Zhi Qi Wong, Lian Deng, Alvin Cengnata, Thuhairah Abdul Rahman, Aletza Mohd Ismail, Renee Lay Hong Lim, Shuhua Xu, Boon-Peng Hoh
{"title":"Expression quantitative trait loci (eQTL): from population genetics to precision medicine.","authors":"Zhi Qi Wong, Lian Deng, Alvin Cengnata, Thuhairah Abdul Rahman, Aletza Mohd Ismail, Renee Lay Hong Lim, Shuhua Xu, Boon-Peng Hoh","doi":"10.1016/j.jgg.2025.02.003","DOIUrl":"10.1016/j.jgg.2025.02.003","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":54825,"journal":{"name":"Journal of Genetics and Genomics","volume":" ","pages":"449-459"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ziwei Chen, Lu Chen, Jingze Tan, Yizhen Mao, Meng Hao, Yi Li, Yi Wang, Jinxi Li, Jiucun Wang, Li Jin, Hong-Xiang Zheng
{"title":"Natural selection shaped the protective effect of the mtDNA lineage against obesity in Han Chinese populations.","authors":"Ziwei Chen, Lu Chen, Jingze Tan, Yizhen Mao, Meng Hao, Yi Li, Yi Wang, Jinxi Li, Jiucun Wang, Li Jin, Hong-Xiang Zheng","doi":"10.1016/j.jgg.2024.06.005","DOIUrl":"10.1016/j.jgg.2024.06.005","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":54825,"journal":{"name":"Journal of Genetics and Genomics","volume":" ","pages":"539-548"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ancient DNA reveals genetic exchange in the Hehuang valley in the context of demic diffusion during the Han dynasty.","authors":"Langyun Wang, Yutong Wang, Bing Sun, Daxuan Zhang, Guanjin Liang, Pengcheng Ma, Hao Zhang, Chunxiang Li, Xiaojun Hu, Quanchao Zhang, Yinqiu Cui","doi":"10.1016/j.jgg.2024.11.013","DOIUrl":"10.1016/j.jgg.2024.11.013","url":null,"abstract":"","PeriodicalId":54825,"journal":{"name":"Journal of Genetics and Genomics","volume":" ","pages":"592-595"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Paleolithic divergence and multiple Neolithic expansions of ancestral nomadic emperor-related paternal lineages.","authors":"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","doi":"10.1016/j.jgg.2024.11.012","DOIUrl":"10.1016/j.jgg.2024.11.012","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":54825,"journal":{"name":"Journal of Genetics and Genomics","volume":" ","pages":"502-512"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
{"title":"Neolithic to Bronze Age human maternal genetic history in Yunnan, China.","authors":"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","doi":"10.1016/j.jgg.2024.09.013","DOIUrl":"10.1016/j.jgg.2024.09.013","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":54825,"journal":{"name":"Journal of Genetics and Genomics","volume":" ","pages":"483-493"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142332644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
{"title":"A multi-ancestry GWAS meta-analysis of facial features and its application in predicting archaic human features.","authors":"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","doi":"10.1016/j.jgg.2024.07.005","DOIUrl":"10.1016/j.jgg.2024.07.005","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":54825,"journal":{"name":"Journal of Genetics and Genomics","volume":" ","pages":"513-524"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141604560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Endogamy and high prevalence of deleterious mutations in India: evidence from strong founder events.","authors":"Pratheusa Machha, Amirtha Gopalan, Yamini Elangovan, Sarath Chandra Mouli Veeravalli, Divya Tej Sowpati, Kumarasamy Thangaraj","doi":"10.1016/j.jgg.2025.02.001","DOIUrl":"10.1016/j.jgg.2025.02.001","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":54825,"journal":{"name":"Journal of Genetics and Genomics","volume":" ","pages":"570-582"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A gain-of-function variant in RICTOR predisposes to human obesity.","authors":"Mengshan Ni, Yinmeng Zhu, Yufei Chen, Shaoqian Zhao, Aibo Gao, Jieli Lu, Weiqing Wang, Ruixin Liu, Weiqiong Gu, Jie Hong, Jiqiu Wang","doi":"10.1016/j.jgg.2025.02.002","DOIUrl":"10.1016/j.jgg.2025.02.002","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":54825,"journal":{"name":"Journal of Genetics and Genomics","volume":" ","pages":"549-558"},"PeriodicalIF":6.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Coordinated regulation of cortical astrocyte maturation by OLIG1 and OLIG2 through BMP7 signaling modulation.","authors":"Ziwu Wang, Yu Tian, Tongye Fu, Feihong Yang, Jialin Li, Lin Yang, Wen Zhang, Wenhui Zheng, Xin Jiang, Zhejun Xu, Yan You, Xiaosu Li, Guoping Liu, Yunli Xie, Zhengang Yang, Dashi Qi, Zhuangzhi Zhang","doi":"10.1016/j.jgg.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.jgg.2025.03.008","url":null,"abstract":"<p><p>Astrocyte maturation is crucial for brain function, yet the mechanisms regulating this process remain poorly understood. In this study, we identify the bHLH transcription factors Olig1 and Olig2 as essential coordinators of cortical astrocyte maturation. We demonstrate that Olig1 and Olig2 work synergistically to regulate cortical astrocyte maturation by modulating Bmp7 expression. Genetic ablation of both Olig1 and Olig2 results in defective astrocyte morphology, including reduced process complexity and an immature gene expression profile. Single-cell RNA sequencing reveals a shift towards a less mature astrocyte state, marked by elevated levels of HOPX and GFAP, resembling human astrocytes. Mechanistically, Olig1 and Olig2 bind directly to the Bmp7 enhancer, repressing its expression to promote astrocyte maturation. Overexpression of Bmp7 in vivo replicates the astrocyte defects seen in Olig1/2 double mutants, confirming the critical role of BMP7 signaling in this process. These findings provide insights into the transcriptional and signaling pathways regulating astrocyte development and highlight Olig1 and Olig2 as key regulators of cortical astrocyte maturation, with potential implications for understanding glial dysfunction in neurological diseases.</p>","PeriodicalId":54825,"journal":{"name":"Journal of Genetics and Genomics","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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