionary and admixture history of humans, as well as the complex process of biological adaptation, have significantly affected the occurrence and development of human diseases. The genetic regulatory basis of human diseases has ancient or recent evolutionary foundations. How to apply the findings of evolutionary medicine and evolutionary principles to the era of precision medicine will accelerate human understanding of the evolutionary mechanisms of disease and health, and at the same time accelerate the entire process of clinical precision health promotion, prevention, diagnosis, control, treatment, and rehabilitation. This study takes the genomic diversity of populations along the Silk Road as a research window to explore the fine-scale genetic structure, admixture history, and local adaptive characteristics of populations in this region and clarifies their impact on human diseases and health. The study found that populations along the Silk Road show genetic differentiation related to language/ethnicity. In addition, natural selection signals related to environmental adaptation to cold, drought, and dietary habits such as heavy oil and heavy salt were also identified.
Academician Chao Liu of the Guangdong Provincial Drug Testing Technology Center (Guangdong Branch of the National Drug Laboratory), Associate Researcher Guanglin He of the Center for Archaeological Science, Sichuan University/West China Institute of Rare Diseases, Sichuan University, and Associate Professor Mengge Wang of the Department of Forensic Medicine, School of Basic Medical Sciences, Chongqing Medical University are the corresponding authors of this article, and Associate Researcher Guanglin He is the first author. This study was supported by the National Natural Science Foundation of China (82402203, 82202078), the Major Project of the National Social Science Fund (23&ZD203), the Open Project of the Key Laboratory of Forensic Genetics, Ministry of Public Security (2022FGKFKT05, 2024FGKFKT02), the Center for Archaeological Science, Sichuan University (23SASA01), the 1路3路5 Project Fund for Disciplinary Excellence of West China Hospital, Sichuan University (ZYJC20002), and the Science and Technology Program of Sichuan Province (2024NSFSC1518).
Corresponding Authors
Chao Liu
Academician of the Chinese Academy of Engineering, doctoral supervisor, chief forensic physician, currently serving as a professional and technical level 1 position at the Guangdong Provincial Drug Testing Technology Center (Guangdong Branch of the National Drug Laboratory). He is one of the main founders of forensic genetics in China, a major initiator of DNA database construction, and a major developer of domestically produced DNA reagents. For 32 years, he has been engaged in DNA testing engineering technology research on the front line of public security, guided by the major needs of national public safety, and has made major breakthroughs in DNA testing of difficult materials, reagent development, database construction, and drowning diagnosis and other engineering technology fields. He has successively won 4 second prizes of the National Science and Technology Progress Award, 3 of which were as the first finisher; he has been the chief editor of 6 monographs, published 173 papers as the first or corresponding author, formulated 10 national and industry standards, and obtained 16 authorized invention patents; he has trained 41 post-doctoral fellows, doctoral, and master students; he created the Key Laboratory of Forensic Pathology of the Ministry of Public Security, the Key Laboratory of Forensic Genetics of Guangdong Province, and the first post-doctoral research station of local public security organs in the country. The technical team he led was awarded the title of "National Advanced Collective of Professional and Technical Talents" by the Ministry of Organization and other 4 ministries, and was awarded the title of "Model Criminal Technology Institute" by the State Council, and won the gold medal in the first National Postdoctoral Innovation and Entrepreneurship Competition. He has successively been selected into the National "Hundred, Thousand, and Ten Thousand Talents Project" and the first batch of Guangdong Province's "Hundred Outstanding Talents Training Project"; he enjoys special government allowances from the State Council, and has been awarded personal first-class merit twice; he has won the honorary titles of National Advanced Worker, National Excellent Science and Technology Worker, National Public Security System Second-Class Hero Model, National May 1st Labor Medal, National Outstanding Middle-aged and Young Experts with Outstanding Contributions, National Public Security Science and Technology Advanced Individual, National Excellent People's Police, Guangdong Nanyue Innovation Award, Guangdong Advanced Worker, and Guangdong Excellent Communist Party Member.
Mengge Wang
Associate Professor, doctoral supervisor, Department of Forensic Medicine, School of Basic Medical Sciences, Chongqing Medical University. PI of the Forensic Genetics and Forensic Genomics Laboratory, mainly focusing on forensic genomics, population evolutionary genomics, and paleogenomics. Serves as an editor or youth editor for several SCI journals such as BMC Genomics, Phenomics, and Frontiers in Ecology and Evolution. Has published more than 40 SCI papers in journals such as Molecular Biology and Evolution, Science China Life Sciences, Journal of Genetics and Genomics, BMC Biology, and Forensic Science International: Genetics as the first/corresponding author (including co-authors). Won the second prize of the Science and Technology Award of the Ministry of Public Security in 2022. Presided over several research projects such as the National Natural Science Foundation of China.
Guanglin He
Specially-appointed Associate Researcher, Center for Archaeological Science, Sichuan University/West China Institute of Rare Diseases, Sichuan University, head of the Human Genetics and Forensic Genomics Laboratory, research interests include forensic genomics, paleogenomics, and evolutionary genomics. Serves as a director of the Sichuan Genetics Society and deputy director of the Third Youth Committee of the Medical Genetics Professional Committee of the Sichuan Medical Association. Serves as an associate editor, editor, or youth editor for several SCI journals such as GPB, BMC Biology, hLife, BMC Genomic Data, and Frontiers in Ecology and Evolution. Obtained a doctorate from Sichuan University in 2020, and engaged in postdoctoral research at the School of Life Sciences, Xiamen University and Nanyang Technological University, Singapore from 2020 to 2022. Has published more than 50 SCI papers in SCI journals such as Molecular Biology and Evolution, Science China Life Sciences, Forensic Science International: Genetics, Journal of Genetics and Genomics, iScience, BMC Biology, European Journal of Human Genetics, and Human Genomics as the first author or corresponding author, and has published papers in SCI journals such as Nature and Science Bulletin as a contributing author. Has presided over several projects such as the National Natural Science Foundation of China and sub-projects of major projects of the National Social Science Fund.