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Genes, Volume 13, Issue 4 (April 2022) – 157 articles

Cover Story (view full-size image): Recent technological advances in chromosome conformation capture (3C)-based techniques, imaging approaches, and ligation-free methods, along with computational methods to analyze the data generated, have revealed 3D genome features of varying scales in the brain; knowledge of these features contributes to our understanding of the genetic mechanisms underlying neuropsychiatric diseases and other brain-related traits. In this review, we discuss how these advances aid in the genetic dissection of brain-related traits. View this paper
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Article
Update on the Phenotypic and Genotypic Spectrum of KIF11-Related Retinopathy
Genes 2022, 13(4), 713; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040713 - 18 Apr 2022
Viewed by 550
Abstract
Background: This study aimed to report the frequency of KIF11-mutations in a large familial exudative vitreoretinopathy (FEVR) population, extend the clinical spectrum of KIF11-associated retinopathy and compare KIF11-associated retinopathy to FEVR with mutations in other genes. Methods: Genetic data collected [...] Read more.
Background: This study aimed to report the frequency of KIF11-mutations in a large familial exudative vitreoretinopathy (FEVR) population, extend the clinical spectrum of KIF11-associated retinopathy and compare KIF11-associated retinopathy to FEVR with mutations in other genes. Methods: Genetic data collected from 696 FEVR families were reviewed. The ocular phenotypes in patients with KIF11 mutations were analyzed and compared with those of FEVR patients with mutations in other genes (FZD4, TSPAN12, LRP5, NDP and JAG1). Results: In a cohort of 696 FEVR families, disease-causing KIF11 mutations were identified in 3.6% of families (25/696). Among 25 KIF11 mutations, 80% (20/25) carried variants of loss of function and 48% (12/25) of variants were de novo. The phenotypes were variable. Compared with FEVR with disease-causing mutations in other genes, chorioretinal dysplasia was observed in 44.2% (31/70) of eyes with KIF11-associated retinopathy and in only 1.3% (1/70) of eyes with FEVR with mutations in other genes (p < 0.01). Increase and straightening of peripheral vessels (ISPV) was observed in 17.1% (12/70) of eyes with KIF11-associated retinopathy, and in 50% (39/78) of eyes with FEVR with mutations in other genes (p < 0.01). Conclusions: The frequency of the KIF11 mutation in FEVR was 3.6% in our database. The manifestation of KIF11-associated retinopathy was variable and different from the phenotype in FEVR caused by other genes. Chorioretinal dysplasia, instead of retinal folds, was the dominant phenotype in KIF11-associated retinopathy. ISPV was rare in KIF11-associated retinopathy. Moreover, our study revealed that most pathogenic KIF11 mutations were de novo. Full article
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Article
Expression Characteristics in Roots, Phloem, Leaves, Flowers and Fruits of Apple circRNA
Genes 2022, 13(4), 712; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040712 - 18 Apr 2022
Viewed by 505
Abstract
Circular RNAs (circRNAs) are covalently closed non-coding RNAs that play pivotal roles in various biological processes. However, circRNAs’ roles in different tissues of apple are currently unknown. A total of 6495 unique circRNAs were identified from roots, phloem, leaves, flowers and fruits; 65.99% [...] Read more.
Circular RNAs (circRNAs) are covalently closed non-coding RNAs that play pivotal roles in various biological processes. However, circRNAs’ roles in different tissues of apple are currently unknown. A total of 6495 unique circRNAs were identified from roots, phloem, leaves, flowers and fruits; 65.99% of them were intergenic circRNAs. Similar to other plants, tissue-specific expression was also observed for apple circRNAs; only 175 (2.69%) circRNAs were prevalently expressed in all five different tissues, while 1256, 1064, 912, 904 and 1080 circRNAs were expressed only in roots, phloem, leaves, flowers and fruit, respectively. The hosting-genes of circRNAs showed significant differences enriched in COG, GO terms or KEGG pathways in five tissues, suggesting the special functions of circRNAs in different tissues. Potential binding interactions between circRNAs and miRNAs were investigated using TargetFinder; 2989 interactions between 647 circRNAs and 192 miRNA were predicated in the present study. It also predicted that Chr00:18744403|18744580-mdm-miR160 might play an important role in the formation of flowers or in regulating the coloration of flowers, Chr10:6857496|6858910–mdm-miR168 might be involved in response to drought stress in roots, and Chr03:1226434|1277176 may absorb mdm-miR482a-3p and play a major role in disease resistance. Two circRNAs were experimentally analyzed by qRT-PCR with divergent primers, the expression levels were consistent with RNA-seq, which indicates that the RNA-seq datasets were reliable. Full article
(This article belongs to the Special Issue Circular RNA: Functions, Applications and Prospects)
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Article
Pcsk6 Deficiency Promotes Cardiomyocyte Senescence by Modulating Ddit3-Mediated ER Stress
Genes 2022, 13(4), 711; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040711 - 18 Apr 2022
Viewed by 622
Abstract
Cardiac aging is a critical determinant of cardiac dysfunction, which contributes to cardiovascular disease in the elderly. Proprotein convertase subtilisin/kexin 6 (PCSK6) is a proteolytic enzyme important for the maintenance of cardiac function and vascular homeostasis. To date, the involvement of PCSK6 in [...] Read more.
Cardiac aging is a critical determinant of cardiac dysfunction, which contributes to cardiovascular disease in the elderly. Proprotein convertase subtilisin/kexin 6 (PCSK6) is a proteolytic enzyme important for the maintenance of cardiac function and vascular homeostasis. To date, the involvement of PCSK6 in cardiac aging remains unknown. Here we report that PCSK6 expression decreased in the hearts of aged mice, where high levels cyclin dependent kinase inhibitor 2A (P16) and cyclin dependent kinase inhibitor 1A (P21) (senescence markers) were observed. Moreover, PCSK6 protein expression was significantly reduced in senescent rat embryonic cardiomyocytes (H9c2) induced by D-galactose. Pcsk6 knockdown in H9c2 cells increased P16 and P21 expression levels and senescence-associated beta-galactosidase activity. Pcsk6 knockdown also impaired cardiomyocyte function, as indicated by increased advanced glycation end products, reactive oxygen species level, and apoptosis. Overexpression of PCSK6 blunted the senescence phenotype and cellular dysfunction. Furthermore, RNA sequencing analysis in Pcsk6-knockdown H9c2 cells identified the up-regulated DNA-damage inducible transcript 3 (Ddit3) gene involved in endoplasmic reticulum (ER) protein processing. Additionally, DDIT3 protein levels were remarkably increased in aged mouse hearts. In the presence of tunicamycin, an ER stress inducer, DDIT3 expression increased in Pcsk6-deficient H9c2 cells but reduced in PCSK6-overexpressing cells. In conclusion, our findings indicate that PCSK6 modulates cardiomyocyte senescence possibly via DDIT3-mediated ER stress. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Article
Estimation of Causal Effect of Age at Menarche on Pubertal Height Growth Using Mendelian Randomization
Genes 2022, 13(4), 710; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040710 - 17 Apr 2022
Viewed by 510
Abstract
We use Mendelian randomization to estimate the causal effect of age at menarche on late pubertal height growth and total pubertal height growth. The instrument SNPs selected from the exposure genome-wide association study (GWAS) are validated in additional population-matched exposure GWASs. Based on [...] Read more.
We use Mendelian randomization to estimate the causal effect of age at menarche on late pubertal height growth and total pubertal height growth. The instrument SNPs selected from the exposure genome-wide association study (GWAS) are validated in additional population-matched exposure GWASs. Based on the inverse variance weighting method, there is a positive causal relationship of age at menarche on late pubertal growth (β^=0.56, 95% CI: (0.34, 0.78), p=3.16×107) and on total pubertal growth (β^=0.36, 95% CI: (0.14, 0.58), p=1.30×103). If the instrument SNPs are not validated in additional exposure GWASs, the estimated effect on late pubertal height growth increases by 3.6% to β^=0.58 (95% CI: (0.42, 0.73), p=4.38×1013) while the estimates on total pubertal height growth increases by 41.7% to β^=0.51 (95% CI: (0.35, 0.67), p=2.96×1011). Full article
(This article belongs to the Special Issue Statistical Genetics in Human Diseases)
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Review
Methodologies for the De novo Discovery of Transposable Element Families
Genes 2022, 13(4), 709; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040709 - 17 Apr 2022
Viewed by 830
Abstract
The discovery and characterization of transposable element (TE) families are crucial tasks in the process of genome annotation. Careful curation of TE libraries for each organism is necessary as each has been exposed to a unique and often complex set of TE families. [...] Read more.
The discovery and characterization of transposable element (TE) families are crucial tasks in the process of genome annotation. Careful curation of TE libraries for each organism is necessary as each has been exposed to a unique and often complex set of TE families. De novo methods have been developed; however, a fully automated and accurate approach to the development of complete libraries remains elusive. In this review, we cover established methods and recent developments in de novo TE analysis. We also present various methodologies used to assess these tools and discuss opportunities for further advancement of the field. Full article
(This article belongs to the Special Issue Mobile Elements in Phylogenomic Reconstructions)
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Article
Molecular Evolutionary Rate Predicts Intraspecific Genetic Polymorphism and Species-Specific Selection
Genes 2022, 13(4), 708; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040708 - 17 Apr 2022
Viewed by 468
Abstract
It is unknown what determines genetic diversity and how genetic diversity is associated with various biological traits. In this work, we provide insight into these issues. By comparing genetic variation of 14,671 mammalian gene trees with thousands of individual human, chimpanzee, gorilla, mouse, [...] Read more.
It is unknown what determines genetic diversity and how genetic diversity is associated with various biological traits. In this work, we provide insight into these issues. By comparing genetic variation of 14,671 mammalian gene trees with thousands of individual human, chimpanzee, gorilla, mouse, and dog/wolf genomes, we found that intraspecific genetic diversity can be predicted by long-term molecular evolutionary rates rather than de novo mutation rates. This relationship was established during the early stage of mammalian evolution. Moreover, we developed a method to detect fluctuations of species-specific selection on genes based on the deviations of intraspecific genetic diversity predicted from long-term rates. We showed that the evolution of epithelial cells, rather than connective tissue, mainly contributed to morphological evolution of different species. For humans, evolution of the immune system and selective sweeps caused by infectious diseases are the most representative examples of adaptive evolution. Full article
(This article belongs to the Special Issue Genetic Structure of Human Populations)
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Article
A target Capture Probe Set Useful for Deep- and Shallow-Level Phylogenetic Studies in Cactaceae
Genes 2022, 13(4), 707; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040707 - 17 Apr 2022
Viewed by 504
Abstract
The molecular phylogenies of Cactaceae have enabled us to better understand their systematics, biogeography, and diversification ages. However, most of the phylogenetic relationships within Cactaceae major groups remain unclear, largely due to the lack of an appropriate set of molecular markers to resolve [...] Read more.
The molecular phylogenies of Cactaceae have enabled us to better understand their systematics, biogeography, and diversification ages. However, most of the phylogenetic relationships within Cactaceae major groups remain unclear, largely due to the lack of an appropriate set of molecular markers to resolve its contentious relationships. Here, we explored the genome and transcriptome assemblies available for Cactaceae and identified putative orthologous regions shared among lineages of the subfamily Cactoideae. Then we developed a probe set, named Cactaceae591, targeting both coding and noncoding nuclear regions for representatives from the subfamilies Pereskioideae, Opuntioideae, and Cactoideae. We also sampled inter- and intraspecific variation to evaluate the potential of this panel to be used in phylogeographic studies. We retrieved on average of 547 orthologous regions per sample. Targeting noncoding nuclear regions showed to be crucial to resolving inter- and intraspecific relationships. Cactaceae591 covers 13 orthologous genes shared with the Angiosperms353 kit and two plastid regions largely used in Cactaceae studies, enabling the phylogenies generated by our panel to be integrated with angiosperm and Cactaceae phylogenies, using these sequences. We highlighted the importance of using coalescent-based species tree approaches on the Cactaceae591 dataset to infer accurate phylogenetic trees in the presence of extensive incomplete lineage sorting in this family. Full article
(This article belongs to the Special Issue Cactaceae Genetics and Genomics)
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Review
Pathogenesis of Type 1 Diabetes: Established Facts and New Insights
Genes 2022, 13(4), 706; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040706 - 16 Apr 2022
Viewed by 843
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous [...] Read more.
Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. In this review, we highlight the interplay between genetic predisposition and other non-genetic factors, such as viral infections, diet, and gut biome, which all potentially contribute to the aetiology of T1D. We also discuss a possible active role for β-cells in initiating the pathological processes. Another component in T1D predisposition is epigenetic influences, which represent a link between genetic susceptibility and environmental factors and may account for some of the disease heterogeneity. Accordingly, a shift towards personalized therapies may improve the treatment results and, therefore, result in better outcomes for individuals in the long-run. There is also a clear need for a better understanding of the preclinical phases of T1D and finding new predictive biomarkers for earlier diagnosis and therapy, with the final goal of reverting or even preventing the development of the disease. Full article
(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)
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Review
The Role of Epigenetic Modifications in Late Complications in Type 1 Diabetes
Genes 2022, 13(4), 705; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040705 - 15 Apr 2022
Viewed by 732
Abstract
Type 1 diabetes is a chronic autoimmune disease in which the destruction of pancreatic β cells leads to hyperglycemia. The prevention of hyperglycemia is very important to avoid or at least postpone the development of micro- and macrovascular complications, also known as late [...] Read more.
Type 1 diabetes is a chronic autoimmune disease in which the destruction of pancreatic β cells leads to hyperglycemia. The prevention of hyperglycemia is very important to avoid or at least postpone the development of micro- and macrovascular complications, also known as late complications. These include diabetic retinopathy, chronic renal failure, diabetic neuropathy, and cardiovascular diseases. The impact of long-term hyperglycemia has been shown to persist long after the normalization of blood glucose levels, a phenomenon known as metabolic memory. It is believed that epigenetic mechanisms such as DNA methylation, histone modifications, and microRNAs, play an important role in metabolic memory. The aim of this review is to address the impact of long-term hyperglycemia on epigenetic marks in late complications of type 1 diabetes. Full article
(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)
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Article
The Length of Leukocyte and Femoral Artery Telomeres in Patients with Peripheral Atherosclerosis
Genes 2022, 13(4), 704; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040704 - 15 Apr 2022
Viewed by 489
Abstract
The length of telomeres (TLs) that protect chromosome ends may reflect the age of cells as well as the degree of genetic material damage caused by external factors. Since leukocyte telomere length is associated with cardiovascular diseases, the aim of this study was [...] Read more.
The length of telomeres (TLs) that protect chromosome ends may reflect the age of cells as well as the degree of genetic material damage caused by external factors. Since leukocyte telomere length is associated with cardiovascular diseases, the aim of this study was to evaluate whether leukocyte TL reflects femoral artery wall telomeres of patients with atherosclerosis and lower limb ischemia. Samples of femoral artery wall and blood were collected from 32 patients qualified to surgical revascularization. The analysis included blood and artery wall telomere length measurement and biochemical parameters. The study indicated that there was a moderate correlation between artery wall TL and leukocyte TL. Leukocyte TL was, on average, two times shorter than artery wall TL and correlated with the number of white blood cells. In turn, artery TL was impacted by total cholesterol level. The results suggest that the length of leukocyte telomeres may reflect artery wall TL and indirectly reflect the processes taking place in the artery wall in patients with atherosclerosis. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Article
Characterization of Altered Molecular Pathways in the Entorhinal Cortex of Alzheimer’s Disease Patients and In Silico Prediction of Potential Repurposable Drugs
Genes 2022, 13(4), 703; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040703 - 15 Apr 2022
Viewed by 623
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterized by a progressive decline in cognitive functions. Accumulation of amyloid-β plaques and neurofibrillary tangles are a typical feature of AD neuropathological changes. The entorhinal cortex (EC) is the first [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterized by a progressive decline in cognitive functions. Accumulation of amyloid-β plaques and neurofibrillary tangles are a typical feature of AD neuropathological changes. The entorhinal cortex (EC) is the first brain area associated with pathologic changes in AD, even preceding atrophy of the hippocampus. In the current study, we have performed a meta-analysis of publicly available expression data sets of the entorhinal cortex (EC) in order to identify potential pathways underlying AD pathology. The meta-analysis identified 1915 differentially expressed genes (DEGs) between the EC from normal and AD patients. Among the downregulated DEGs, we found a significant enrichment of biological processes pertaining to the “neuronal system” (R-HSA-112316) and the “synaptic signaling” (GO:0099536), while the “regulation of protein catabolic process” (GO:00042176) and “transport of small molecules” (R-HSA-382551) resulted in enrichment among both the upregulated and downregulated DEGs. Finally, by means of an in silico pharmacology approach, we have prioritized drugs and molecules potentially able to revert the transcriptional changes associated with AD pathology. The drugs with a mostly anti-correlated signature were: efavirenz, an anti-retroviral drug; tacrolimus, a calcineurin inhibitor; and sirolimus, an mTOR inhibitor. Among the predicted drugs, those potentially able to cross the blood-brain barrier have also been identified. Overall, our study found a disease-specific set of dysfunctional biological pathways characterizing the EC in AD patients and identified a set of drugs that could in the future be exploited as potential therapeutic strategies. The approach used in the current study has some limitations, as it does not account for possible post-transcriptional events regulating the cellular phenotype, and also, much clinical information about the samples included in the meta-analysis was not available. However, despite these limitations, our study sets the basis for future investigations on the pathogenetic processes occurring in AD and proposes the repurposing of currently used drugs for the treatment of AD patients. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Article
A Penalization Method for Estimating Heterogeneous Covariate Effects in Cancer Genomic Data
Genes 2022, 13(4), 702; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040702 - 15 Apr 2022
Viewed by 412
Abstract
In high-throughput profiling studies, extensive efforts have been devoted to searching for the biomarkers associated with the development and progression of complex diseases. The heterogeneity of covariate effects associated with the outcomes across subjects has been noted in the literature. In this paper, [...] Read more.
In high-throughput profiling studies, extensive efforts have been devoted to searching for the biomarkers associated with the development and progression of complex diseases. The heterogeneity of covariate effects associated with the outcomes across subjects has been noted in the literature. In this paper, we consider a scenario where the effects of covariates change smoothly across subjects, which are ordered by a known auxiliary variable. To this end, we develop a penalization-based approach, which applies a penalization technique to simultaneously select important covariates and estimate their unique effects on the outcome variables of each subject. We demonstrate that, under the appropriate conditions, our method shows selection and estimation consistency. Additional simulations demonstrate its superiority compared to several competing methods. Furthermore, applying the proposed approach to two The Cancer Genome Atlas datasets leads to better prediction performance and higher selection stability. Full article
(This article belongs to the Special Issue Application of Bioinformatics in Human Cancers)
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Article
The Impact of Sex, Circadian Disruption, and the ClockΔ19/Δ19 Genotype on Alcohol Drinking in Mice
Genes 2022, 13(4), 701; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040701 - 15 Apr 2022
Cited by 1 | Viewed by 753
Abstract
Shift work is associated with increased alcohol drinking, more so in males than females, and is thought to be a coping mechanism for disrupted sleep cycles. However, little is presently known about the causal influence of circadian rhythm disruptions on sex differences in [...] Read more.
Shift work is associated with increased alcohol drinking, more so in males than females, and is thought to be a coping mechanism for disrupted sleep cycles. However, little is presently known about the causal influence of circadian rhythm disruptions on sex differences in alcohol consumption. In this study, we disrupted circadian rhythms in female and male mice using both environmental (i.e., shifting diurnal cycles) and genetic (i.e., ClockΔ19/Δ19 mutation) manipulations, and measured changes in alcohol consumption and preference using a two-bottle choice paradigm. Alcohol consumption and preference, as well as food and water consumption, total caloric intake, and weight were assessed in adult female and male ClockΔ19/Δ19 mutant mice or wild-type (WT) litter-mates, housed under a 12-hour:12-hour light:dark (L:D) cycle or a shortened 10-hour:10-hour L:D cycle. Female WT mice (under both light cycles) increased their alcohol consumption and preference over time, a pattern not observed in male WT mice. Compared to WT mice, ClockΔ19/Δ19 mice displayed increased alcohol consumption and preference. Sex differences were not apparent in ClockΔ19/Δ19 mice, with or without shifting diurnal cycles. In conclusion, sex differences in alcohol consumption patterns are evident and increase with prolonged access to alcohol. Disrupting circadian rhythms by mutating the Clock gene greatly increases alcohol consumption and abolishes sex differences present in WT animals. Full article
(This article belongs to the Special Issue Genetics and Genomics of Addiction)
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Article
Partial fads2 Gene Knockout Diverts LC-PUFA Biosynthesis via an Alternative Δ8 Pathway with an Impact on the Reproduction of Female Zebrafish (Danio rerio)
Genes 2022, 13(4), 700; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040700 - 15 Apr 2022
Viewed by 562
Abstract
The zebrafish (Danio rerio) genome contains a single gene fads2 encoding a desaturase (FADS2) with both Δ6 and Δ5 activities, the key player in the endogenous biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), which serve essential functions as membrane components, sources [...] Read more.
The zebrafish (Danio rerio) genome contains a single gene fads2 encoding a desaturase (FADS2) with both Δ6 and Δ5 activities, the key player in the endogenous biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), which serve essential functions as membrane components, sources of energy and signaling molecules. LC-PUFAs include the precursors of eicosanoids and are thus predicted to be indispensable molecules for reproductive health in virtually all vertebrates. In mice, an amniotic vertebrate, fads2 deletion mutants, both males and females, have been confirmed to be sterile. In anamniotic vertebrates, such as fish, there is still no information available on the reproductive (in)ability of fads2 mutants, although zebrafish have become an increasingly important model of lipid metabolism, including some aspects of the generation of germ cells and early embryonic development. In the present study, we apply the CRISPR/Cas9 genome editing system to induce mutations in the zebrafish genome and create crispants displaying a degree of fads2 gene editing within the range of 50–80%. Focusing on adult G0 crispant females, we investigated the LC-PUFA profiles of eggs. Our data suggest an impaired pathway of the LC-PUFA biosynthesis of the ω6 and ω3 series in the first-rate limiting steps of the conversion of linoleic acid (LA) into γ-linolenic acid (GLA), and α-linolenic acid (ALA) into stearidonic acid (SDA), respectively, finally resulting in bad-quality eggs. Our data suggest the existence of an alternative Δ8 pathway, which bypasses the first endogenous LC-PUFA biosynthetic step in zebrafish in vivo, and suggest that the zebrafish bifunctional FADS2 enzyme is actually a trifunctional Δ6/Δ5/Δ8 desaturase. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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Article
Dietary Restriction and Rapamycin Affect Brain Aging in Mice by Attenuating Age-Related DNA Methylation Changes
Genes 2022, 13(4), 699; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040699 - 15 Apr 2022
Viewed by 588
Abstract
The fact that dietary restriction (DR) and long-term rapamycin treatment (RALL) can ameliorate the aging process has been reported by many researchers. As the interface between external and genetic factors, epigenetic modification such as DNA methylation may have latent effects on the aging [...] Read more.
The fact that dietary restriction (DR) and long-term rapamycin treatment (RALL) can ameliorate the aging process has been reported by many researchers. As the interface between external and genetic factors, epigenetic modification such as DNA methylation may have latent effects on the aging rate at the molecular level. To understand the mechanism behind the impacts of dietary restriction and rapamycin on aging, DNA methylation and gene expression changes were measured in the hippocampi of different-aged mice. Examining the single-base resolution of DNA methylation, we discovered that both dietary restriction and rapamycin treatment can maintain DNA methylation in a younger state compared to normal-aged mice. Through functional enrichment analysis of genes in which DNA methylation or gene expression can be affected by DR/RALL, we found that DR/RALL may retard aging through a relationship in which DNA methylation and gene expression work together not only in the same gene but also in the same biological process. This study is instructive for understanding the maintenance of DNA methylation by DR/RALL in the aging process, as well as the role of DR and RALL in the amelioration of aging. Full article
(This article belongs to the Special Issue Bioinformatic Analysis of NGS Data)
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Article
In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology
Genes 2022, 13(4), 698; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040698 - 15 Apr 2022
Viewed by 465
Abstract
The L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene encodes an important mitochondrial enzyme. However, its altered activity results in excessive levels of L-2-hydroxyglutarate, which results in diverse psychiatric features of intellectual disability. In the current study, we executed an in-silico analysis of all reported L2HGDH missense [...] Read more.
The L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene encodes an important mitochondrial enzyme. However, its altered activity results in excessive levels of L-2-hydroxyglutarate, which results in diverse psychiatric features of intellectual disability. In the current study, we executed an in-silico analysis of all reported L2HGDH missense and nonsense variants in order to investigate their biological significance. Among the superimposed 3D models, the highest similarity index for a wild-type structure was shown by the mutant Glu336Lys (87.26%), while the lowest similarity index value was shown by Arg70* (10.00%). Three large active site pockets were determined using protein active site prediction, in which the 2nd largest pocket was shown to encompass the substrate L-2-hydroxyglutarate (L2HG) binding residues, i.e., 89Gln, 195Tyr, 402Ala, 403Gly and 404Val. Moreover, interactions of wild-type and mutant L2HGDH variants with the close functional interactor D2HGDH protein resulted in alterations in the position, number and nature of networking residues. We observed that the binding of L2HG with the L2HGDH enzyme is affected by the nature of the amino acid substitution, as well as the number and nature of bonds between the substrate and protein molecule, which are able to affect its biological activity. Full article
(This article belongs to the Special Issue Bioinformatics Analysis for Diseases)
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Article
Case Review: Whole-Exome Sequencing Analyses Identify Carriers of a Known Likely Pathogenic Intronic BRCA1 Variant in Ovarian Cancer Cases Clinically Negative for Pathogenic BRCA1 and BRCA2 Variants
Genes 2022, 13(4), 697; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040697 - 15 Apr 2022
Viewed by 568
Abstract
Background: Detecting pathogenic intronic variants resulting in aberrant splicing remains a challenge in routine genetic testing. We describe germline whole-exome sequencing (WES) analyses and apply in silico predictive tools of familial ovarian cancer (OC) cases reported clinically negative for pathogenic BRCA1 and BRCA2 [...] Read more.
Background: Detecting pathogenic intronic variants resulting in aberrant splicing remains a challenge in routine genetic testing. We describe germline whole-exome sequencing (WES) analyses and apply in silico predictive tools of familial ovarian cancer (OC) cases reported clinically negative for pathogenic BRCA1 and BRCA2 variants. Methods: WES data from 27 familial OC cases reported clinically negative for pathogenic BRCA1 and BRCA2 variants and 53 sporadic early-onset OC cases were analyzed for pathogenic variants in BRCA1 or BRCA2. WES data from carriers of pathogenic BRCA1 or BRCA2 variants were analyzed for pathogenic variants in 10 other OC predisposing genes. Loss of heterozygosity analysis was performed on tumor DNA from variant carriers. Results: BRCA1 c.5407-25T>A intronic variant, identified in two affected sisters and one sporadic OC case, is predicted to create a new splice effecting transcription of BRCA1. WES data from BRCA1 c.5407-25T>A carriers showed no evidence of pathogenic variants in other OC predisposing genes. Sequencing the tumor DNA from the variant carrier showed complete loss of the wild-type allele. Conclusions: The findings support BRCA1 c.5407-25T>A as a likely pathogenic variant and highlight the importance of investigating intronic sequences as causal variants in OC families where the involvement of BRCA1 is highly suggestive. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Article
Preferential X Chromosome Inactivation as a Mechanism to Explain Female Preponderance in Myasthenia Gravis
Genes 2022, 13(4), 696; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040696 - 15 Apr 2022
Viewed by 479
Abstract
Myasthenia gravis (MG) is a neuromuscular autoimmune disease characterized by prevalence in young women (3:1). Several mechanisms proposed as explanations for gender bias, including skewed X chromosome inactivation (XCI) and dosage or sex hormones, are often involved in the development of autoimmunity. The [...] Read more.
Myasthenia gravis (MG) is a neuromuscular autoimmune disease characterized by prevalence in young women (3:1). Several mechanisms proposed as explanations for gender bias, including skewed X chromosome inactivation (XCI) and dosage or sex hormones, are often involved in the development of autoimmunity. The skewed XCI pattern can lead to an unbalanced expression of some X-linked genes, as observed in several autoimmune disorders characterized by female predominance. No data are yet available regarding XCI and MG. We hypothesize that the preferential XCI pattern may contribute to the female bias observed in the onset of MG, especially among younger women. XCI analysis was performed on blood samples of 284 women between the ages of 20 and 82. XCI was tested using the Human Androgen Receptor Assay (HUMARA). XCI patterns were classified as random (XCI < 75%) and preferential (XCI ≥ 75%). In 121 informative patients, the frequency of skewed XCI patterns was 47%, significantly higher than in healthy controls (17%; p ≤ 0.00001). Interestingly, the phenomenon was observed mainly in younger patients (<45 years; p ≤ 0.00001). Furthermore, considering the XCI pattern and the other clinical characteristics of patients, no significant differences were found. In conclusion, we observed preferential XCI in MG female patients, suggesting its potential role in the aetiology of MG, as observed in other autoimmune diseases in women. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Neuromuscular Diseases)
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Article
Schizophrenia and Bipolar Polygenic Risk Scores in Relation to Intracranial Volume
Genes 2022, 13(4), 695; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040695 - 14 Apr 2022
Viewed by 544
Abstract
Schizophrenia and bipolar disorder are neurodevelopmental disorders with overlapping symptoms and a shared genetic background. Deviations in intracranial volume (ICV)—a marker for neurodevelopment—differ between schizophrenia and bipolar disorder. Here, we investigated whether genetic risk for schizophrenia and bipolar disorder is related to ICV [...] Read more.
Schizophrenia and bipolar disorder are neurodevelopmental disorders with overlapping symptoms and a shared genetic background. Deviations in intracranial volume (ICV)—a marker for neurodevelopment—differ between schizophrenia and bipolar disorder. Here, we investigated whether genetic risk for schizophrenia and bipolar disorder is related to ICV in the general population by using the UK Biobank data (n = 20,196). Polygenic risk scores for schizophrenia (SZ-PRS) and bipolar disorder (BD-PRS) were computed for 12 genome wide association study P-value thresholds (PT) for each individual and correlations with ICV were investigated. Partial correlations were performed at each PT to investigate whether disease specific genetic risk variants for schizophrenia and bipolar disorder show different relationships with ICV. ICV showed a negative correlation with SZ-PRS at PT ≥ 0.005 (r < −0.02, p < 0.005). ICV was not associated with BD-PRS; however, a positive correlation between BD-PRS and ICV at PT = 0.2 and PT = 0.4 (r = +0.02, p < 0.005) appeared when the genetic overlap between schizophrenia and bipolar disorder was accounted for. Despite small effect sizes, a higher load of schizophrenia risk genes is associated with a smaller ICV in the general population, while risk genes specific for bipolar disorder are correlated with a larger ICV. These findings suggest that schizophrenia and bipolar disorder risk genes, when accounting for the genetic overlap between both disorders, have opposite effects on early brain development. Full article
(This article belongs to the Special Issue Genetic Basis Underlying Neuropsychiatric Disorders)
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Article
Expanding the Phenotype of B3GALNT2-Related Disorders
Genes 2022, 13(4), 694; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040694 - 14 Apr 2022
Viewed by 466
Abstract
Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) that include a broad phenotypic spectrum ranging from late-onset limb-girdle muscular dystrophy to severe muscle–eye–brain disease, Walker–Warburg syndrome, and Fukuyama congenital muscular dystrophy. In addition to clinical heterogeneity, CMDs are characterized by genetic heterogeneity. [...] Read more.
Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) that include a broad phenotypic spectrum ranging from late-onset limb-girdle muscular dystrophy to severe muscle–eye–brain disease, Walker–Warburg syndrome, and Fukuyama congenital muscular dystrophy. In addition to clinical heterogeneity, CMDs are characterized by genetic heterogeneity. To date, 18 genes have been associated with CMDs. One of them is B3GALNT2, which encodes the β-1,3-N-acetylgalactosaminyltransferase 2 that glycosylates α-dystroglycan. In this study, using exome sequencing, we identify a homozygous frameshift variant in B3GALNT2 due to a mixed uniparental disomy of chromosome 1 in a 7-year-old girl with global developmental delay, severely delayed active language development, and autism spectrum disorder but without any symptoms of muscular dystrophy. In addition to this case, we also provide an overview of all previously reported cases, further expanding the phenotypic spectrum. Full article
(This article belongs to the Special Issue Advances in Genetic Diagnosis for Neurodevelopmental Disorders)
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Article
G-Protein Subunit Gamma 4 as a Potential Biomarker for Predicting the Response of Chemotherapy and Immunotherapy in Bladder Cancer
Genes 2022, 13(4), 693; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040693 - 14 Apr 2022
Cited by 1 | Viewed by 565
Abstract
Background: GNG4, a member of the G-protein γ family, is a marker of poor overall survival (OS) rates in some malignancies. However, the potential role of GNG4 in bladder cancer (BLCA) is unknown. It is also unclear whether GNG4 may be utilized as [...] Read more.
Background: GNG4, a member of the G-protein γ family, is a marker of poor overall survival (OS) rates in some malignancies. However, the potential role of GNG4 in bladder cancer (BLCA) is unknown. It is also unclear whether GNG4 may be utilized as a marker to guide chemotherapy or immunotherapy. Methods: Single-cell RNA sequencing data were used to explore the expression of GNG4 in tumor microenvironment of BLCA. Bulk RNA sequencing data from TCGA were used to evaluate the relationship between GNG4 expression and biological features, such as immune cell infiltrations and gene mutations. The associations between GNG4 expression and survival in BLCA patients under or not under immunotherapy were evaluated using seven BLCA cohorts. Results: GNG4 was specifically expressed in exhausted CD4+ T cells. And the high expression of the GNG4 was associated with high level of immune cell infiltration. The high-GNG4-expression group displayed a better response to immunotherapy, whereas patients in the low-GNG4-expression group often benefited from chemotherapy. Moreover, the high-GNG4 group was more similar to the basal group, whereas the low-GNG4 group was similar to the luminal group. Conclusions: GNG4 may be a potential biomarker for the prediction of the response to therapy in BLCA. Higher GNG4 expression can be used as a predictor of response to immunotherapy, and lower GNG4 expression can be used as a predictor of response to chemotherapy. Full article
(This article belongs to the Special Issue The Role of RNA Processing and Metabolism in Tumors)
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Article
MED12 Regulates Smooth Muscle Cell Functions and Participates in the Development of Aortic Dissection
Genes 2022, 13(4), 692; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040692 - 14 Apr 2022
Viewed by 541
Abstract
Aortic dissection (AD) is a life-threatening disease with high morbidity and mortality, and effective pharmacotherapeutic remedies for it are lacking. Therefore, AD’s molecular pathogenesis and etiology must be elucidated. The aim of this study was to investigate the possible mechanism of mediator complex [...] Read more.
Aortic dissection (AD) is a life-threatening disease with high morbidity and mortality, and effective pharmacotherapeutic remedies for it are lacking. Therefore, AD’s molecular pathogenesis and etiology must be elucidated. The aim of this study was to investigate the possible mechanism of mediator complex subunit 12 (human: MED12, mouse: Med12)involvement in AD. Firstly, we examined the expression of MED12 protein (human: MED12, mouse: Med12) in the aortic tissues of AD patients and AD mice. Subsequently, Med12 gene silencing was accomplished with RNA interference (siRNA). The effects of Med12 on AD and the possible biological mechanisms were investigated based on the proliferation, senescence, phenotypic transformation, and its involved signal pathway of mouse aortic smooth muscle cells (MOVAS), s. The results show that the expression of MED12 in the aortae of AD patients and AD mice was decreased. Moreover, the downregulation of Med12 inhibited the proliferation of MOVAS and promoted senescence. Further research found that Med12, as an inhibitor of the TGFβ1 signaling pathway, reduced the expression of Med12 and enhanced the activity of the TGFβ1 nonclassical signaling pathway, while TGFβ1 inhibited the phenotype transformation and proliferation of MOVAS by inhibiting Med12 synthesis. In conclusion, Med12 affected the phenotype, proliferation, and senescence of MOVAS through the TGFβ signaling pathway. This study provides a potential new target for the prevention and treatment of AD. Full article
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Article
Elevated Expression of miR-200c/141 in MDA-MB-231 Cells Suppresses MXRA8 Levels and Impairs Breast Cancer Growth and Metastasis In Vivo
Genes 2022, 13(4), 691; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040691 - 14 Apr 2022
Viewed by 555
Abstract
Breast cancer cells with mesenchymal characteristics, particularly the claudin-low subtype, express extremely low levels of miR-200s. Therefore, this study examined the functional impact of restoring miR-200 expression in a human claudin-low breast cancer cell line MDA-MB-231. MDA-MB-231 cells were stably transfected with a [...] Read more.
Breast cancer cells with mesenchymal characteristics, particularly the claudin-low subtype, express extremely low levels of miR-200s. Therefore, this study examined the functional impact of restoring miR-200 expression in a human claudin-low breast cancer cell line MDA-MB-231. MDA-MB-231 cells were stably transfected with a control vector (MDA-231EV) or the miR-200c/141 cluster (MDA-231c141). Injection of MDA-231c141 cells into the 4th mammary gland of NCG mice produced tumors that developed significantly slower than tumors produced by MDA-231EV cells. Spontaneous metastasis to the lungs was also significantly reduced in MDA-231c141 cells compared to MDA-231EV cells. RNA sequencing of MDA-231EV and MDA-231c141 tumors identified genes including MXRA8 as being downregulated in the MDA-231c141 tumors. MXRA8 was further investigated as elevated levels of MXRA8 were associated with reduced distant metastasis free survival in breast cancer patients. Quantitative RT-PCR and Western blotting confirmed that MXRA8 expression was significantly higher in mammary tumors induced by MDA-231EV cells compared to those induced by MDA-231c141 cells. In addition, MXRA8 protein was present at high levels in metastatic tumor cells found in the lungs. This is the first study to implicate MXRA8 in human breast cancer, and our data suggests that miR-200s inhibit growth and metastasis of claudin-low mammary tumor cells in vivo through downregulating MXRA8 expression. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Article
Comparative Genomic Hybridization to Microarrays in Fetuses with High-Risk Prenatal Indications: Polish Experience with 7400 Pregnancies
Genes 2022, 13(4), 690; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040690 - 14 Apr 2022
Viewed by 502
Abstract
The aim of this study was to determine the suitability of the comparative genomic hybridization to microarray (aCGH) technique for prenatal diagnosis, but also to assess the frequency of chromosomal aberrations that may lead to fetal malformations but are not included in the [...] Read more.
The aim of this study was to determine the suitability of the comparative genomic hybridization to microarray (aCGH) technique for prenatal diagnosis, but also to assess the frequency of chromosomal aberrations that may lead to fetal malformations but are not included in the diagnostic report. We present the results of the aCGH in a cohort of 7400 prenatal cases, indicated for invasive testing due to ultrasound abnormalities, high-risk for serum screening, thickened nuchal translucency, family history of genetic abnormalities or congenital abnormalities, and advanced maternal age (AMA). The overall chromosomal aberration detection rate was 27.2% (2010/7400), including 71.2% (1431/2010) of numerical aberrations and 28.8% (579/2010) of structural aberrations. Additionally, the detection rate of clinically significant copy number variants (CNVs) was 6.8% (505/7400) and 0.7% (57/7400) for variants of unknown clinical significance. The detection rate of clinically significant submicroscopic CNVs was 7.9% (334/4204) for fetuses with structural anomalies, 5.4% (18/336) in AMA, 3.1% (22/713) in the group of abnormal serum screening and 6.1% (131/2147) in other indications. Using the aCGH method, it was possible to assess the frequency of pathogenic chromosomal aberrations, of likely pathogenic and of uncertain clinical significance, in the groups of cases with different indications for an invasive test. Full article
(This article belongs to the Special Issue New Insights into Genetic Risk Assessment in Congenital Diseases)
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Article
Oncogenic Role of Connective Tissue Growth Factor Is Associated with Canonical TGF-β Cascade in Colorectal Cancer
Genes 2022, 13(4), 689; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040689 - 14 Apr 2022
Viewed by 559
Abstract
TGF-β signaling pathways promote tumour development and control several downstream genes such as CTGF and MMPs. This study aimed to investigate the association between CTGF and MMP-1 mRNA expressions with clinicopathological status and survival rate in colorectal cancer patients. We investigated expression levels [...] Read more.
TGF-β signaling pathways promote tumour development and control several downstream genes such as CTGF and MMPs. This study aimed to investigate the association between CTGF and MMP-1 mRNA expressions with clinicopathological status and survival rate in colorectal cancer patients. We investigated expression levels of CTGF and MMP-1 genes in paraffin-embedded tumours and adjacent normal tissue blocks (ADJ) by Real Time-PCR. Then, the expression of Smad2 and Smad4 proteins in the TGF-β canonical pathway was evaluated by immunohistochemistry. Finally, the correlation between CTGF, MMP-1, and the canonical TGF-β-signalling pathway with the clinicopathological features was investigated. Expression levels of MMP-1and CTGF were higher in tumours compared with adjacent normal tissues. Overexpression levels of MMP-1 and CTGF were associated with lymph node metastasis, distant metastasis, tumour histopathological grading, advanced stage, and poor survival (p < 0.05). Additionally, a significant association between the upregulation of MMP-1 and tumour location was noted. Upregulation of Smad2 and Smad4 proteins were also significantly correlated with lymph node metastasis, distant metastasis, advanced stage, and poor survival (p < 0.0001). This study showed that canonical TGF-β signalling regulates both CTGF and MMP-1 expression and CRC progression. Moreover, TGF-β signalling and its downstream genes could be used as novel biomarkers and novel approaches for targeted therapy in CRC. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Case Report
Identification of a Novel SHANK2 Pathogenic Variant in a Patient with a Neurodevelopmental Disorder
Genes 2022, 13(4), 688; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040688 - 14 Apr 2022
Viewed by 560
Abstract
Genetic defects in the SHANK2 gene, encoding for synaptic scaffolding protein, are associated with a variety of neurodevelopmental conditions, including autism spectrum disorders and mild to moderate intellectual disability. Until now, limited patient clinical descriptions have been published. Only 13 unrelated patients with [...] Read more.
Genetic defects in the SHANK2 gene, encoding for synaptic scaffolding protein, are associated with a variety of neurodevelopmental conditions, including autism spectrum disorders and mild to moderate intellectual disability. Until now, limited patient clinical descriptions have been published. Only 13 unrelated patients with SHANK2 pathogenic variations or microdeletions have been reported worldwide. By Exome Sequencing, we identified a de novo stop-gain variant, c.334C>T, p.(Gln112*), in an Italian patient with a neurodevelopmental disorder. The patient (9 years old) presented the following facial features: a flat profile, thick eyebrows, long eyelashes, a bulbous nasal tip and a prominent columella, retracted ears, dental anomalies. The patient showed speech delay and mild neuromotor delay but not autism spectrum disorder. In conclusion, this patient with a novel pathogenic variant in SHANK2 enlarges the phenotypic spectrum of SHANK2-mutated patients and demonstrates that the severity of SHANK2-associated disorders is highly variable. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Article
Development and Optimization of a Silica Column-Based Extraction Protocol for Ancient DNA
Genes 2022, 13(4), 687; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040687 - 13 Apr 2022
Viewed by 1027
Abstract
Rapid and cost-effective retrieval of endogenous DNA from ancient specimens remains a limiting factor in palaeogenomic research. Many methods have been developed to increase ancient DNA yield, but modifications to existing protocols are often based on personal experience rather than systematic testing. Here, [...] Read more.
Rapid and cost-effective retrieval of endogenous DNA from ancient specimens remains a limiting factor in palaeogenomic research. Many methods have been developed to increase ancient DNA yield, but modifications to existing protocols are often based on personal experience rather than systematic testing. Here, we present a new silica column-based extraction protocol, where optimizations were tested in controlled experiments. Using relatively well-preserved permafrost samples, we tested the efficiency of pretreatment of bone and tooth powder with a bleach wash and a predigestion step. We also tested the recovery efficiency of MinElute and QIAquick columns, as well as Vivaspin columns with two molecular weight cut-off values. Finally, we tested the effect of uracil-treatment with two different USER enzyme concentrations. We find that neither bleach wash combined with a predigestion step, nor predigestion by itself, significantly increased sequencing efficiency. Initial results, however, suggest that MinElute columns are more efficient for ancient DNA extractions than QIAquick columns, whereas different molecular weight cut-off values in centrifugal concentrator columns did not have an effect. Uracil treatments are effective at removing DNA damage even at concentrations of 0.15 U/µL (as compared to 0.3 U/µL) of ancient DNA extracts. Full article
(This article belongs to the Special Issue State-of-the-Art in Forensic Genetics)
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Article
Robust Mutation Profiling of SARS-CoV-2 Variants from Multiple Raw Illumina Sequencing Data with Cloud Workflow
Genes 2022, 13(4), 686; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040686 - 13 Apr 2022
Cited by 1 | Viewed by 792
Abstract
Several variants of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are emerging all over the world. Variant surveillance from genome sequencing has become crucial to determine if mutations in these variants are rendering the virus more infectious, potent, or resistant to [...] Read more.
Several variants of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are emerging all over the world. Variant surveillance from genome sequencing has become crucial to determine if mutations in these variants are rendering the virus more infectious, potent, or resistant to existing vaccines and therapeutics. Meanwhile, analyzing many raw sequencing data repeatedly with currently available code-based bioinformatics tools is tremendously challenging to be implemented in this unprecedented pandemic time due to the fact of limited experts and computational resources. Therefore, in order to hasten variant surveillance efforts, we developed an installation-free cloud workflow for robust mutation profiling of SARS-CoV-2 variants from multiple Illumina sequencing data. Herein, 55 raw sequencing data representing four early SARS-CoV-2 variants of concern (Alpha, Beta, Gamma, and Delta) from an open-access database were used to test our workflow performance. As a result, our workflow could automatically identify mutated sites of the variants along with reliable annotation of the protein-coding genes at cost-effective and timely manner for all by harnessing parallel cloud computing in one execution under resource-limitation settings. In addition, our workflow can also generate a consensus genome sequence which can be shared with others in public data repositories to support global variant surveillance efforts. Full article
(This article belongs to the Special Issue Bioinformatics Analysis for Diseases)
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Article
High Concentration or Combined Treatment of Antisense Oligonucleotides for Spinal Muscular Atrophy Perturbed SMN2 Splicing in Patient Fibroblasts
Genes 2022, 13(4), 685; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040685 - 13 Apr 2022
Viewed by 584
Abstract
Spinal muscular atrophy (SMA) is caused by survival motor neuron 1 SMN1 deletion. The survival motor neuron 2 (SMN2) encodes the same protein as SMN1 does, but it has a splicing defect of exon 7. Some antisense oligonucleotides (ASOs) have been proven to [...] Read more.
Spinal muscular atrophy (SMA) is caused by survival motor neuron 1 SMN1 deletion. The survival motor neuron 2 (SMN2) encodes the same protein as SMN1 does, but it has a splicing defect of exon 7. Some antisense oligonucleotides (ASOs) have been proven to correct this defect. One of these, nusinersen, is effective in SMA-affected infants, but not as much so in advanced-stage patients. Furthermore, the current regimen may exhibit a ceiling effect. To overcome these problems, high-dose ASOs or combined ASOs have been explored. Here, using SMA fibroblasts, we examined the effects of high-concentration ASOs and of combining two ASOs. Three ASOs were examined: one targeting intronic splicing suppressor site N1 (ISS-N1) in intron 7, and two others targeting the 3′ splice site and 5′ region of exon 8. In our experiments on all ASO types, a low or intermediate concentration (50 or 100 nM) showed better splicing efficiency than a high concentration (200 nM). In addition, a high concentration of each ASO created a cryptic exon in exon 6. When a mixture of two different ASOs (100 nM each) was added to the cells, the cryptic exon was included in the mRNA. In conclusion, ASOs at a high concentration or used in combination may show less splicing correction and cryptic exon creation. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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Article
PanelDesign: Integrating Epidemiological Information into the Design of Diagnostic NGS Gene Panels
Genes 2022, 13(4), 684; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040684 - 13 Apr 2022
Viewed by 388
Abstract
We report upon PanelDesign, a framework to support the design of diagnostic next generation DNA sequencing panels with epidemiological information. Two publicly available resources, namely Genomics England PanelApp and Orphadata, were combined into a single data set to allow genes in a given [...] Read more.
We report upon PanelDesign, a framework to support the design of diagnostic next generation DNA sequencing panels with epidemiological information. Two publicly available resources, namely Genomics England PanelApp and Orphadata, were combined into a single data set to allow genes in a given NGS panel to be ranked according to the frequency of the associated diseases, thereby highlighting potential core genes as defined by the Eurogenetest/ESHG guidelines for diagnostic next generation DNA sequencing. In addition, PanelDesign can be used to evaluate the contribution of different genes to a given disease following ACMG (American College of Medical Genetics) technical standards. Full article
(This article belongs to the Special Issue Genetic Tests)
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