Journal of Genetics and Genomics

3D genome organization in the central nervous system, implications for neuropsychological disorders

Daijing Sun, Jie Weng, Yuhao Dong, Yan Jiang

2021, 48(12): 1045-1056. doi: 10.1016/j.jgg.2021.06.017

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Abstract:
Chromosomes in eukaryotic cell nuclei are highly compacted and finely organized into hierarchical three-dimensional (3D) configuration. In recent years, scientists have gained deeper understandings of 3D genome structures and revealed novel evidence linking 3D genome organization to various important cell events on the molecular level. Most importantly, alteration of 3D genome architecture has emerged as an intriguing higher order mechanism that connects disease-related genetic variants in multiple heterogenous and polygenic neuropsychological disorders, delivering novel insights into the etiology. In this review, we provide a brief overview of the hierarchical structures of 3D genome and two proposed regulatory models, loop extrusion and phase separation. We then focus on recent Hi-C data in the central nervous system and discuss 3D genome alterations during normal brain development and in mature neurons. Most importantly, we make a comprehensive review on current knowledge and discuss the role of 3D genome in multiple neuropsychological disorders, including schizophrenia, repeat expansion disorders, 22q11 deletion syndrome, and others.

Two zinc-finger proteins control the initiation and elongation of long stalk trichomes in tomato

Ren Li, Xiaotian Wang, Shuaibin Zhang, Xin Liu, Zhen Zhou, Zhiqiang Liu, Ketao Wang, Yanbao Tian, Haijing Wang, Youjun Zhang, Xia Cui

2021, 48(12): 1057-1069. doi: 10.1016/j.jgg.2021.09.001

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Abstract:
Plant glandular trichomes are epidermal secretory structures that are important for plant resistance to pests. Although several regulatory genes have been characterized in trichome development, the molecular mechanisms conferring glandular trichome morphogenesis are unclear. We observed the differences in trichomes in cultivated tomato cv. ‘Moneymaker’ (MM) and the wild species Solanum pimpinellifolium PI365967 (PP), and used a recombinant inbred line (RIL) population to identify the genes that control trichome development in tomato. We found that the genomic variations in two genes, HAIR (H) and SPARSE HAIR (SH), contribute to the trichome differences between MM and PP. H and SH encode two paralogous C2H2 zinc-finger proteins that function redundantly in regulating trichome formation. Loss-of-function h/sh double mutants exhibited a significantly decreased number of Type I trichomes and complete loss of long stalk trichomes. Molecular and genetic analyses further indicate that H and SH act upstream of ZFP5. Overexpression of ZFP5 partially restored the trichome defects in NIL-h^PPsh^PP. Moreover, H and SH expression is induced by high temperatures, and their mutations inhibit the elongation of trichomes that reduce the plant repellent to whiteflies. Our findings confirm that H and SH are two vital transcription factors controlling initiation and elongation of Type I and III multicellular trichomes in tomato.

Copy number variation profile-based genomic typing of premenstrual dysphoric disorder in Chinese

Hong Xue, Zhenggang Wu, Xi Long, Ata Ullah, Si Chen, Wai-Kin Mat, Peng Sun, Ming-Zhou Gao, Jie-Qiong Wang, Hai-Jun Wang, Xia Li, Wen-Jun Sun, Ming-Qi Qiao

2021, 48(12): 1070-1080. doi: 10.1016/j.jgg.2021.08.012

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Abstract:
Premenstrual dysphoric disorder (PMDD) affects nearly 5% of women of reproductive age. Symptomatic heterogeneity, together with largely unknown genetics, has greatly hindered its effective treatment. In the present study, analysis of genomic sequencing-based copy number variations (CNVs) called from 100 kb white blood cell DNA sequence windows by means of semisupervized clustering led to the segregation of patient genomes into the D and V groups, which correlated with the depression and invasion clinical types, respectively, with 89.0% consistency. Application of diagnostic CNV features selected using the correlation-based machine learning method enabled the classification of the CNVs obtained into the D group, V group, total patient group, and control group with an average accuracy of 83.0%. The power of the diagnostic CNV features was 0.98 on average, suggesting that these CNV features could be used for the molecular diagnosis of the major clinical types of PMDD. This demonstrated concordance between the CNV profiles and clinical types of PMDD supported the validity of symptom-based diagnosis of PMDD for differentiating between its two major clinical types, as well as the predominantly genetic nature of PMDD with a host of overlaps between multiple susceptibility genes/pathways and the diagnostic CNV features as indicators of involvement in PMDD etiology.

Chemical screening reveals Ronidazole is a superior prodrug to Metronidazole for nitroreductase-induced cell ablation system in zebrafish larvae

Siting Lai, Ankita Kumari, Jixiang Liu, Yiyue Zhang, Wenqing Zhang, Kuangyu Yen, Jin Xu

2021, 48(12): 1081-1090. doi: 10.1016/j.jgg.2021.07.015

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Abstract:
The Metronidazole (MTZ)/nitroreductase (NTR)-mediated cell ablation system is the most commonly used chemical-genetic cell ablation method in zebrafish. This system can specifically ablate target cells under spatial and temporal control. The MTZ/NTR system has become a widely used cell ablation system in biological, developmental, and functional studies. However, the inadequate cell-ablation ability of some cell types and the side effects of high concentration MTZ impede extensive applications of the MTZ/NTR system. In the present study, the US drug collection library was searched to extend the NTR system. Six MTZ analogs were found, and the cell-ablation ability of these analogs was tested in zebrafish larvae. The results revealed that two of the NTR substrates, Furazolidone and Ronidazole, ablated target cells more efficiently than MTZ at lower concentrations. Furthermore, the working concentration of Ronidazole, but not Furazolidone and MTZ, did not affect axonal bridge formation during spinal cord regeneration. Our results, taken together, indicate that Ronidazole is a superior prodrug to MTZ for the NTR system, especially for the study of neuron regeneration in zebrafish larvae.

Circular RNA ubiquitin-associated protein 2 enhances autophagy and promotes colorectal cancer progression and metastasis via miR-582-5p/FOXO1 signaling

Feifei Chen, Lei Guo, Jiehui Di, Man Li, Dong Dong, Dongsheng Pei

2021, 48(12): 1091-1103. doi: 10.1016/j.jgg.2021.07.017

Abstract (187) PDF (21)

Abstract:
Numerous circular RNAs (circRNAs) have been identified as vital regulators in various cancers. The newly reported circular RNA ubiquitin-associated protein 2 (circUBAP2) is a critical player in cell growth and metastasis in various types of cancers, although its role in colorectal cancer (CRC) has yet to be fully elucidated. We find that circUBAP2 is upregulated in CRC tissues and cell lines to induce autophagy both in vitro and in vivo. The effects of circUBAP2 on migration, invasion, and proliferation may be partially related to autophagy. Mechanistically, we uncover that circUBAP2 can directly interact with miR-582-5p and subsequently act as a microRNA sponge to regulate the expression of the miR-582-5p target gene forkhead box protein O1 (FOXO1) and downstream signaling molecules, which collectively advance the progression and metastasis of CRC. These results suggest that circUBAP2 acts as an oncogene via a novel circUBAP2/miR-582-5p/FOXO1 axis, providing a potential biomarker and therapeutic target for CRC management.

Population-based carrier screening and prenatal diagnosis of fragile X syndrome in East Asian populations

Qiwei Guo, Yih-Yuan Chang, Chien-Hao Huang, Yu-Shan Hsiao, Yu-Chiao Hsiao, I-Fan Chiu, Yulin Zhou, Haixia Zhang, Tsang-Ming Ko

2021, 48(12): 1104-1110. doi: 10.1016/j.jgg.2021.04.012

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Abstract:
Identification of carriers of fragile X syndrome (FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39, 458 East Asian adult women and prenatal diagnosis from 87 FXS carriers. The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization; the integral risks of full mutation expansion were approximately 6.0%, 43.8%, and 100% for premutation alleles with 55–74, 75–89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG (adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75–89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FXS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXS-associated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FXS intervention.

Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

Changshuo Wei, Ke-Jia Shan, Weiguang Wang, Shuya Zhang, Qing Huan, Wenfeng Qian

2021, 48(12): 1111-1121. doi: 10.1016/j.jgg.2021.12.003

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Abstract:
The rapid accumulation of mutations in the SARS-CoV-2 Omicron variant that enabled its outbreak raises questions as to whether its proximal origin occurred in humans or another mammalian host. Here, we identified 45 point mutations that Omicron acquired since divergence from the B.1.1 lineage. We found that the Omicron spike protein sequence was subjected to stronger positive selection than that of any reported SARS-CoV-2 variants known to evolve persistently in human hosts, suggesting a possibility of host-jumping. The molecular spectrum of mutations (i.e., the relative frequency of the 12 types of base substitutions) acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients but resembled the spectra associated with virus evolution in a mouse cellular environment. Furthermore, mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor. Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.

GenOrigin: A comprehensive protein-coding gene origination database on the evolutionary timescale of life

Yi-Bo Tong, Meng-Wei Shi, Sheng Hu Qian, Yu-Jie Chen, Zhi-Hui Luo, Yi-Xuan Tu, Yu-Li Xiong, Ying-Jie Geng, Chunyan Chen, Zhen-Xia Chen

2021, 48(12): 1122-1129. doi: 10.1016/j.jgg.2021.03.018

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Abstract:
The origination of new genes contributes to the biological diversity of life. New genes may quickly build their network, exert important functions, and generate novel phenotypes. Dating gene age and inferring the origination mechanisms of new genes, like primate-specific genes, is the basis for the functional study of the genes. However, no comprehensive resource of gene age estimates across species is available. Here, we systematically date the age of 9, 102, 113 protein-coding genes from 565 species in the Ensembl and Ensembl Genomes databases, including 82 bacteria, 57 protists, 134 fungi, 58 plants, 56 metazoa, and 178 vertebrates, using a protein-family-based pipeline with Wagner parsimony algorithm. We also collect gene age estimate data from other studies and uniformly distribute the gene age estimates to time ranges in a million years for comparison across studies. All the data are cataloged into GenOrigin (http://genorigin.chenzxlab.cn/), a user-friendly new database of gene age estimates, where users can browse gene age estimates by species, age, and gene ontology. In GenOrigin, the information such as gene age estimates, annotation, gene ontology, ortholog, and paralog, as well as detailed gene presence/absence views for gene age inference based on the species tree with evolutionary timescale, is provided to researchers for exploring gene functions.

Ancient Y-DNA with reconstructed phylogeny provides insights into the demographic history of paternal haplogroup N1a2-F1360

Pengcheng Ma, Xuan Yang, Shi Yan, Chunxiang Li, Shizhu Gao, Binghua Han, Kan Hou, Martine Robbeets, Lan-Hai Wei, Yinqiu Cui

2021, 48(12): 1130-1133. doi: 10.1016/j.jgg.2021.07.018

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TEP1 is a risk gene for sporadic cerebral palsy

Yangong Wang, Yiran Xu, Hongwei Li, Tianxiang Tang, Yimeng Qiao, Ye Cheng, Lingling Zhang, Juan Song, Yu Su, Xiaoli Zhang, Jun Wang, Qing Shang, Lili Song, Chao Gao, Dengna Zhu, Xiaoyang Wang, Changlian Zhu, Qinghe Xing

2021, 48(12): 1134-1138. doi: 10.1016/j.jgg.2021.08.010

Abstract (326) PDF (36)

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Molecular evolution of spermatogenesis-related genes in abdominal testicular mammals supports the cooling hypothesis

Xiaoyue Ding, Huiyuan Wei, Xu Zhou, Long Gu, Fangfang Yu, Yu Zheng, Shixia Xu, Guang Yang, Wenhua Ren

2021, 48(12): 1139-1141. doi: 10.1016/j.jgg.2021.05.010

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2021 Vol. 48, No. 12