Genes

15 pages, 679 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Leveraging Gene-Level Prediction as Informative Covariate in Hypothesis Weighting Improves Power for Rare Variant Association Studies

by Ying Ji, Rui Chen, Quan Wang, Qiang Wei, Ran Tao and Bingshan Li

Genes 2022, 13(2), 381; https://doi.org/10.3390/genes13020381 - 19 Feb 2022

Viewed by 2849

Abstract

Gene-based rare variant association studies (RVASs) have low power due to the infrequency of rare variants and the large multiple testing burden. To correct for multiple testing, traditional false discovery rate (FDR) procedures which depend solely on P-values are often used. Recently, Independent [...] Read more.

Gene-based rare variant association studies (RVASs) have low power due to the infrequency of rare variants and the large multiple testing burden. To correct for multiple testing, traditional false discovery rate (FDR) procedures which depend solely on P-values are often used. Recently, Independent Hypothesis Weighting (IHW) was developed to improve the detection power while maintaining FDR control by leveraging prior information for each hypothesis. Here, we present a framework to increase power of gene-based RVASs by incorporating prior information using IHW. We first build supervised machine learning models to assign each gene a prediction score that measures its disease risk, using the input of multiple biological features, fed with high-confidence risk genes and local background genes selected near GWAS significant loci as the training set. Then we use the prediction scores as covariates to prioritize RVAS results via IHW. We demonstrate the effectiveness of this framework through applications to RVASs in schizophrenia and autism spectrum disorder. We found sizeable improvements in the number of significant associations compared to traditional FDR approaches, and independent evidence supporting the relevance of the genes identified by our framework but not traditional FDR, demonstrating the potential of our framework to improve power of gene-based RVASs. Full article

(This article belongs to the Special Issue Statistical Genetics in Human Diseases)

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8 pages, 1609 KiB

Open AccessEditor’s ChoiceArticle

FDDM1 and FDDM2, Two SGS3-like Proteins, Function as a Complex to Affect DNA Methylation in Arabidopsis

by Shengjun Li, Weilong Yang, Yunfeng Liu, Guangyong Li, Xiang Liu, Yaling Liu, James R. Alfano, Chi Zhang and Bin Yu

Genes 2022, 13(2), 339; https://doi.org/10.3390/genes13020339 - 12 Feb 2022

Viewed by 2451

Abstract

DNA methylation is an important epigenetic modification required for the specific regulation of gene expression and the maintenance of genome stability in plants and animals. However, the mechanism of DNA demethylation remains largely unknown. Here, we show that two SGS3-like proteins, FACTOR OF [...] Read more.

DNA methylation is an important epigenetic modification required for the specific regulation of gene expression and the maintenance of genome stability in plants and animals. However, the mechanism of DNA demethylation remains largely unknown. Here, we show that two SGS3-like proteins, FACTOR OF DNA DEMETHYLATION 1 (FDDM1) and FDDM2, negatively affect the DNA methylation levels at ROS1-dependend DNA loci in Arabidopsis. FDDM1 binds dsRNAs with 5′ overhangs through its XS (rice gene X and SGS3) domain and forms a heterodimer with FDDM2 through its XH (rice gene X Homology) domain. A lack of FDDM1 or FDDM2 increased DNA methylation levels at several ROS1-dependent DNA loci. However, FDDM1 and FDDM2 may not have an additive effect on DNA methylation levels. Moreover, the XS and XH domains are required for the function of FDDM1. Taken together, these results suggest that FDDM1 and FDDM2 act as a heterodimer to positively modulate DNA demethylation. Our finding extends the function of plant-specific SGS3-like proteins. Full article

(This article belongs to the Section Plant Genetics and Genomics)

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23 pages, 4197 KiB

Open AccessEditor’s ChoiceArticle

Whole Genome DNA Methylation Profiling of D2 Medium Spiny Neurons in Mouse Nucleus Accumbens Using Two Independent Library Preparation Methods

by Yuxiang Li, Haiyang Xu, Javed M. Chitaman and Jian Feng

Genes 2022, 13(2), 306; https://doi.org/10.3390/genes13020306 - 6 Feb 2022

Cited by 2 | Viewed by 3827

Abstract

DNA methylation plays essential roles in various cellular processes. Next-generation sequencing has enabled us to study the functional implication of DNA methylation across the whole genome. However, this approach usually requires a substantial amount of genomic DNA, which limits its application to defined [...] Read more.

DNA methylation plays essential roles in various cellular processes. Next-generation sequencing has enabled us to study the functional implication of DNA methylation across the whole genome. However, this approach usually requires a substantial amount of genomic DNA, which limits its application to defined cell types within a discrete brain region. Here, we applied two separate protocols, Accel-NGS Methyl-Seq (AM-seq) and Enzymatic Methyl-seq (EM-seq), to profile the methylome of D2 dopamine receptor-expressing medium spiny neurons (D2-MSNs) in mouse nucleus accumbens (NAc). Using 40 ng DNA extracted from FACS-isolated D2-MSNs, we found that both methods yielded comparably high-quality methylome data. Additionally, we identified numerous unmethylated regions (UMRs) as cell type-specific regulatory regions. By comparing the NAc D2-MSN methylome with the published methylomes of mouse prefrontal cortex excitatory neurons and neural progenitor cells (NPCs), we identified numerous differentially methylated CpG and non-CpG regions. Our study not only presents a comparison of these two low-input DNA whole genome methylation profiling protocols, but also provides a resource of DNA methylome of mouse accumbal D2-MSNs, a neuron type that has critical roles in addiction and other neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Gene Expression and Chromatin Modification in the Brain)

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25 pages, 3321 KiB

Open AccessEditor’s ChoiceArticle

Balanced Polymorphism at the Pgm-1 Locus of the Pompeii Worm Alvinella pompejana and Its Variant Adaptability Is Only Governed by Two QE Mutations at Linked Sites

by Alexis Bioy, Anne-Sophie Le Port, Emeline Sabourin, Marie Verheye, Patrice Piccino, Baptiste Faure, Stéphane Hourdez, Jean Mary and Didier Jollivet

Genes 2022, 13(2), 206; https://doi.org/10.3390/genes13020206 - 24 Jan 2022

Cited by 2 | Viewed by 3057

Abstract

The polychaete Alvinella pompejana lives exclusively on the walls of deep-sea hydrothermal chimneys along the East Pacific Rise (EPR), and displays specific adaptations to withstand the high temperatures and hypoxia associated with this highly variable habitat. Previous studies have revealed the existence of [...] Read more.

The polychaete Alvinella pompejana lives exclusively on the walls of deep-sea hydrothermal chimneys along the East Pacific Rise (EPR), and displays specific adaptations to withstand the high temperatures and hypoxia associated with this highly variable habitat. Previous studies have revealed the existence of a balanced polymorphism on the enzyme phosphoglucomutase associated with thermal variations, where allozymes 90 and 100 exhibit different optimal activities and thermostabilities. Exploration of the mutational landscape of phosphoglucomutase 1 revealed the maintenance of four highly divergent allelic lineages encoding the three most frequent electromorphs over the geographic range of A. pompejana. This polymorphism is only governed by two linked amino acid replacements, located in exon 3 (E155Q and E190Q). A two-niche model of selection, including ‘cold’ and ‘hot’ conditions, represents the most likely scenario for the long-term persistence of these isoforms. Using directed mutagenesis and the expression of the three recombinant variants allowed us to test the additive effect of these two mutations on the biochemical properties of this enzyme. Our results are coherent with those previously obtained from native proteins, and reveal a thermodynamic trade-off between protein thermostability and catalysis, which is likely to have maintained these functional phenotypes prior to the geographic separation of populations across the Equator about 1.2 million years ago. Full article

(This article belongs to the Section Population and Evolutionary Genetics and Genomics)

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12 pages, 851 KiB

Open AccessEditor’s ChoiceArticle

Expanding the Clinical Phenotype of 19q Interstitial Deletions: A New Case with 19q13.32-q13.33 Deletion and Short Review of the Literature

by Elena-Silvia Shelby, Michael Morris, Liliana Pădure, Andrada Mirea, Relu Cocoș, Alexandru Cărămizaru, Simona Șerban-Sosoi, Andrei Pîrvu and Ioana Streață

Genes 2022, 13(2), 212; https://doi.org/10.3390/genes13020212 - 24 Jan 2022

Cited by 2 | Viewed by 4235

Abstract

19q13 microdeletion syndrome is a very rare genetic disease characterized by pre- and postnatal growth retardation, intellectual disability, expressive language impairment, ectodermal dysplasia, and slender habitus. Since the description of the first case in 1998, less than 30 cases have been reported worldwide. [...] Read more.

19q13 microdeletion syndrome is a very rare genetic disease characterized by pre- and postnatal growth retardation, intellectual disability, expressive language impairment, ectodermal dysplasia, and slender habitus. Since the description of the first case in 1998, less than 30 cases have been reported worldwide. This article aims to review the knowledge gathered so far on this subject and to present the case of a 10-year-old girl admitted to the National University Center for Children Neurorehabilitation “Dr. Nicolae Robanescu” in November of 2018 who presented a slender habitus, growth retardation, facial dysmorphism, skeletal abnormalities, and ectodermal dysplasia. Array-CGH analysis revealed a 1.53 Mb deletion in the 19q13.32-q13.33 region. MLPA for the FKRP gene revealed that the microdeletion was de novo. The patient’s phenotype overlapped with the clinical features of 19q13 microdeletion syndrome. To our knowledge, this is the first case of 19q13 microdeletion syndrome to ever be reported in Romania. We believe our case presents additional features that have never been previously reported in this syndrome, namely, dilatation of the third ventricle and subependymal cyst, left iris coloboma, and tracheomalacia. Moreover, unlike the other 19q13 microdeletion cases that presented with dystonia, our patient also presented dystonia but, interestingly, without having haploinsufficiency of the KMT2B gene. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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17 pages, 7896 KiB

Open AccessEditor’s ChoiceArticle

MtWRP1, a Novel Fabacean Specific Gene, Regulates Root Nodulation and Plant Growth in Medicago truncatula

by Wei Chen, Yingjun Chi, Jinglong Zhang, Binqiang Bai, Xiaomin Ji and Yixin Shen

Genes 2022, 13(2), 193; https://doi.org/10.3390/genes13020193 - 22 Jan 2022

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Abstract

Fabaceans symbiotically interact with nitrogen-fixing rhizobacteria to form root nodules. Some fabacean specific proteins play important roles in the symbiosis. WRKY-related Protein (WRP) is a novel fabacean specific protein, whose functions have not been well characterized. In this study, MtWRP1 was functionally characterized [...] Read more.

Fabaceans symbiotically interact with nitrogen-fixing rhizobacteria to form root nodules. Some fabacean specific proteins play important roles in the symbiosis. WRKY-related Protein (WRP) is a novel fabacean specific protein, whose functions have not been well characterized. In this study, MtWRP1 was functionally characterized in Medicago truncatula. It contains a WRKY domain at C-terminal and a novel transmembrane (TM) domain at N-terminal, and its WRKY domain was highly similar to the N-terminal WRKY domain of the group I WRKY proteins. The TM domain was highly homologous to the eukaryotic cytochrome b561 (Cytb561) proteins from birds. Subcellular localization revealed that MtWRP1 was targeted to the Golgi apparatus through the novel TM domain. MtWRP1 was highly expressed in roots and nodules, suggesting its possible roles in the regulation of root growth and nodulation. Both MtWRP1-overexpression transgenic M. truncatula and MtWRP1 mutants showed altered root nodulation and plant growth performance. Specifically, the formation of root nodules was significantly reduced in the absence of MtWRP1. These results demonstrated that MtWRP1 plays critical roles in root nodulation and plant growth. Full article

(This article belongs to the Special Issue Mining the Excellent Functional Genes of Forage)

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13 pages, 25329 KiB

Open AccessEditor’s ChoiceArticle

Identification and Functional Analysis of the Regulatory Elements in the pHSPA6 Promoter

by Shuyu Jiao, Chunyan Bai, Chunyun Qi, Heyong Wu, Lanxin Hu, Feng Li, Kang Yang, Chuheng Zhao, Hongsheng Ouyang, Daxin Pang, Xiaochun Tang and Zicong Xie

Genes 2022, 13(2), 189; https://doi.org/10.3390/genes13020189 - 21 Jan 2022

Cited by 2 | Viewed by 3268

Abstract

Functional and expressional research of heat shock protein A6 (HSPA6) suggests that the gene is of great value for neurodegenerative diseases, biosensors, cancer, etc. Based on the important value of pigs in agriculture and biomedicine and to advance knowledge of this little-studied HSPA [...] Read more.

Functional and expressional research of heat shock protein A6 (HSPA6) suggests that the gene is of great value for neurodegenerative diseases, biosensors, cancer, etc. Based on the important value of pigs in agriculture and biomedicine and to advance knowledge of this little-studied HSPA member, the stress-sensitive sites in porcine HSPA6 (pHSPA6) were investigated following different stresses. Here, two heat shock elements (HSEs) and a conserved region (CR) were identified in the pHSPA6 promoter by a CRISPR/Cas9-mediated precise gene editing strategy. Gene expression data showed that sequence disruption of these regions could significantly reduce the expression of pHSPA6 under heat stress. Stimulation studies indicated that these regions responded not only to heat stress but also to copper sulfate, MG132, and curcumin. Further mechanism studies showed that downregulated pHSPA6 could significantly affect some important members of the HSP family that are involved in HSP40, HSP70, and HSP90. Overall, our results provide a new approach for investigating gene expression and regulation that may contribute to gene regulatory mechanisms, drug target selection, and breeding stock selection. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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15 pages, 3862 KiB

Open AccessEditor’s ChoiceArticle

Research on Frequent Itemset Mining of Imaging Genetics GWAS in Alzheimer’s Disease

by Hong Liang, Luolong Cao, Yue Gao, Haoran Luo, Xianglian Meng, Ying Wang, Jin Li and Wenjie Liu

Genes 2022, 13(2), 176; https://doi.org/10.3390/genes13020176 - 19 Jan 2022

Cited by 1 | Viewed by 2689

Abstract

As an efficient method, genome-wide association study (GWAS) is used to identify the association between genetic variation and pathological phenotypes, and many significant genetic variations founded by GWAS are closely associated with human diseases. However, it is not enough to mine only a [...] Read more.

As an efficient method, genome-wide association study (GWAS) is used to identify the association between genetic variation and pathological phenotypes, and many significant genetic variations founded by GWAS are closely associated with human diseases. However, it is not enough to mine only a single marker effect variation on complex biological phenotypes. Mining highly correlated single nucleotide polymorphisms (SNP) is more meaningful for the study of Alzheimer's disease (AD). In this paper, we used two frequent pattern mining (FPM) framework, the FP-Growth and Eclat algorithms, to analyze the GWAS results of functional magnetic resonance imaging (fMRI) phenotypes. Moreover, we applied the definition of confidence to FP-Growth and Eclat to enhance the FPM framework. By calculating the conditional probability of identified SNPs, we obtained the corresponding association rules to provide support confidence between these important SNPs. The resulting SNPs showed close correlation with hippocampus, memory, and AD. The experimental results also demonstrate that our framework is effective in identifying SNPs and provide candidate SNPs for further research. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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