The Center for Archaeological Science, Sichuan University was invited to present research progress and prospects on reconstructing ancient and modern human population genetic genealogy based on ancestral recombination graphs.

On August 30, 2024, the Center for Archaeological Science, Sichuan University, the Rare Disease Research Institute of West China Hospital, Sichuan University, Hui-Jun Yuan/Guang-Lin He research team, and the Chao Liu Academician research team of the Guangdong Provincial Drug Experiment Technology Center (Guangdong Branch of the National Drug Laboratory) jointly published a review article entitled "Research progress and prospects of reconstructing the genetic pedigree of ancient and modern human populations based on ancestral recombination graphs" in the journal *Hereditas*. This review introduces the theoretical basis of ARG reconstruction, summarizes the early applications of genetic pedigree and the methods and progress of constructing ARG, and further discusses the application potential of ARG and the challenges and future prospects of reconstructing ARG, aiming to deepen the understanding of the theoretical basis and application scenarios of ARG, and promote the application of ARG in evolutionary genomics and medical genomics.

With the release of large-scale genome resources of ancient and modern populations, the innovation of computational biology tools, and the improvement of computing power related to big data mining, the field of genomics is undergoing a revolutionary change. These advances and changes not only significantly deepen people's understanding of the complex evolutionary processes of human origin, migration, and admixture, but also reveal the impact of these processes on human disease and health status, accelerate people's research on the genetic basis of human health and disease, and provide new ways to explore the evolutionary history of population evolution and the evolutionary trajectory of the genetic basis of disease recorded in the human genome. Ancestral recombination graph (ARG) technology reconstructs the evolutionary relationship between genome fragments by analyzing recombination events and coalescence characteristics in different regions of the whole genome. ARG records all coalescence and recombination events since the divergence of the studied genome sequences, and indicates the complete pedigree of each genome location, which is an ideal data structure for genome analysis.

This review mainly includes 5 parts:

(1) Theoretical basis of ARG reconstruction. Even individuals who seem superficially unrelated can theoretically find a common ancestor if traced back far enough in time. This indicates that there is a potential genetic connection between all modern humans. DNA fragments are transmitted to a common ancestor through specific paths, thereby forming a local genetic pedigree of the genome location.

(2) Early applications of genetic pedigree. Forensic geneticists use genetic pedigrees to identify suspects in cases and the identities of missing persons, solving a series of cold cases and accumulated cases such as the Golden State Killer and Buckskin Girl.

(3) Methods and progress of constructing ARG. Since Hein et al. first introduced the method of constructing ARG based on parsimony in 1990, more than 20 methods have been developed for ARG construction (as shown in the figure below). This article selects four methods that are widely used by researchers for introduction.

(4) Application of evolutionary genomics. A core issue of evolutionary genomics is how to most effectively represent and analyze genomic diversity to gain insight into the key processes, forces, and events that shape biological evolutionary history. Based on ARG, we can screen natural selection signals, infer the spatiotemporal evolutionary trajectory of allele frequencies, construct a unified genetic pedigree of modern and ancient human genomes, and identify genetic introgression of Neanderthals and Denisovans.

(5) Genotype imputation and pedigree association analysis. Genotype imputation is a mature strategy that can enhance the effectiveness of association studies based on chip data. Based on ARG, we can identify and utilize those genetic variations that are outside the haplotype reference panel.

Methodological progress in constructing ARG

In general, integrating genetic pedigree relationships and genomic variation data is not only of great value to population and individual genetics, but also can correct geographic confounding differences in rare and common variations in genetic association studies, and powerfully infer potential evolutionary events, processes, and parameters, such as mutation time, natural selection, and contact between ancient populations. In addition, tree sequences can be used to integrate different data sources and construct a reference pedigree tree sequence structure of human genomic variation that can be updated as new variations are discovered. This structure, combined with efficient tree sequence algorithms, can realize diverse statistical genetic operations, including genotyping, genotype imputation, and haplotype phasing. At the same time, this structure can also be used to effectively share data in a privacy-preserving manner, that is, by describing the dataset based on inferred ancestors rather than individual samples.

Professor Hui-Jun Yuan and Associate Researcher Guang-Lin He of the Center for Archaeological Science, Sichuan University, and the Rare Disease Research Institute of West China Hospital, Sichuan University, and Academician Chao Liu of the Guangdong Provincial Drug Experiment Technology Center (Guangdong Branch of the National Drug Laboratory) are the co-corresponding authors of the article. Qing-Xin Yang, a master's student at the School of Forensic Medicine of Kunming Medical University, and Dr. Meng-Ge Wang of the Center for Archaeological Science, Sichuan University, and the Rare Disease Research Institute of West China Hospital, Sichuan University, are the co-authors of the article. The related work was supported by the National Natural Science Foundation of China, the Open Project of the Center for Archaeological Science, Sichuan University, the Major Project of the National Social Science Fund, and the 1.3.5 Project of West China Hospital, Sichuan University.

Qing-Xin Yang, Meng-Ge Wang, Chao Liu, Hui-Jun Yuan, Guang-Lin He. Research progress and prospects of reconstructing the genetic pedigree of ancient and modern human populations based on ancestral recombination graphs[J]. Hereditas, 2024, 46(10): 849-859. doi: 10.16288/j.yczz.24-150