Journal of Genetics and Genomics

Genomic sequencing as a key primary recommendation for neonatal hyperbilirubinemia: a population-based multicenter study

Dabin Huang, Xia Gu, et al.

doi: 10.1016/j.jgg.2025.09.002

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Abstract:
Genetic variations are risk factors for neonatal hyperbilirubinemia (NHB), a common cause of infant hospitalization in the first postnatal week, but their contribution and long-term impacts remain unclear. This population-based multicenter study enrolls 1,780 hospitalized NHB newborns and 38,158 genetically screened newborns across 20 hospitals (2019–2022). Excluding cases with clear clinical causes, 977 NHB cases are categorized into genetic variation-positive and -negative groups. Results show significantly higher NHB-related gene variants (81.63% vs. 65.62%) and positive variation rates (36.29% vs. 9.4%) in NHB cases than in the general newborn population (all P < 0.001). Among the 977 NHB cases, 325 (33.3%) have positive variants, with higher rates of severe hyperbilirubinemia (16.9% vs. 9.7%, P = 0.001), prolonged jaundice (36.3% vs. 27.6%, P = 0.005), and cholestasis/hypercholanaemia (23.7% vs. 14.7%, P < 0.001) in the positive group. Cumulative genetic variants in bilirubin metabolism pathways exhibit dose-dependent associations with increased risks of complications. Long-term follow-up reveals that UGT1A1 variants prolong jaundice up to 1 month, while severe SLC10A1 variants cause persistent cholestasis/hypercholanaemia beyond 9 months. This large-scale evidence highlights genetic factors as key NHB determinants, with implications for neonatal care protocols to integrate genetic testing and establish long-term surveillance for variant carriers.

Integrative multi-omics and genomic prediction reveal genetic basis of early salt tolerance in alfalfa

Fei He, Ming Xu, et al.

doi: 10.1016/j.jgg.2025.09.001

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Abstract:

The genetic basis of early-stage salt tolerance in alfalfa (Medicago sativa L.), a key factor limiting its productivity, remains poorly understand. To dissect this complex trait, we integrate genome-wide association study (GWAS) and transcriptomics (RNA-seq) from 176 accessions within a machine learning based genomic prediction framework. Analysis reveals weak genetic correlations among four salt-tolerance traits and a gradual decline in performance under increasing salt stress. GWAS identify 60 significant associated SNPs, with the highest number detected under 100 mM salt stress. Salt tolerance exhibits an additive effect from favorable haplotypes, which are most abundant in Chinese accessions. GWAS-associated genes are related to key regulators of hormone signaling and osmotic adjustment, while transcriptome analysis indicates a global repression of stress-responsive transcription factors. Integrating these multi-omics datasets allow us to identify 14 candidate genes, including MsHSD1 (seed dormancy) and MsMTATP6 (energy metabolism). Crucially, incorporating these markers into genomic prediction models improve cross-population predictive accuracy to an average of 54.4%. This study provides insights into the genetic architecture of salt tolerance in alfalfa and offers valuable markers to facilitate molecular breeding.

ATPase-deficient CHD7 disease variant disrupts neural development via chromatin dysregulation

Guangfu Wang, Zhuxi Huang, et al.

doi: 10.1016/j.jgg.2025.08.012

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Abstract:
Chromodomain helicase DNA binding protein 7 (CHD7), an ATP-dependent chromatin remodeler, plays versatile roles in neurodevelopment. However, the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood. Here, we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders. Through in vitro neural induction and differentiation assays combined with mouse brain analyses, we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development. Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes, marked by the open chromatin architecture and active histone modifications. Collectively, our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human disease.

Deciphering the genetic regulation of flowering time in rapeseed for early-maturation breeding

Minghao Zhang, Wei Chang, et al.

doi: 10.1016/j.jgg.2025.08.011

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Abstract:
Flowering time is a critical agronomic trait with a profound effect on the productivity and adaptability of rapeseed (Brassica napus L.). Strategically advancing flowering time can reduce the risk of yield losses due to extreme climatic conditions and facilitate the cultivation of subsequent crops on the same land, thereby enhancing overall agricultural efficiency. In this review, we synthesize current information on flowering time regulation in rapeseed through an integrated analysis of its genetic, hormonal, and environmental dimensions, emphasizing their crosstalk and implications for yield. We consolidate multi-omics evidence from population genetics, functional genomics, and systems biology to create a haplotype-based framework that overcomes the trade-off between flowering time and yield, providing support for the precision breeding of early-maturing cultivars. The insights presented here could inform future research on flowering time regulation and guide strategies for increasing rapeseed productivity.

Estimating genetic load from 5000 Chinese exomes

Xiaoyue Du, Xiaoxi Zhang, et al.

doi: 10.1016/j.jgg.2025.08.009

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Abstract:
Recent advancements in genome sequencing have enabled the estimation of genetic load through deleterious mutation profiling. However, Chinese populations remain underexplored in this context. We analyze whole-exome sequencing data from 5002 individuals, encompassing major Han subgroups—North Han (N-Han), South Han (S-Han), and Guangxi Han (G-Han)—as well as 13 ethnic minorities. Notably, G-Han exhibits significant genetic affinity with the Zhuang population. Systematic curation of 2110 ClinVar pathogenic or likely pathogenic variants reveals 93.4% are ultra-rare. Exceptions include GJB2 rs72474224-A (hearing loss), which shows higher frequencies in Zhuang and G-Han, and β-thalassemia-associated HBB variants (rs33986703-A and rs33950507-T), which are elevated in G-Han compared to other Han subgroups. Among 96 autosomal dominant mutation carriers, LDLR variants are predominant (∼25%), with comparable frequencies across Han subgroups. Adaptive signatures highlight gene-environment interactions: MTHFR rs1801133-A (UV adaptation) declines southward, while ALDH2 rs671-A (alcohol metabolism) displayed the opposite trend. ABCC11 rs17822931-A, associated with tropical adaptation, is particularly prevalent in G-Han. Gene-based rare-variant collapsing analyses identify an elevated risk of retinitis pigmentosa in S-Han (PRPF4, TUB). Our findings demonstrate that genetic load in Chinese populations is influenced by demographic history, population structure, and regional adaptation, emphasizing the importance of population-specific frameworks in precision medicine.

Rapamycin alleviates neurodegeneration in a Drosophila model of spinocerebellar ataxia type 51

Cuijie Wei, Taoyun Ji, et al.

doi: 10.1016/j.jgg.2025.08.010

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Abstract:
Spinocerebellar ataxia (SCA) type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene. These repeats are translated into a glutamine-rich protein, THAP11-polyQ, which forms protein aggregates and exhibits toxicity in cell models; however, the underlying mechanism remains unclear. In this study, we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses. Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss, locomotor deficiency, and reduced survival. RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway, and electron microscopy of transgenic flies shows an increase in multilamellar bodies, suggesting involvement of autophagy in SCA51. Consequently, we treat the fly model with rapamycin, an mTOR inhibitor known to enhance autophagy. This treatment reduces toxic THAP11-polyQ protein aggregates, significantly alleviates neuronal degeneration, and improves locomotor function, consistent with the rescue effects observed upon overexpression of Atg8a. Overall, these findings suggest that the Drosophila model, which recapitulates the neurodegenerative features of SCA51, can be used to investigate pathogenic mechanisms, and that rapamycin holds promising potential as a therapeutic approach for this disease.