Journal of Genetics and Genomics

Translation machinery: the basis of translational control

Shu Yuan, Guilong Zhou, Guoyong Xu

2024, 51(4): 367-378. doi: 10.1016/j.jgg.2023.07.009

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Abstract:
Messenger RNA (mRNA) translation consists of initiation, elongation, termination, and ribosome recycling, carried out by the translation machinery, primarily including tRNAs, ribosomes, and translation factors (TrFs). Translational regulators transduce signals of growth and development, as well as biotic and abiotic stresses, to the translation machinery, where global or selective translational control occurs to modulate mRNA translation efficiency (TrE). As the basis of translational control, the translation machinery directly determines the quality and quantity of newly synthesized peptides and, ultimately, the cellular adaption. Thus, regulating the availability of diverse machinery components is reviewed as the central strategy of translational control. We provide classical signaling pathways (e.g., integrated stress responses) and cellular behaviors (e.g., liquid–liquid phase separation) to exemplify this strategy within different physiological contexts, particularly during host–microbe interactions. With new technologies developed, further understanding this strategy will speed up translational medicine and translational agriculture.

Mechanisms underlying key agronomic traits and implications for molecular breeding in soybean

Chao Fang, Haiping Du, Lingshuang Wang, Baohui Liu, Fanjiang Kong

2024, 51(4): 379-393. doi: 10.1016/j.jgg.2023.09.004

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Abstract:
Soybean (Glycine max [L.] Merr.) is an important crop that provides protein and vegetable oil for human consumption. As soybean is a photoperiod-sensitive crop, its cultivation and yield are limited by the photoperiodic conditions in the field. In contrast to other major crops, soybean has a special plant architecture and a special symbiotic nitrogen fixation system, representing two unique breeding directions. Thus, flowering time, plant architecture, and symbiotic nitrogen fixation are three critical or unique yield-determining factors. This review summarizes the progress made in our understanding of these three critical yield-determining factors in soybean. Meanwhile, we propose potential research directions to increase soybean production, discuss the application of genomics and genomic-assisted breeding, and explore research directions to address future challenges, particularly those posed by global climate changes.

Characterizing structural variants based on graph-genotyping provides insights into pig domestication and local adaption

Xin Li, Quan Liu, Chong Fu, Mengxun Li, Changchun Li, Xinyun Li, Shuhong Zhao, Zhuqing Zheng

2024, 51(4): 394-406. doi: 10.1016/j.jgg.2023.11.005

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Abstract:
Structural variants (SVs), such as deletions (DELs) and insertions (INSs), contribute substantially to pig genetic diversity and phenotypic variation. Using a library of SVs discovered from long-read primary assemblies and short-read sequenced genomes, we map pig genomic SVs with a graph-based method for re-genotyping SVs in 402 genomes. Our results demonstrate that those SVs harboring specific trait-associated genes may greatly shape pig domestication and local adaptation. Further characterization of SVs reveals that some population-stratified SVs may alter the transcription of genes by affecting regulatory elements. We identify that the genotypes of two DELs (296-bp DEL, chr7: 52,172,101–52,172,397; 278-bp DEL, chr18: 23,840,143–23,840,421) located in muscle-specific enhancers are associated with the expression of target genes related to meat quality (FSD2) and muscle fiber hypertrophy (LMOD2 and WASL) in pigs. Our results highlight the role of SVs in domestic porcine evolution, and the identified candidate functional genes and SVs are valuable resources for future genomic research and breeding programs in pigs.

Coiled-coil domain-containing 38 is required for acrosome biogenesis and fibrous sheath assembly in mice

Yaling Wang, Xueying Huang, Guoying Sun, Jingwen Chen, Bangguo Wu, Jiahui Luo, Shuyan Tang, Peng Dai, Feng Zhang, Jinsong Li, Lingbo Wang

2024, 51(4): 407-418. doi: 10.1016/j.jgg.2023.09.002

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Abstract:
During spermiogenesis, haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes, which are required for successful fertilization. Severe deformities in flagella cause a male infertility syndrome, multiple morphological abnormalities of the flagella (MMAF), while acrosomal hypoplasia in some cases leads to sub-optimal embryonic developmental potential. However, evidence regarding the occurrence of acrosomal hypoplasia in MMAF is limited. Here, we report the generation of base-edited mice knocked out for coiled-coil domain-containing 38 (Ccdc38) via inducing a nonsense mutation and find that the males are infertile. The Ccdc38-KO sperm display acrosomal hypoplasia and typical MMAF phenotypes. We find that the acrosomal membrane is loosely anchored to the nucleus and fibrous sheaths are disorganized in Ccdc38-KO sperm. Further analyses reveal that Ccdc38 knockout causes a decreased level of TEKT3, a protein associated with acrosome biogenesis, in testes and an aberrant distribution of TEKT3 in sperm. We finally show that intracytoplasmic sperm injection overcomes Ccdc38-related infertility. Our study thus reveals a previously unknown role for CCDC38 in acrosome biogenesis and provides additional evidence for the occurrence of acrosomal hypoplasia in MMAF.

Epigenetic and transcriptional landscapes during cerebral cortex development in a microcephaly mouse model

Qing Yang, Qiang Cao, Yue Yu, Xianxin Lai, Jiahao Feng, Xinjie Li, Yinan Jiang, Yazhou Sun, Zhong-Wei Zhou, Xin Li

2024, 51(4): 419-432. doi: 10.1016/j.jgg.2023.10.006

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Abstract:
The cerebral cortex is a pivotal structure integral to advanced brain functions within the mammalian central nervous system. DNA methylation and hydroxymethylation play important roles in regulating cerebral cortex development. However, it remains unclear whether abnormal cerebral cortex development, such as microcephaly, could rescale the epigenetic landscape, potentially contributing to dysregulated gene expression during brain development. In this study, we characterize and compare the DNA methylome/hydroxymethylome and transcriptome profiles of the cerebral cortex across several developmental stages in wild-type (WT) mice and Mcph1 knockout (Mcph1-del) mice with severe microcephaly. Intriguingly, we discover a global reduction of 5′-hydroxymethylcytosine (5hmC) level, primarily in TET1-binding regions, in Mcph1-del mice compared to WT mice during juvenile and adult stages. Notably, genes exhibiting diminished 5hmC levels and concurrently decreased expression are essential for neurodevelopment and brain functions. Additionally, genes displaying a delayed accumulation of 5hmC in Mcph1-del mice are significantly associated with the establishment and maintenance of the nervous system during the adult stage. These findings reveal that aberrant cerebral cortex development in the early stages profoundly alters the epigenetic regulation program, which provides unique insights into the molecular mechanisms underpinning diseases related to cerebral cortex development.

A mutation in TBXT causes congenital vertebral malformations in humans and mice

Shuxia Chen, Yunping Lei, Yajun Yang, Chennan Liu, Lele Kuang, Li Jin, Richard H. Finnell, Xueyan Yang, Hongyan Wang

2024, 51(4): 433-442. doi: 10.1016/j.jgg.2023.09.009

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Abstract:
T-box transcription factor T (TBXT; T) is required for mesodermal formation and axial skeletal development. Although it has been extensively studied in various model organisms, human congenital vertebral malformations (CVMs) involving T are not well established. Here, we report a family with 15 CVM patients distributed across 4 generations. All affected individuals carry a heterozygous mutation, T c.596A>G (p.Q199R), which is not found in unaffected family members, indicating co-segregation of the genotype and phenotype. In vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity, but reduces its transcriptional activity compared to the wild-type. To determine the pathogenicity of this mutation in vivo, we generated a Q199R knock-in mouse model that recapitulates the human CVM phenotype. Most heterozygous Q199R mice show subtle kinked or shortened tails, while homozygous mice exhibit tail filaments and severe vertebral deformities. Overall, we show that the Q199R mutation in T causes CVM in humans and mice, providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.

IMAGGS: a radiogenomic framework for identifying multi-way associations in breast cancer subtypes

Shuyu Liang, Sicheng Xu, Shichong Zhou, Cai Chang, Zhiming Shao, Yuanyuan Wang, Sheng Chen, Yunxia Huang, Yi Guo

2024, 51(4): 443-453. doi: 10.1016/j.jgg.2023.09.010

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Abstract:
Investigating correlations between radiomic and genomic profiling in breast cancer (BC) molecular subtypes is crucial for understanding disease mechanisms and providing personalized treatment. We present a well-designed radiogenomic framework image–gene–gene set (IMAGGS), which detects multi-way associations in BC subtypes by integrating radiomic and genomic features. Our dataset consists of 721 patients, each of whom has 12 ultrasound (US) images captured from different angles and gene mutation data. To better characterize tumor traits, 12 multi-angle US images are fused using two distinct strategies. Then, we analyze complex many-to-many associations between phenotypic and genotypic features using a machine learning algorithm, deviating from the prevalent one-to-one relationship pattern observed in previous studies. Key radiomic and genomic features are screened using these associations. In addition, gene set enrichment analysis is performed to investigate the joint effects of gene sets and delve deeper into the biological functions of BC subtypes. We further validate the feasibility of IMAGGS in a glioblastoma multiforme dataset to demonstrate the scalability of IMAGGS across different modalities and diseases. Taken together, IMAGGS provides a comprehensive characterization for diseases by associating imaging, genes, and gene sets, paving the way for biological interpretation of radiomics and development of targeted therapy.

The Os14-3-3 family genes regulate grain size in rice