Journal of Genetics and Genomics

Expression quantitative trait loci (eQTL): from population genetics to precision medicine

Zhi Qi Wong, Lian Deng, Alvin Cengnata, Thuhairah Abdul Rahman, Aletza Mohd Ismail, Renee Lay Hong Lim, Shuhua Xu, Boon-Peng Hoh

2025, 52(4): 449-459. doi: 10.1016/j.jgg.2025.02.003

Abstract (2)

Abstract:
Evidence has shown that differential transcriptomic profiles among human populations from diverse ancestries, supporting the role of genetic architecture in regulating gene expression alongside environmental stimuli. Genetic variants that regulate gene expression, known as expression quantitative trait loci (eQTL), are primarily shaped by human migration history and evolutionary forces, likewise, regulation of gene expression in principle could have been influenced by these events. Therefore, a comprehensive understanding of how human evolution impacts eQTL offers important insights into how phenotypic diversity is shaped. Recent studies, however, suggest that eQTL is enriched in genes that are selectively constrained. Whether eQTL is minimally affected by selective pressures remains an open question and requires comprehensive investigations. In addition, such studies are primarily dominated by the major populations of European ancestry, leaving many marginalized populations underrepresented. These observations indicate there exists a fundamental knowledge gap in the role of genomics variation on phenotypic diversity, which potentially hinders precision medicine. This article aims to revisit the abundance of eQTL across diverse populations and provide an overview of their impact from the population and evolutionary genetics perspective, subsequently discuss their influence on phenomics, as well as challenges and opportunities in the applications to precision medicine.

Forensic investigative genetic genealogy: expanding pedigree tracing and genetic inquiry in the genomic era

Mengge Wang, Hongyu Chen, Lintao Luo, Yuguo Huang, Shuhan Duan, Huijun Yuan, Renkuan Tang, Chao Liu, Guanglin He

2025, 52(4): 460-472. doi: 10.1016/j.jgg.2024.06.016

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Genetic genealogy provides crucial insights into the complex biological relationships within contemporary and ancient human populations by analyzing shared alleles and chromosomal segments that are identical by descent to understand kinship, migration patterns, and population dynamics. Within forensic science, forensic investigative genetic genealogy (FIGG) has gained prominence by leveraging next-generation sequencing technologies and population-specific genomic resources, opening useful investigative avenues. In this review, we synthesize current knowledge, underscore recent advancements, and discuss the growing role of FIGG in forensic genomics. FIGG has been pivotal in revitalizing dormant inquiries and offering genetic leads in numerous cold cases. Its effectiveness relies on the extensive single-nucleotide polymorphism profiles contributed by individuals from diverse populations to specialized genomic databases. Advances in computational genomics and the growth of human genomic databases have spurred a profound shift in the application of genetic genealogy across forensics, anthropology, and ancient DNA studies. As the field progresses, FIGG is evolving from a nascent practice into a more sophisticated and specialized discipline, shaping the future of forensic investigations.

Ancient genomic analysis of a Chinese hereditary elite from the Northern and Southern Dynasties

Yao Yu, Xiaomin Yang, Daiyun Liu, Panxin Du, Hailiang Meng, Zixiao Huang, Jianxue Xiong, Yi Ding, Xiaoying Ren, Edward Allen, Hui Wang, Sheng Han, Li Jin, Chuan-Chao Wang, Shaoqing Wen

2025, 52(4): 473-482. doi: 10.1016/j.jgg.2024.07.009

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China's Northern and Southern Dynasties period (3rd–6th centuries AD) marked a significant era of ethnic integration in northern China. However, previous ancient DNA studies have primarily focused on northern ethnic groups, with limited research on the genetic formation of the hereditary elite family, especially considering their abundant archaeological record and clear material identity. In this study, we obtain the ancient genome of a hereditary elite family, Gao Bin (高宾, 503 AD–572 AD), at 0.6473-fold coverage with 475,132 single-nucleotide polymorphisms (SNPs) on the 1240k panel. His mitochondrial haplogroup belongs to Z4 and Y-haplogroup to O1a1a2b-F2444*. The genetic profile of Gao Bin is most similar to that of the northern Han Chinese. He can be modeled as deriving all his ancestry from Late Neolithic to Iron Age Yellow River farmers without influence from Northeast Asia, Korea, or the Mongolian Plateau. Our study sheds light on the genetic formation of hereditary elite families in the context of the Southern and Northern Dynasties ethnic integration.

Neolithic to Bronze Age human maternal genetic history in Yunnan, China

Xinyu Wei, Ming Zhang, Rui Min, Zhilong Jiang, Jiayang Xue, Zhonghua Zhu, Haibing Yuan, Xiaorui Li, Dongyue Zhao, Peng Cao, Feng Liu, Qingyan Dai, Xiaotian Feng, Ruowei Yang, Xiaohong Wu, Changcheng Hu, Minmin Ma, Xu Liu, Yang Wan, Fan Yang, Ranchao Zhou, Lihong Kang, Guanghui Dong, Wanjing Ping, Tianyi Wang, Bo Miao, Fan Bai, Yuxin Zheng, Yuxiao Liu, Melinda A. Yang, Wenjun Wang, E. Andrew Bennett, Qiaomei Fu

2025, 52(4): 483-493. doi: 10.1016/j.jgg.2024.09.013

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Yunnan in southwest China is a geographically and ethnically complex region at the intersection of southern China and Southeast Asia, and a focal point for human migrations. To clarify its maternal genetic history, we generated 152 complete mitogenomes from 17 Yunnan archaeological sites. Our results reveal distinct genetic histories segregated by geographical regions. Maternal lineages of ancient populations from northwestern and northern Yunnan exhibit closer affinities with past and present-day populations from northern East Asia and Xizang, providing important genetic evidence for the migration and interaction of populations along the Tibetan-Yi corridor since the Neolithic. Between 5500 and 1800 years ago, central Yunnan populations maintained their internal genetic relationships, including a 7000-year-old basal lineage of the rare and widely dispersed haplogroup M61. At the Xingyi site, changes in mitochondrial DNA haplogroups occurred between the Late Neolithic and Bronze Age, with haplogroups shifting from those predominant in the Yellow River region to those predominant in coastal southern China. These results highlight the high diversity of Yunnan populations during the Neolithic to Bronze Age.

Ancient genomes illuminate the demographic history of Shandong over the past two millennia

Qu Shen, Zhigang Wu, Jinguo Zan, Xiaomin Yang, Jianxin Guo, Zhi Ji, Baitong Wang, Yilan Liu, Xiaolu Mao, Xinyi Wang, Xinyue Zou, Hongming Zhou, Yanying Peng, Hao Ma, Haifeng He, Tianyou Bai, Mengting Xu, Shaoqing Wen, Li Jin, Qun Zhang, Chuan-Chao Wang

2025, 52(4): 494-501. doi: 10.1016/j.jgg.2024.07.008

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Shandong province, located in the Lower Yellow River, is one of the birthplaces of ancient Chinese civilization. However, the comprehensive genetic histories of this region have remained largely unknown until now due to a lack of ancient human genomes. Here, we present 21 ancient genomes from Shandong dating from the Warring States period to the Northern Dynasties. Unlike the early Neolithic samples from Shandong, the historical samples are most closely related to post-Late Neolithic populations of the Middle Yellow River Basin, suggesting a population turnover in Shandong from the Neolithic Age to the Historical era. In addition, we detect a close genetic affinity between the historical samples in Shandong and present-day Han Chinese, showing long-term genetic stability in Han Chinese, at least since the Warring States period.

Paleolithic divergence and multiple Neolithic expansions of ancestral nomadic emperor-related paternal lineages

Mengge Wang, Qiuxia Sun, Yuhang Feng, Lan-Hai Wei, Kaijun Liu, Lintao Luo, Yuguo Huang, Kun Zhou, Haibing Yuan, Hongliang Lv, Yu Lu, Jing Cheng, Shaoqing Wen, Chuan-Chao Wang, Renkuan Tang, Fengxiao Bu, Chao Liu, Huijun Yuan, Zhiyong Wang, Guanglin He

2025, 52(4): 502-512. doi: 10.1016/j.jgg.2024.11.012

Abstract (2)

Abstract:
The reconstruction of demographic history using ancient and modern genomic resources reveals extensive interactions and admixture between ancient nomadic pastoralists and the social organizations of the Chinese Central Plain. However, the extent to which Y-chromosome genetic legacies from nomadic emperor-related ancestral lineages influence the Chinese paternal gene pool remains unclear. Here, we genotype 2717 ethnolinguistically diverse samples belonging to C2a lineages, perform whole-genome sequencing on 997 representative samples, and integrate these data with ancient genomic sequences. We reconstruct the evolutionary histories of Northern Zhou-, Qing emperor-, and pastoralist-related lineages to assess their genetic impact on modern Chinese populations. This reassembled fine-scale Y-chromosome phylogeny identifies deep divergence and five Neolithic expansion events contributing differently to the formation of northern Chinese populations. Phylogeographic modeling indicates that the nomadic empires of the Northern Zhou and Qing dynasties genetically originated from the Mongolian Plateau. Phylogenetic topology and shared haplotype patterns show that three upstream ancestors of Northern Zhou (C2a1a1b1a2a1b-FGC28857), Donghu tribe (C2a1a1b1-F1756), and Qing (C2a1a3a2-F10283) emperor-related lineages expanded during the middle Neolithic, contributing significantly to genetic flow between ancient northeastern Asians and modern East Asians. Notably, this study reveals limited direct contributions of Emperor Wu of Northern Zhou's lineages to modern East Asians.

A multi-ancestry GWAS meta-analysis of facial features and its application in predicting archaic human features

Siyuan Du, Jieyi Chen, Jiarui Li, Wei Qian, Sijie Wu, Qianqian Peng, Yu Liu, Ting Pan, Yi Li, Sibte Syed Hadi, Jingze Tan, Ziyu Yuan, Jiucun Wang, Kun Tang, Zhuo Wang, Yanqin Wen, Xinran Dong, Wenhao Zhou, Andrés Ruiz-Linares, Yongyong Shi, Li Jin, Fan Liu, Manfei Zhang, Sijia Wang

2025, 52(4): 513-524. doi: 10.1016/j.jgg.2024.07.005

Abstract (1)

Abstract:
Facial morphology, a complex trait influenced by genetics, holds great significance in evolutionary research. However, due to limited fossil evidence, the facial characteristics of Neanderthals and Denisovans have remained largely unknown. In this study, we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study (GWAS), including 9674 East Asians and 10,115 Europeans, quantitatively assessing 78 facial traits using 3D facial images. We identify 71 genomic loci associated with facial features, including 21 novel loci. We develop a facial polygenic score (FPS) that enables the prediction of facial features based on genetic information. Interestingly, the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features. Furthermore, we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records. Our results suggest that Neanderthals and Denisovans likely share similar facial features, such as a wider but shorter nose and a wider endocanthion distance. The decreased mouth width is characterized specifically in Denisovans. The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.

Genomic characterization reveals distinct mutational landscape of acral melanoma in East Asian

Fenghao Zhang, Xiaowen Wu, Tao Jiao, Haizhen Du, Qian Guo, Chuanliang Cui, Zhihong Chi, Xinan Sheng, Dezhi Jiang, Yuhong Zhang, Jiayan Wu, Yan Kong, Lu Si

2025, 52(4): 525-538. doi: 10.1016/j.jgg.2024.12.018

Abstract (0)

Abstract:
Acral melanoma, the most common melanoma subtype in East Asia, is associated with a poor prognosis. This study aims to comprehensively analyze the genomic characteristics of acral melanoma in East Asians. We conduct whole-genome sequencing of 55 acral melanoma tumors and perform data mining with relevant clinical data. Our findings reveal a unique mutational profile in East Asian acral melanoma, characterized by fewer point mutations and structural variations, a higher prevalence of NRAS mutations, and a lower frequency of BRAF mutations compared to patients of European descent. Notably, we identify previously underestimated ultraviolet radiation signatures and their significant association with BRAF and NRAS mutations. Structural rearrangement signatures indicate distinct mutational processes in BRAF-driven versus NRAS-driven tumors. We also find that homologous recombination deficiency with MAPK pathway mutations correlated with poor prognosis. The structural variations and amplifications in EP300, TERT, RAC1, and LZTR1 point to potential therapeutic targets tailored to East Asian populations. The high prevalence of whole-genome duplication events in BRAF/NRAS-mutated tumors suggests a synergistic carcinogenic effect that warrants further investigation. In summary, our study provides important insights into the genetic underpinnings of acral melanoma in East Asians, creating opportunities for targeted therapies.

Natural selection shaped the protective effect of the mtDNA lineage against obesity in Han Chinese populations

Ziwei Chen, Lu Chen, Jingze Tan, Yizhen Mao, Meng Hao, Yi Li, Yi Wang, Jinxi Li, Jiucun Wang, Li Jin, Hong-Xiang Zheng

2025, 52(4): 539-548. doi: 10.1016/j.jgg.2024.06.005

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Mitochondria play a key role in lipid metabolism, and mitochondrial DNA (mtDNA) mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function. In this study, we investigate mtDNA variants that may affect obesity risk in 2877 Han Chinese individuals from 3 independent populations. The association analysis of 16 basal mtDNA haplogroups with body mass index, waist circumference, and waist-to-hip ratio reveals that only haplogroup M7 is significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort, verified by the analysis of a single population, i.e., the Zhengzhou population. Furthermore, subhaplogroup analysis suggests that M7b1a1 is the most likely haplogroup associated with a decreased obesity risk, and the variation T12811C (causing Y159H in ND5) harbored in M7b1a1 may be the most likely candidate for altering the mitochondrial function. Specifically, we find that proportionally more nonsynonymous mutations accumulate in M7b1a1 carriers, indicating that M7b1a1 is either under positive selection or subject to a relaxation of selective constraints. We also find that nuclear variants, especially in DACT2 and PIEZO1, may functionally interact with M7b1a1.

A gain-of-function variant in RICTOR predisposes to human obesity

Mengshan Ni, Yinmeng Zhu, Yufei Chen, Shaoqian Zhao, Aibo Gao, Jieli Lu, Weiqing Wang, Ruixin Liu, Weiqiong Gu, Jie Hong, Jiqiu Wang

2025, 52(4): 549-558. doi: 10.1016/j.jgg.2025.02.002

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mTORC1/2 play central roles as signaling hubs of cell growth and metabolism and are therapeutic targets for several diseases. However, the human genetic evidence linking mutations of mTORC1/2 to obesity remains elusive. Using whole-exome sequencing of 1944 cases with severe obesity and 2161 healthy lean controls, we identify a rare RICTOR p.I116V variant enriched in 9 unrelated cases. In Rictor null mouse embryonic fibroblasts, overexpression of the RICTOR p.I116V mutant increases phosphorylation of AKT, a canonical mTORC2 substrate, compared with wild-type RICTOR, indicating a gain-of-function change. Consistent with the human obesity phenotype, the knock-in mice carrying homogenous Rictor p.I116V variants gain more body weight under a high-fat diet. Additionally, the stromal vascular fraction cells derived from inguinal white adipose tissue of knock-in mice display an enhanced capacity for adipocyte differentiation via AKT activity. These findings demonstrate that the rare gain-of-function RICTOR p.I116V mutation activates AKT signaling, promotes adipogenesis, and contributes to obesity in humans.

A rare KLHDC4 variant Glu510Lys is associated with genetic susceptibility and promotes tumor metastasis in nasopharyngeal carcinoma

Xi-Xi Cheng, Guo-Wang Lin, Ya-Qing Zhou, Yi-Qi Li, Shuai He, Yang Liu, Yan-Ni Zeng, Yun-Miao Guo, Shu-Qiang Liu, Wan Peng, Pan-Pan Wei, Chun-Ling Luo, Jin-Xin Bei

2025, 52(4): 559-569. doi: 10.1016/j.jgg.2024.12.008

Abstract (2)

Abstract:
Various genetic association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with nasopharyngeal carcinoma (NPC) risk. However, these studies have predominantly focused on common variants, leaving the contribution of rare variants to the “missing heritability” largely unexplored. Here, we integrate genotyping data from 3925 NPC cases and 15,048 healthy controls to identify a rare SNP, rs141121474, resulting in a Glu510Lys mutation in KLHDC4 gene linked to increased NPC risk. Subsequent analyses reveal that KLHDC4 is highly expressed in NPC and correlates with poorer prognosis. Functional characterizations demonstrate that KLHDC4 acts as an oncogene in NPC cells, enhancing their migratory and metastatic capabilities, with these effects being further augmented by the Glu510Lys mutation. Mechanistically, the Glu510Lys mutant exhibits increased interaction with Vimentin compared to the wild-type KLHDC4 (KLHDC4-WT), leading to elevated Vimentin protein stability and modulation of the epithelial-mesenchymal transition process, thereby promoting tumor metastasis. Moreover, Vimentin knockdown significantly mitigates the oncogenic effects induced by overexpression of both KLHDC4-WT and the Glu510Lys variant. Collectively, our findings highlight the critical role of the rare KLHDC4 variant rs141121474 in NPC progression and propose its potential as a diagnostic and therapeutic target for NPC patients.

Endogamy and high prevalence of deleterious mutations in India: evidence from strong founder events

Pratheusa Machha, Amirtha Gopalan, Yamini Elangovan, Sarath Chandra Mouli Veeravalli, Divya Tej Sowpati, Kumarasamy Thangaraj

2025, 52(4): 570-582. doi: 10.1016/j.jgg.2025.02.001

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Founder events influence recessive diseases in highly endogamous populations. Several Indian populations have experienced significant founder events due to strict endogamy. However, the clinical implications of it remain underexplored. Therefore, we perform whole-exome sequencing of 281 individuals from four South Indian populations, characterized by high IBD scores. Our study reveals a high inbreeding rate of 59% across the populations. We identify ∼29.2% of the variants that are exclusively present in a single population and uncover 1284 unreported exonic variants, underscoring the underrepresentation of Indian populations in global databases. Among these, 23 are predicted to be deleterious, all of which are present in a heterozygous state; they may be pathogenic when homozygous, an expected phenomenon in endogamous populations. Approximately 16%–33% of the identified pathogenic variants showed significantly higher occurrence rates compared with the South Asian populations from 1000 Genomes dataset. Pharmacogenomic analysis revealed distinct allele frequencies of variants in CYP450 and non-CYP450 genes, highlighting heterogeneous drug responses and associated risks. We report a high prevalence of ankylosing spondylitis in Reddy population, linked to the HLA-B*27:04 allele and strong founder effect. Our findings highlight the need for extensive genomic research in understudied Indian populations for a better understanding of disease risk and evolving strategies for precision and preventive medicine.

ERVcancer: a web resource designed for querying activation of human endogenous retroviruses across major cancer types

Xiaoyun Lei, Song Mao, Yinshuang Li, Shi Huang, Jinchen Li, Wei Du, Chunmei Kuang, Kai Yuan

2025, 52(4): 583-591. doi: 10.1016/j.jgg.2024.09.004

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Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome, integrated into the dynamic regulatory network of cellular potency during early embryonic development. In recent studies, resurgent the transcriptional activity of HERVs has been frequently observed in many types of human cancers, suggesting their potential functions in the occurrence and progression of malignancy. However, a dedicated web resource for querying the relationship between the activation of HERVs and cancer development is lacking. Here, we construct a database to explore the sequence information, expression profiles, survival prognosis, and genetic interactions of HERVs in diverse cancer types. Our database currently contains RNA sequencing data of 580 HERVs across 16,246 samples, including that of 6478 tumoral and 634 normal tissues, 932 cancer cell lines, as well as 151 early embryonic and 8051 human adult tissues. The primary goal is to provide an easily accessible and user-friendly database for professionals in the fields of bioinformatics, pathology, pharmacology, and related areas, enabling them to efficiently screen the activity of HERVs of interest in normal and cancerous tissues and evaluate the clinical relevance. The ERVcancer database is available at http://kyuanlab.com/ervcancer/.

Ancient DNA reveals genetic exchange in the Hehuang valley in the context of demic diffusion during the Han dynasty

Langyun Wang, Yutong Wang, Bing Sun, Daxuan Zhang, Guanjin Liang, Pengcheng Ma, Hao Zhang, Chunxiang Li, Xiaojun Hu, Quanchao Zhang, Yinqiu Cui

2025, 52(4): 592-595. doi: 10.1016/j.jgg.2024.11.013

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Genome-wide DNA methylation profile and predictive biomarkers in premature ovarian insufficiency

Xinmiao He, Xinyue Chang, Shuning Zhuang, Jianing Liu, Yuteng Wang, Yingying Qin, Ting Guo

2025, 52(4): 596-599. doi: 10.1016/j.jgg.2024.10.004

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2025 Vol. 52, No. 4