Current Articles

2024, Volume 51,  Issue 12

Review
Sex chromosome turnover and biodiversity in fishes
Jingrong Wang, Wenjing Tao, Thomas D. Kocher, Deshou Wang
2024, 51(12): 1351-1360. doi: 10.1016/j.jgg.2024.08.008
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The impact of sex chromosomes and their turnover in speciation remains a subject of ongoing debate in the field of evolutionary biology. Fishes are the largest group of vertebrates, and they exhibit unparalleled sexual plasticity, as well as diverse sex-determining (SD) genes, sex chromosomes, and sex-determination mechanisms. This diversity is hypothesized to be associated with the frequent turnover of sex chromosomes in fishes. Although it is evident that amh and amhr2 are repeatedly and independently recruited as SD genes, their relationship with the rapid turnover of sex chromosomes and the biodiversity of fishes remains unknown. We summarize the canonical models of sex chromosome turnover and highlight the vital roles of gene mutation and hybridization with empirical evidence. We revisit Haldane's rule and the large X-effect and propose the hypothesis that sex chromosomes accelerate speciation by multiplying genotypes via hybridization. By integrating recent findings on the turnover of SD genes, sex chromosomes, and sex-determination systems in fish species, this review provides insights into the relationship between sex chromosome evolution and biodiversity in fishes.

Nanopore sequencing: flourishing in its teenage years
Tianyuan Zhang, Hanzhou Li, Mian Jiang, Huiyu Hou, Yunyun Gao, Yali Li, Fuhao Wang, Jun Wang, Kai Peng, Yong-Xin Liu
2024, 51(12): 1361-1374. doi: 10.1016/j.jgg.2024.09.007
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Over the past decade, nanopore sequencing has experienced significant advancements and changes, transitioning from an initially emerging technology to a significant instrument in the field of genomic sequencing. However, as advancements in next-generation sequencing technology persist, nanopore sequencing also improves. This paper reviews the developments, applications, and outlook on nanopore sequencing technology. Currently, nanopore sequencing supports both DNA and RNA sequencing, making it widely applicable in areas such as telomere-to-telomere (T2T) genome assembly, direct RNA sequencing (DRS), and metagenomics. The openness and versatility of nanopore sequencing have established it as a preferred option for an increasing number of research teams, signaling a transformative influence on life science research. As the nanopore sequencing technology advances, it provides a faster, more cost-effective approach with extended read lengths, demonstrating the significant potential for complex genome assembly, pathogen detection, environmental monitoring, and human disease research, offering a fresh perspective in sequencing technologies.

Original Research
Capn3b-deficient zebrafish model reveals a key role of autoimmune response in LGMDR1
Yayue Chen, Delai Huang, Aixuan Xie, Ying Shan, Shuyi Zhao, Ce Gao, Jun Chen, Hui Shi, Weihuan Fang, Jinrong Peng
2024, 51(12): 1375-1388. doi: 10.1016/j.jgg.2024.09.011
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Mutations in calcium-dependent papain-like protease CALPAIN3 (CAPN3) cause Limb-Girdle Muscular Dystrophy Recessive Type 1 (LGMDR1), the most common limb-girdle muscular dystrophy in humans. In addition to progressive muscle weakness, persistent inflammatory infiltration is also a feature of LGMDR1. Despite the underlying mechanism remaining poorly understood, we consider that it may relate to the newly defined role of CAPN3/Capn3b in the nucleolus. Here, we report that the loss of function of zebrafish capn3b, the counterpart of human CAPN3, induces an autoimmune response akin to that in LGMDR1 patients. capn3b mutant larvae are more susceptible to Listeria monocytogenes injection, characterized by recruiting more macrophages. Under germ-free conditions, transcriptome analysis of the capn3b mutant muscle reveals a significant upregulation of the chemokine-production-related genes. Coincidently, more neutrophils are recruited to the injury site imposed by either muscle stabbing or tail fin amputation. Nucleolar proteomic analysis and enzymatic assays reveal NKAP, an activating factor of the NF-κB pathway, to be a target of CAPN3. We conclude that the accumulation of Nkap and other factors in the capn3b mutant may be involved in the over-activation of innate immunity. Our studies indicate that the zebrafish capn3b mutant is a powerful model for studying the immunity-related progression of human LGMDR1.

RFC2 may contribute to the pathogenicity of Williams syndrome revealed in a zebrafish model
Ji-Won Park, Tae-Ik Choi, Tae-Yoon Kim, Yu-Ri Lee, Dilan Wellalage Don, Jaya K. George-Abraham, Laurie A. Robak, Cristina C. Trandafir, Pengfei Liu, Jill A. Rosenfeld, Tae Hyeong Kim, Florence Petit, Yoo-Mi Kim, Chong Kun Cheon, Yoonsung Lee, Cheol-Hee Kim
2024, 51(12): 1389-1403. doi: 10.1016/j.jgg.2024.09.016
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Williams syndrome (WS) is a rare multisystemic disorder caused by recurrent microdeletions on 7q11.23, characterized by intellectual disability, distinctive craniofacial and dental features, and cardiovascular problems. Previous studies have explored the roles of individual genes within these microdeletions in contributing to WS phenotypes. Here, we report five patients with WS with 1.4 Mb-1.5 Mb microdeletions that include RFC2, as well as one patient with a 167-kb microdeletion involving RFC2 and six patients with intragenic variants within RFC2. To investigate the potential involvement of RFC2 in WS pathogenicity, we generate a rfc2 knockout (KO) zebrafish using CRISPR-Cas9 technology. Additionally, we generate a KO zebrafish of its paralog gene, rfc5, to better understand the functions of these RFC genes in development and disease. Both rfc2 and rfc5 KO zebrafish exhibit similar phenotypes reminiscent of WS, including small head and brain, jaw and dental defects, and vascular problems. RNA-seq analysis reveals that genes associated with neural cell survival and differentiation are specifically affected in rfc2 KO zebrafish. In addition, heterozygous rfc2 KO adult zebrafish demonstrate an anxiety-like behavior with increased social cohesion. These results suggest that RFC2 may contribute to the pathogenicity of WS, as evidenced by the zebrafish model.

Nitrogen inhibition of nitrogenase activity involves the modulation of cytosolic invertase in soybean nodule
Qinzhen Xu, Xin Wang, Nan Wang, Suning Li, Xiaolei Yao, Huaqin Kuang, Zhimin Qiu, Danxia Ke, Wenqiang Yang, Yuefeng Guan
2024, 51(12): 1404-1412. doi: 10.1016/j.jgg.2024.06.013
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Legume symbiotic nitrogen fixation (SNF) is suppressed by inorganic nitrogen (N) in the soil. High N inhibition of nitrogenase activity is associated with the deprivation of carbon allocation and metabolism in nodules. However, the underlying molecular mechanisms remain unclear. Here, we identify GmCIN1, which encodes a cytosolic invertase, as a gateway for the N-tuning of sucrose utilization in nodules. GmCIN1 is enriched in mature soybean nodules, and its expression is regulated by nitrogen status. The knockout of GmCIN1 using genome editing partially mimics the inhibitory effects of N on nitrogenase activity and sugar content and the impact of high N on nodule transcriptomes. This indicates that GmCIN1 partially mediates the high N inhibition of nodule activity. Moreover, ChIP-qPCR and EMSA reveal that SNAP1/2 transcription factors directly bind to the GmCIN1 promoter. In addition, SNAP1/2 may be involved in the repression of GmCIN1 expression in mature nodules at high N concentrations. Our findings provide insights into the involvement of the transcriptional tuning of carbon (C) metabolism genes by N-signaling modulators in the N-induced inhibition of nitrogenase activity.

A single-nucleotide polymorphism in PvPW1 encoding β-1,3-glucanase 9 is associated with pod width in Phaseolus vulgaris L.
Kun Xu, Jinlong Zhu, Hong Zhai, Qiang Yang, Keqin Zhou, Qijian Song, Jing Wu, Dajun Liu, Yanhua Li, Zhengjun Xia
2024, 51(12): 1413-1422. doi: 10.1016/j.jgg.2024.09.020
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Pod width influences pod size, shape, yield, and consumer preference in snap beans (Phaseolus vulgaris L.). In this study, we map PvPW1, a quantitative trait locus associated with pod width in snap beans, through genotyping and phenotyping of recombinant plants. We identify Phvul.006G072800, encoding the β-1,3-glucanase 9 protein, as the causal gene for PvPW1. The PvPW1G3555 allele is found to positively regulate pod width, as revealed by an association analysis between pod width phenotype and the PvPW1G3555C genotype across 17 bi-parental F2 populations. In total, 97.7% of the 133 wide pod accessions carry PvPW1G3555, while 82.1% of the 78 narrow pod accessions carry PvPW1C3555, indicating strong selection pressure on PvPW1 during common bean breeding. Re-sequencing data from 59 common bean cultivars identify an 8-bp deletion in the intron linked to PvPW1C3555, leading to the development of the InDel marker of PvM436. Genotyping 317 common bean accessions with PvM436 demonstrated that accessions with PvM436247 and PvM436227 alleles have wider pods compared to those with PvM436219 allele, establishing PvM436 as a reliable marker for molecular breeding in snap beans. These findings highlight PvPW1 as a critical gene regulating pod width and underscore the utility of PvM436 in marker-assisted selection for snap bean breeding.

Age-dependent genetic architectures of chicken body weight explored by multidimensional GWAS and molQTL analyses
Conghao Zhong, Xiaochang Li, Dailu Guan, Boxuan Zhang, Xiqiong Wang, Liang Qu, Huaijun Zhou, Lingzhao Fang, Congjiao Sun, Ning Yang
2024, 51(12): 1423-1434. doi: 10.1016/j.jgg.2024.09.003
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Chicken body weight (BW) is a critical trait in breeding. Although genetic variants associated with BW have been investigated by genome-wide association studies (GWAS), the contributions of causal variants and their molecular mechanisms remain largely unclear in chickens. In this study, we construct a comprehensive genetic atlas of chicken BW by integrative analysis of 30 age points and 5 quantitative trait loci (QTL) across 27 tissues. We find that chicken growth is a cumulative non-linear process, which can be divided into three distinct stages. Our GWAS analysis reveals that BW-related genetic variations show ordered patterns in these three stages. Genetic variations in chromosome 1 may regulate the overall growth process, likely by modulating the hypothalamus-specific expression of SLC25A30 and retina-specific expression of NEK3. Moreover, genetic variations in chromosome 4 and chromosome 27 may play dominant roles in regulating BW during Stage 2 (8-22 weeks) and Stage 3 (23-72 weeks), respectively. In summary, our study presents a comprehensive genetic atlas regulating developmental stage-specific changes in chicken BW, thus providing important resources for genomic selection in breeding programs.

CtIP regulates G2/M transition and bipolar spindle assembly during mouse oocyte meiosis
Wei Yue, Hong-Yong Zhang, Heide Schatten, Tie-Gang Meng, Qing-Yuan Sun
2024, 51(12): 1435-1446. doi: 10.1016/j.jgg.2024.09.005
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CtBP-interacting protein (CtIP) is known for its multifaceted roles in DNA repair and genomic stability, directing the homologous recombination-mediated DNA double-stranded break repair pathway via DNA end resection, an essential error-free repair process vital for genome stability. Mammalian oocytes are highly prone to DNA damage accumulation due to prolonged G2/prophase arrest. Here, we explore the functions of CtIP in meiotic cell cycle regulation via a mouse oocyte model. Depletion of CtIP by siRNA injection results in delayed germinal vesicle breakdown and failed polar body extrusion. Mechanistically, CtIP deficiency increases DNA damage and decreases the expression and nuclear entry of CCNB1, resulting in marked impairment of meiotic resumption, which can be rescued by exogenous CCNB1 overexpression. Furthermore, depletion of CtIP disrupts microtubule-organizing centers coalescence at spindle poles as indicated by failed accumulation of γ-tubulin, p-Aurora kinase A, Kif2A, and TPX2, leading to abnormal spindle assembly and prometaphase arrest. These results provide valuable insights into the important roles of CtIP in the G2/M checkpoint and spindle assembly in mouse oocyte meiotic cell cycle regulation.

ATN-161 alleviates caerulein-induced pancreatitis
Rong-rong Gao, Lan-yue Ma, Jian-wei Chen, Yu-xiang Wang, Yu-yan Li, Zi-yuan Zhou, Zhao-hua Deng, Jing Zhong, Ya-hai Shu, Yang Liu, Qi Chen
2024, 51(12): 1447-1458. doi: 10.1016/j.jgg.2024.10.002
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Pancreatitis is a common gastrointestinal disorder that causes hospitalization with significant morbidity and mortality. The mechanistic pathophysiology of pancreatitis is complicated, limiting the discovery of pharmacological intervention methods. Here, we show that the administration of ATN-161, an antagonist of Integrin-α5, significantly mitigates the pathological condition of acute pancreatitis induced by caerulein. We find that CK19-positive pancreatic ductal cells align parallel to blood vessels in the pancreas. In the caerulein-induced acute pancreatitis model, the newly emergent CK19-positive cells are highly vascularized, with a significant increase in vascular density and endothelial cell number. Single-cell RNA sequencing analysis shows that ductal and endothelial cells are intimate interacting partners, suggesting the existence of a ductal-endothelial interface in the pancreas. Pancreatitis dramatically reduces the crosstalk in the ductal-endothelial interface but promotes the Spp-1/Integrin-α5 signaling. Blocking this signaling with ATN-161 significantly reduces acinar-to-ductal metaplasia, pathological angiogenesis, and restores other abnormal defects induced by caerulein. Our work reveals the therapeutic potential of ATN-161 as an uncharacterized pharmacological method to alleviate the symptoms of pancreatitis.

bmp10 maintains cardiac function by regulating iron homeostasis
Ruiqin Hu, Genfang Li, Peng Hu, Hongbo Niu, Wenhao Li, Shouwen Jiang, Guijun Guan, Qianghua Xu, Mingli Liu, Liangbiao Chen
2024, 51(12): 1459-1473. doi: 10.1016/j.jgg.2024.10.003
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Heart disease remains the leading cause of death worldwide. Iron imbalance, whether deficiency or overload, contributes to heart failure. However, the molecular mechanisms governing iron homeostasis in the heart are poorly understood. Here, we demonstrate that mutation of bmp10, a heart-born morphogen crucial for embryonic heart development, results in severe anemia and cardiac hypertrophy in zebrafish. Initially, bmp10 deficiency causes cardiac iron deficiency, which later progresses to iron overload due to the dysregulated hepcidin/ferroportin axis in cardiac cells, leading to ferroptosis and heart failure. Early iron supplementation in bmp10-/- mutants rescues erythropoiesis, while iron chelation in juvenile fishes significantly alleviates cardiac hypertrophy. We further demonstrate that the interplay between HIF1α-driven hypoxic signaling and the IL6/p-STAT3 inflammatory pathways is critical for regulating cardiac iron metabolism. Our findings reveal BMP10 as a key regulator of iron homeostasis in the vertebrate heart and highlight the potential of targeting the BMP10-hepcidin-iron axis as a therapeutic strategy for iron-related cardiomyopathy.

Method
Synchronized lineage tracing of cell membranes and nuclei by dual recombinases and dual fluorescent
Xueying Yang, Shun He, Xufeng Li, Zhihou Guo, Haichang Wang, Zhuonan Zhang, Xin Song, Ke Jia, Lingjuan He, Bin Zhou
2024, 51(12): 1474-1484. doi: 10.1016/j.jgg.2024.07.006
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Genetic lineage tracing has been widely employed to investigate cell lineages and fate. However, conventional reporting systems often label the entire cytoplasm, making it challenging to discern cell boundaries. Additionally, single Cre-loxP recombination systems have limitations in tracing specific cell populations. This study proposes three reporting systems utilizing Cre, Dre, and Dre+Cre mediated recombination. These systems incorporate tdTomato expression on the cell membrane and PhiYFP expression within the nucleus, allowing for clear observation of the nucleus and membrane. The efficacy of these systems is successfully demonstrated by labeling cardiomyocytes and hepatocytes. The potential for dynamic visualization of the cell membrane is showcased using intravital imaging microscopy or three-dimensional imaging. Furthermore, by combining this dual recombinase system with the ProTracer system, hepatocyte proliferation is traced with enhanced precision. This reporting system holds significant importance for advancing the understanding of cell fate studies in development, homeostasis, and diseases.

A programmable CRISPR/dCas9-based epigenetic editing system enabling loci-targeted histone citrullination and precise transcription regulation
Xiaoya Zhang, Abhisek Bhattacharya, Chunxiang Pu, Yan Dai, Jia Liu, Lang Rao, Chaoguang Tian
2024, 51(12): 1485-1493. doi: 10.1016/j.jgg.2024.05.010
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Histone citrullination, an important post-translational modification mediated by peptidyl arginine deiminases, is essential for many physiological processes and epigenetic regulation. However, the causal relationship between histone citrullination and specific gene regulation remains unresolved. In this study, we develop a programmable epigenetic editor by fusing the peptidyl arginine deiminase (PAD) PPAD from Porphyromonas gingivalis with dCas9. With the assistance of gRNA, PPAD-dCas9 can recruit PPADs to specific genomic loci, enabling direct manipulation of the epigenetic landscape and regulation of gene expression. Our citrullination editor allows for the site-specific manipulation of histone H3R2,8,17 and H3R26 at target human gene loci, resulting in the activation or suppression of different genes in a locus-specific manner. Moreover, the epigenetic effects of the citrullination editor are specific and sustained. This epigenetic editor offers an accurate and efficient tool for exploring gene regulation of histone citrullination.

A-to-G/C/T and C-to-T/G/A dual-function base editor for creating multi-nucleotide variants
Bingxiu Ma, Han Wu, Shixue Gou, Meng Lian, Cong Xia, Kaiming Yang, Long Jin, Junyuan Liu, Yunlin Wu, Yahai Shu, Haizhao Yan, Zhanjun Li, Liangxue Lai, Yong Fan
2024, 51(12): 1494-1504. doi: 10.1016/j.jgg.2024.10.001
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Multi-nucleotide variants (MNVs) are critical genetic variants associated with various genetic diseases. However, tools for precisely installing MNVs are limited. In this study, we present the development of a dual-base editor, BDBE, by integrating TadA-dual and engineered human N-methylpurine DNA glycosylase (eMPG) into nCas9 (D10A). Our results demonstrate that BDBE effectively converts A-to-G/C/T (referred to as A-to-B) and C-to-T/G/A (referred to as C-to-D) simultaneously, yielding nine types of dinucleotides from adjacent CA nucleotides while maintaining minimal off-target effects. Notably, BDBE4 exhibits exceptional performance across multiple human cell lines and successfully simulated all nine dinucleotide MNVs from the gnomAD database. These findings indicate that BDBE significantly expands the product range of base editors and offers a valuable resource for advancing MNV research.

Research Communications
CancerSRT: a spatially resolved transcriptomics database for human cancers
Yuying Huo, Jiakang Wang, Chengcheng Liu, Jinxia Wang, Chen Wang, Wenbo Guo, Zhiyuan Yuan, Tiantian Guo, Jin Gu, Xiangyu Li
2024, 51(12): 1505-1508. doi: 10.1016/j.jgg.2024.08.012
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HMG-3 contributes to meiotic chromosome maintenance and inhibits reproductive aging in C. elegans
Fengguo Zhang, Yuanyuan Liu, Yanmei Li, Xiuxiu Liu, Yingchun Zhang, Guohai Su
2024, 51(12): 1509-1512. doi: 10.1016/j.jgg.2024.08.005
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Variants within KIF5B are associated with weight loss through mitochondrial transport alteration in sheep
Jieran Chen, Haitao Wang, Tingting Li, Yuting Zhang, Yan Chen, Na Zhang, Hengqian Yang, Zhichao Zhang, Ziyuan Duan, Xia Li, Daxiang Wang, Zhixiong He, Fan Hu, Jianfeng Gao, Runlin Z. Ma, Xun Huang, Qiuyue Liu
2024, 51(12): 1513-1516. doi: 10.1016/j.jgg.2024.09.009
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Localized production of LECT2 by orthotopic histiocytes during inflammation
Zhenhan Huang, Xiaojun Yang, Xun Qin, Kemin Chen, Wei Liu, Jin Xu, Jianchao Li, Wenqing Zhang, Zhibin Huang
2024, 51(12): 1517-1520. doi: 10.1016/j.jgg.2024.09.017
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The ABF transcription factor TaABF2 interacts with TaSnRK2s to ameliorate drought tolerance in wheat
Linying Du, Ming Yu, Qiannan Wang, Zhenbing Ma, Shumin Li, Li Ding, Fangfang Li, Weijun Zheng, Xiaojing Wang, Hude Mao
2024, 51(12): 1521-1524. doi: 10.1016/j.jgg.2024.09.022
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FishCODE: a web-based information platform for comprehensive omics data exploration in fish research
Heng Li, Wanting Zhang, Keyi Ren, Hong Yang, Lei Zhang, Waqar Younas, Yingyin Cheng, Yaping Wang, Mijuan Shi, Xiao-Qin Xia
2024, 51(12): 1525-1528. doi: 10.1016/j.jgg.2024.09.019
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A haplotype-resolved genome reveals the genetic basis of spine formation in Atelerix albiventris
Libo Jiang, Jianing Xu, Mengyuan Zhu, Zhongfan Lv, Zemin Ning, Fengtang Yang
2024, 51(12): 1529-1532. doi: 10.1016/j.jgg.2024.06.012
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