Genes

11 pages, 1563 KiB

Open AccessEditor’s ChoiceArticle

A Novel Non-Allelic Homologous Recombination Event in a Parent with an 11;22 Reciprocal Translocation Leading to 22q11.2 Deletion Syndrome

by Steven Pastor, Oanh Tran, Daniel E. McGinn, T. Blaine Crowley, Elaine H. Zackai, Donna M. McDonald-McGinn and Beverly S. Emanuel

Genes 2022, 13(9), 1668; https://doi.org/10.3390/genes13091668 - 17 Sep 2022

Viewed by 3307

Abstract

The most prevalent microdeletion in the human population occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has eluded characterization due to a combination of size, regional complexity, and haplotype diversity. To further complicate matters, [...] Read more.

The most prevalent microdeletion in the human population occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has eluded characterization due to a combination of size, regional complexity, and haplotype diversity. To further complicate matters, it is not well represented in the human reference genome. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo, hemizygous deletion approximately 3 Mbp in size occurring by non-allelic homologous recombination (NAHR) mediated by the LCR22s. The ability to fully delineate an individual’s 22q11.2 regional structure will likely be important for studies designed to assess an unaffected individual’s risk for generating rearrangements in germ cells, potentially leading to offspring with 22q11.2DS. Towards understanding these risk factors, optical mapping has been previously employed to successfully elucidate the structure and variation of LCR22s across 30 families affected by 22q11.2DS. The father in one of these families carries a t(11;22)(q23;q11) translocation. Surprisingly, it was determined that he is the parent-of-deletion-origin. NAHR, which occurred between his der(22) and intact chromosome 22, led to a 22q11.2 deletion in his affected child. The unaffected sibling of the proband with 22q11.2DS inherited the father’s normal chromosome 22, which did not aberrantly recombine. This unexpected observation definitively shows that haplotypes that engage in NAHR can also be inherited intact. This study is the first to identify all structures involving a rearranged chromosome 22 that also participates in NAHR leading to a 22q11.2 deletion. Full article

(This article belongs to the Special Issue 22q11.2 Deletion Syndrome)

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18 pages, 3384 KiB

Open AccessEditor’s ChoiceArticle

Nonsense-Mediated Decay Targeted RNA (ntRNA): Proposal of a ntRNA–miRNA–lncRNA Triple Regulatory Network Usable as Biomarker of Prognostic Risk in Patients with Kidney Cancer

by Zhiyue Zhou, Fuyan Hu, Dan Huang, Qingjia Chi and Nelson L. S. Tang

Genes 2022, 13(9), 1656; https://doi.org/10.3390/genes13091656 - 15 Sep 2022

Viewed by 2857

Abstract

The most prevalent subtype of renal cell carcinoma (RCC), kidney renal clear cell carcinoma (KIRC) may be associated with a poor prognosis in a high number of cases, with a stage-specific prognostic stratification currently in use. No reliable biomarkers have been utilized so [...] Read more.

The most prevalent subtype of renal cell carcinoma (RCC), kidney renal clear cell carcinoma (KIRC) may be associated with a poor prognosis in a high number of cases, with a stage-specific prognostic stratification currently in use. No reliable biomarkers have been utilized so far in clinical practice despite the efforts in biomarker research in the last years. Nonsense-mediated mRNA decay (NMD) is a critical safeguard against erroneous transcripts, particularly mRNA transcripts containing premature termination codons (called nonsense-mediated decay targeted RNA, ntRNA). In this study, we first characterized 296 differentially expressed ntRNAs that were independent of the corresponding gene, 261 differentially expressed miRNAs, and 4653 differentially expressed lncRNAs. Then, we constructed a hub ntRNA–miRNA–lncRNA triple regulatory network associated with the prognosis of KIRC. Moreover, the results of immune infiltration analysis indicated that this network may influence the changes of the tumor immune microenvironment. A prognostic model derived from the genes and immune cells associated with the network was developed to distinguish between high- and low-risk patients, which was a better prognostic than other models, constructed using different biomarkers. Additionally, correlation of methylation and ntRNAs in the network suggested that some ntRNAs were regulated by methylation, which is helpful to further study the causes of abnormal expression of ntRNAs. In conclusion, this study highlighted the possible clinical implications of ntRNA functions in KIRC, proposing potential significant biomarkers that could be utilized to define the prognosis and design personalized treatment plans in kidney cancer management in the next future. Full article

(This article belongs to the Section Bioinformatics)

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4 pages, 200 KiB

Open AccessEditor’s ChoiceEditorial

Evolutionary New Genes in a Growing Paradigm

by Esther Betrán and Manyuan Long

Genes 2022, 13(9), 1605; https://doi.org/10.3390/genes13091605 - 8 Sep 2022

Cited by 3 | Viewed by 2075

Abstract

How new genes evolve has become an interesting problem in biology, particularly in evolutionary biology [...] Full article

(This article belongs to the Special Issue How Do New Genes Originate and Evolve?)

3 pages, 191 KiB

Open AccessEditor’s ChoiceEditorial

The Future of Pharmacogenomics Requires New Discoveries and Innovative Education

by Emiliano Giardina and Stefania Zampatti

Genes 2022, 13(9), 1575; https://doi.org/10.3390/genes13091575 - 2 Sep 2022

Cited by 2 | Viewed by 2308

Abstract

Since the beginning of pharmacology, several variations in responses to drugs have been recorded [...] Full article

(This article belongs to the Special Issue Pharmacogenomics: Precision Medicine and Drug Response)

15 pages, 3128 KiB

Open AccessEditor’s ChoiceArticle

Transcriptomic Analysis Reveals the Correlation between End-of-Day Far Red Light and Chilling Stress in Setaria viridis

by Shilei Sun, Qingjia Liu, Xiuru Dai and Xianglan Wang

Genes 2022, 13(9), 1565; https://doi.org/10.3390/genes13091565 - 31 Aug 2022

Cited by 1 | Viewed by 1988

Abstract

Low temperature and end-of-day far-red (EOD-FR) light signaling are two key factors limiting plant production and geographical location worldwide. However, the transcriptional dynamics of EOD-FR light conditions during chilling stress remain poorly understood. Here, we performed a comparative RNA-Seq-based approach to identify differentially [...] Read more.

Low temperature and end-of-day far-red (EOD-FR) light signaling are two key factors limiting plant production and geographical location worldwide. However, the transcriptional dynamics of EOD-FR light conditions during chilling stress remain poorly understood. Here, we performed a comparative RNA-Seq-based approach to identify differentially expressed genes (DEGs) related to EOD-FR and chilling stress in Setaria viridis. A total of 7911, 324, and 13431 DEGs that responded to low temperature, EOD-FR and these two stresses were detected, respectively. Further DEGs analysis revealed that EOD-FR may enhance cold tolerance in plants by regulating the expression of genes related to cold tolerance. The result of weighted gene coexpression network analysis (WGCNA) using 13431 nonredundant DEGs exhibited 15 different gene network modules. Interestingly, a CO-like transcription factor named BBX2 was highly expressed under EOD-FR or chilling conditions. Furthermore, we could detect more expression levels when EOD-FR and chilling stress co-existed. Our dataset provides a valuable resource for the regulatory network involved in EOD-FR signaling and chilling tolerance in C₄ plants. Full article

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

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13 pages, 10742 KiB

Open AccessEditor’s ChoiceArticle

Identification of Differentially Expressed Genes and Prediction of Expression Regulation Networks in Dysfunctional Endothelium

by Fang Cheng, Yujie Zeng, Minzhu Zhao, Ying Zhu, Jianbo Li and Renkuan Tang

Genes 2022, 13(9), 1563; https://doi.org/10.3390/genes13091563 - 30 Aug 2022

Viewed by 2598

Abstract

The detection of early coronary atherosclerosis (ECA) is still a challenge and the mechanism of endothelial dysfunction remains unclear. In the present study, we aimed to identify differentially expressed genes (DEGs) and the regulatory network of miRNAs as well as TFs in dysfunctional [...] Read more.

The detection of early coronary atherosclerosis (ECA) is still a challenge and the mechanism of endothelial dysfunction remains unclear. In the present study, we aimed to identify differentially expressed genes (DEGs) and the regulatory network of miRNAs as well as TFs in dysfunctional endothelium to elucidate the possible pathogenesis of ECA and find new potential markers. The GSE132651 data set of the GEO database was used for the bioinformatic analysis. Principal component analysis (PCA), the identification of DEGs, correlation analysis between significant DEGs, the prediction of regulatory networks of miRNA and transcription factors (TFs), the validation of the selected significant DEGs, and the receiver operating characteristic (ROC) curve analysis as well as area under the curve (AUC) values were performed. We identified ten genes with significantly upregulated signatures and thirteen genes with significantly downregulated signals. Following this, we found twenty-two miRNAs regulating two or more DEGs based on the miRNA–target gene regulatory network. TFs with targets ≥ 10 were E2F1, RBPJ, SSX3, MMS19, POU3F3, HOXB5, and KLF4. Finally, three significant DEGs (TOX, RasGRP3, TSPAN13) were selected to perform validation experiments. Our study identified TOX, RasGRP3, and TSPAN13 in dysfunctional endothelium and provided potential biomarkers as well as new insights into the possible molecular mechanisms of ECA. Full article

(This article belongs to the Special Issue Bioinformatics of Disease Genes)

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18 pages, 2885 KiB

Open AccessEditor’s ChoiceArticle

Reducing Virus Infection Risk in Space Environments through Nutrient Supplementation

by Hui Li, Ya-Wen Xue, Yuan Quan and Hong-Yu Zhang

Genes 2022, 13(9), 1536; https://doi.org/10.3390/genes13091536 - 26 Aug 2022

Cited by 1 | Viewed by 2749

Abstract

Space exploration has brought many challenges to human physiology. In order to evaluate and reduce possible pathological reactions triggered by space environments, we conducted bioinformatics analyses on the methylation data of the Mars 520 mission and human transcriptome data in the experiment simulating [...] Read more.

Space exploration has brought many challenges to human physiology. In order to evaluate and reduce possible pathological reactions triggered by space environments, we conducted bioinformatics analyses on the methylation data of the Mars 520 mission and human transcriptome data in the experiment simulating gravity changes. The results suggest that gene expression levels and DNA methylation levels were changed under the conditions of isolation and gravity changes, and multiple viral infection-related pathways were found in the enrichment analysis results of changed genes including Epstein Barr virus (EBV) infection, Hepatitis B virus (HBV) infection, Herpes simplex virus (HSV) infection and Kaposi’s sarcoma-associated herpesvirus (KHSV) infection. In this study, we found that Epigallocatechin-3-gallate (EGCG) and vitamin D are helpful in reducing viral infection risk. In addition, the causal associations between nutrients and viral infections were calculated using Two sample Mendelian Randomization (2SMR) method, the results indicated that vitamin D can reduce EBV infection and HBV infection risk. In summary, our study suggests that space environments increase the risk of human viral infection, which may be reduced by supplementing EGCG and vitamin D. These results can be used to formulate medical plans for astronauts, which have practical application value for future space exploration. Full article

(This article belongs to the Section Bioinformatics)

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10 pages, 1748 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of the Impact of the Peregrine Falcon (Falco peregrinus peregrinus) Reintroduction Process on Captive-Bred Population

by Karol O. Puchała, Zuzanna Nowak-Życzyńska, Sławomir Sielicki and Wanda Olech

Genes 2022, 13(8), 1487; https://doi.org/10.3390/genes13081487 - 20 Aug 2022

Cited by 1 | Viewed by 2592

Abstract

The main objective of this study was to determine the impact of increased demand for peregrine falcons via breeding (mainly Polish, Czech, German and Slovak) on the genetic structure of the birds. In the analysis, 374 specimens from six countries were sampled in [...] Read more.

The main objective of this study was to determine the impact of increased demand for peregrine falcons via breeding (mainly Polish, Czech, German and Slovak) on the genetic structure of the birds. In the analysis, 374 specimens from six countries were sampled in 2008–2019 (omitting 2009), and all the birds analyzed were released into the wild as part of the Polish reintroduction program. The assessment of genetic variation was based on a well-known panel of 10 microsatellite markers described for the species. We calculated a fixation index for the samples from each year, and based on this, we determined the level of inbreeding. We also performed an analysis using the Bayesian cluster method, assuming that 1–19 hypothetical populations would define the division that best fit the samples. The most probable division was into two groups; in the first group, the samples from individuals delivered in 2013 were most often segregated; moreover, in this year, a jump in inbreeding, expressed by the fixation index, was observed. Full article

(This article belongs to the Special Issue Genetic Structure of World Animal Populations)

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12 pages, 1237 KiB

Open AccessEditor’s ChoiceArticle

Investigation of Linear Amplification Using Abasic Site-Containing Primers Coupled to Routine STR Typing for LT-DNA Analysis

by Xiaoqin Qian, Zhimin Li, Zhihan Zhou, Jinglei Qian, Yining Yao, Chengchen Shao, Qiqun Tang and Jianhui Xie

Genes 2022, 13(8), 1386; https://doi.org/10.3390/genes13081386 - 4 Aug 2022

Viewed by 2454

Abstract

Obtaining a full short tandem repeat (STR) profile from a low template DNA (LT-DNA) still presents a challenge for conventional methods due to significant stochastic effects and polymerase slippage. A novel amplification method with a lower cost and higher accuracy is required to [...] Read more.

Obtaining a full short tandem repeat (STR) profile from a low template DNA (LT-DNA) still presents a challenge for conventional methods due to significant stochastic effects and polymerase slippage. A novel amplification method with a lower cost and higher accuracy is required to improve the DNA amount. Previous studies suggested that DNA polymerases without bypass activity could not perform processive DNA synthesis beyond abasic sites in vitro and our results showed a lack of bypass activity for Phusion, Pfu and KAPA DNA polymerases in this study. Based on this feature, we developed a novel linear amplification method, termed Linear Aamplification for double-stranded DNA using primers with abasic sites near 3′ end (abLAFD), to limit the replication error. The amplification efficiency was evaluated by qPCR analysis with a result of approximately a 130-fold increase in target DNA. In a LT-DNA analysis, the abLAFD method can be employed as a pre-PCR. Similar to nested PCRs, primer sets used for the abLAFD method were designed as external primers suitable for commercial multiplex STR amplification assays. The practical performance of the abLAFD method was evaluated by coupling it to a routine PP21 STR analysis using 50 pg and 25 pg DNA. Compared to reference profiles, all abLAFD profiles showed significantly recovered alleles, increased average peak height and heterozygote balance with a comparable stutter ratio. Altogether, our results support the theory that the abLAFD method is a promising strategy coupled to STR typing for forensic LT-DNA analysis. Full article

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

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20 pages, 2643 KiB

Open AccessEditor’s ChoiceArticle

Genetic Analysis and Status of Brown Bear Sub-Populations in Three National Parks of Greece Functioning as Strongholds for the Species’ Conservation

by Tzoulia-Maria Tsalazidou-Founta, Evangelia A. Stasi, Maria Samara, Yorgos Mertzanis, Maria Papathanassiou, Pantelis G. Bagos, Spyros Psaroudas, Vasiliki Spyrou, Yorgos Lazarou, Athanasios Tragos, Yannis Tsaknakis, Elpida Grigoriadou, Athanasios Korakis, Maria Satra, Charalambos Billinis and ARCPROM project

Genes 2022, 13(8), 1388; https://doi.org/10.3390/genes13081388 - 4 Aug 2022

Cited by 2 | Viewed by 2962

Abstract

In order to optimize the appropriate conservation actions for the brown bear (Ursus arctos L.) population in Greece, we estimated the census (Nc) and effective (Ne) population size as well as the genetic status of brown bear sub-populations in three National Parks [...] Read more.

In order to optimize the appropriate conservation actions for the brown bear (Ursus arctos L.) population in Greece, we estimated the census (Nc) and effective (Ne) population size as well as the genetic status of brown bear sub-populations in three National Parks (NP): Prespa (MBPNP), Pindos (PINDNP), and Rhodopi (RMNP). The Prespa and Pindos sub-populations are located in western Greece and the Rhodopi population is located in eastern Greece. We extracted DNA from 472 hair samples and amplified through PCR 10 microsatellite loci. In total, 257 of 472 samples (54.5%) were genotyped for 6–10 microsatellite loci. Genetic analysis revealed that the Ne was 35, 118, and 61 individuals in MBPNP, PINDNP, and RMNP, respectively, while high levels of inbreeding were found in Prespa and Rhodopi but not in Pindos. Moreover, analysis of genetic structure showed that the Pindos population is genetically distinct, whereas Prespa and Rhodopi show mutual overlaps. Finally, we found a notable gene flow from Prespa to Rhodopi (10.19%) and from Rhodopi to Prespa (14.96%). Therefore, targeted actions for the conservation of the bears that live in the abovementioned areas must be undertaken, in order to ensure the species’ viability and to preserve the corridors that allow connectivity between the bear sub-populations in Greece. Full article

(This article belongs to the Special Issue Genetics in Wildlife and Fisheries Conservation and Management)

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11 pages, 732 KiB

Open AccessEditor’s ChoiceArticle

TIRAP Rs8177376, Rs611953, Rs3802814, and Rs8177374 Polymorphisms and Their Association with Cervical Cancer Phenotype and Prognosis

by Justina Bekampytė, Aistė Savukaitytė, Agnė Bartnykaitė, Rasa Ugenskienė, Eglė Žilienė, Arturas Inčiūra and Elona Juozaitytė

Genes 2022, 13(8), 1365; https://doi.org/10.3390/genes13081365 - 29 Jul 2022

Cited by 1 | Viewed by 1720

Abstract

Cervical cancer is one of the most common cancers in women worldwide, which is typically caused by human papillomavirus (HPV). Usually, the toll-like receptor (TLR) signaling pathways eliminate the virus from the organism, but in some cases, persistent infection may develop. Unfortunately, the [...] Read more.

Cervical cancer is one of the most common cancers in women worldwide, which is typically caused by human papillomavirus (HPV). Usually, the toll-like receptor (TLR) signaling pathways eliminate the virus from the organism, but in some cases, persistent infection may develop. Unfortunately, the mechanism of immune tolerance is still unclear. Therefore, this study aimed to analyze TIRAP rs8177376, rs611953, rs3802814, and rs8177374 polymorphisms and to identify their impact on cervical cancer phenotype and prognosis. This study included 172 cervical cancer patients. Genotyping was performed using the PCR-RFLP assay. Univariate and multivariate logistic regression and Cox′s regression models were applied for statistical analysis. The results revealed that older age at the time of diagnosis was statistically linked with the rs8177376 T allele (OR = 2.901, 95% Cl 1.750–4.808, p = 0.000) and the rs611953 G allele (OR = 3.258, 95% Cl 1.917–5.536, p = 0.000). Moreover, the T allele of rs8177376 (OR = 0.424, 95% Cl 0.220–0.816, p = 0.010) was found to be statistically associated with the lower tumor grade. Thus, TIRAP polymorphisms might be employed in the future as potential biomarkers for determining the phenotype and prognosis of cervical cancer. Full article

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

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11 pages, 41123 KiB

Open AccessEditor’s ChoiceArticle

PPP1R7 Is a Novel Translocation Partner of CBFB via t(2;16)(q37;q22) in Acute Myeloid Leukemia

by Lulu Wang, Wei Wang, Hannah C. Beird, Xueqian Cheng, Hong Fang, Guilin Tang, Gokce A. Toruner, C. Cameron Yin, M. James You, Ghayas C. Issa, Gautam Borthakur, Guang Peng, Joseph D. Khoury, L. Jeffrey Medeiros and Zhenya Tang

Genes 2022, 13(8), 1367; https://doi.org/10.3390/genes13081367 - 29 Jul 2022

Viewed by 2986

Abstract

In a subset of acute myeloid leukemia (AML) cases, the core binding factor beta subunit gene (CBFB) was rearranged via inv(16)(p13.1q22) or t(16;16)(p13.1;q22), in which the smooth muscle myosin heavy chain 11 gene (MYH11) was the partner (CBFB::MYH11 [...] Read more.

In a subset of acute myeloid leukemia (AML) cases, the core binding factor beta subunit gene (CBFB) was rearranged via inv(16)(p13.1q22) or t(16;16)(p13.1;q22), in which the smooth muscle myosin heavy chain 11 gene (MYH11) was the partner (CBFB::MYH11). Rare variants of CBFB rearrangement occurring via non-classic chromosomal aberrations have been reported, such as t(1;16), t(2;16), t(3;16), t(5;16), and t(16;19), but the partners of CBFB have not been characterized. We report a case of AML with a complex karyotype, including t(2;16)(q37;q22), in which the protein phosphatase 1 regulatory subunit 7 gene (PPP1R7) at chromosome 2q37 was rearranged with CBFB (CBFB::PPP1R7). This abnormality was inconspicuous by conventional karyotype and interphase fluorescence in situ hybridization (FISH), thus leading to an initial interpretation of inv(16)(p13.1q22); however, metaphase FISH showed that the CBFB rearrangement involved chromosome 2. Using whole genome and Sanger sequencing, the breakpoints were identified as being located in intron 5 of CBFB and intron 7 of PPP1R7. A microhomology of CAG was found in the break and reconnection sites of CBFB and PPP1R7, thus supporting the formation of CBFB::PPP1R7 by microhomology-mediated end joining. Full article

(This article belongs to the Section Cytogenomics)

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13 pages, 820 KiB

Open AccessEditor’s ChoiceArticle

Web-Based Protein Interactions Calculator Identifies Likely Proteome Coevolution with Alzheimer’s Disease-Associated Proteins

by Katrisa M. Ward, Brandon D. Pickett, Mark T. W. Ebbert, John S. K. Kauwe and Justin B. Miller

Genes 2022, 13(8), 1346; https://doi.org/10.3390/genes13081346 - 27 Jul 2022

Cited by 1 | Viewed by 2493

Abstract

Protein–protein functional interactions arise from either transitory or permanent biomolecular associations and often lead to the coevolution of the interacting residues. Although mutual information has traditionally been used to identify coevolving residues within the same protein, its application between coevolving proteins remains largely [...] Read more.

Protein–protein functional interactions arise from either transitory or permanent biomolecular associations and often lead to the coevolution of the interacting residues. Although mutual information has traditionally been used to identify coevolving residues within the same protein, its application between coevolving proteins remains largely uncharacterized. Therefore, we developed the Protein Interactions Calculator (PIC) to efficiently identify coevolving residues between two protein sequences using mutual information. We verified the algorithm using 2102 known human protein interactions and 233 known bacterial protein interactions, with a respective 1975 and 252 non-interacting protein controls. The average PIC score for known human protein interactions was 4.5 times higher than non-interacting proteins (p = 1.03 × 10⁻¹⁰⁸) and 1.94 times higher in bacteria (p = 1.22 × 10⁻³⁵). We then used the PIC scores to determine the probability that two proteins interact. Using those probabilities, we paired 37 Alzheimer’s disease-associated proteins with 8608 other proteins and determined the likelihood that each pair interacts, which we report through a web interface. The PIC had significantly higher sensitivity and residue-specific resolution not available in other algorithms. Therefore, we propose that the PIC can be used to prioritize potential protein interactions, which can lead to a better understanding of biological processes and additional therapeutic targets belonging to protein interaction groups. Full article

(This article belongs to the Special Issue Genetics: Insights into Alzheimer’s Disease)

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13 pages, 1907 KiB

Open AccessEditor’s ChoiceReview

Themes of Biological Inheritance in Early Nineteenth Century Sheep Breeding as Revealed by J. M. Ehrenfels

by Péter Poczai and Jorge A. Santiago-Blay

Genes 2022, 13(8), 1311; https://doi.org/10.3390/genes13081311 - 23 Jul 2022

Cited by 1 | Viewed by 3057

Abstract

Among the so-called sheep breeders interested in biological inheritance in the late eighteenth and early nineteenth centuries and well before Gregor Johann Mendel, J. M. Ehrenfels (1767–1843) produced some of the most cogent writings on the subject. Although earlier in his career Ehrenfels [...] Read more.

Among the so-called sheep breeders interested in biological inheritance in the late eighteenth and early nineteenth centuries and well before Gregor Johann Mendel, J. M. Ehrenfels (1767–1843) produced some of the most cogent writings on the subject. Although earlier in his career Ehrenfels was a strong advocate of environmental factors as influencers on the appearance of organisms, as a result of his discussions with Imre Festetics, he became convinced that whatever is passed from parents to progeny is more important and it is dependent on a “genetic force, the mother of all living things”. The sheep breeders kept issues of inheritance at the forefront of the Central European cultural context late into the nineteenth century. Full article

(This article belongs to the Special Issue Molecular Mechanism Analysis of Important Traits and Breeding of New Breeds of Sheep)

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11 pages, 308 KiB

Open AccessEditor’s ChoiceArticle

Genetic Polymorphism at 15 Codons of the Prion Protein Gene in 156 Goats from Romania

by Maria Rodica Gurau, Elena Negru, Teodor Ionescu, Anca Amalia Udriste, Călina Petruța Cornea and Stelian Baraitareanu

Genes 2022, 13(8), 1316; https://doi.org/10.3390/genes13081316 - 23 Jul 2022

Cited by 1 | Viewed by 1995

Abstract

Background: The variability of prion protein gene (PRNP) codons and the frequency of alleles (K222, D146, and S146) that appear to confer genetic resistance to classical scrapie are still unknown in several goat populations/breeds prevalent in Romania. This work aims to [...] Read more.

Background: The variability of prion protein gene (PRNP) codons and the frequency of alleles (K222, D146, and S146) that appear to confer genetic resistance to classical scrapie are still unknown in several goat populations/breeds prevalent in Romania. This work aims to assess the genetic polymorphism at 15 PRNP codons in Romanian goat populations to inform the development of goat breeding programs for scrapie resistance. Methods: Whole blood and hair follicles from Carpathian (50), French Alpine (53), and Banat’s White (53) breed goats were sampled to extract genomic DNA for genetic analyses and Sanger sequencing. In the targeted goat groups, one classical scrapie-positive Banat’s White goat was included. Results: The codons without polymorphisms were G37G, W102W, N146N, R151R, S173S, and I218I. The following non-synonymous polymorphisms of PRNP were recorded: P110P, P110S, P110T, T110T, G127G, G127S, I142I, I142M, T142I, H143H, P143P, R143R, R154R, H154R, P168P, Q168Q, Q211Q, Q211R, Q222Q, H222Q, K222K, S240S, P240P, P240S, and S240P. Conclusions: PRNP polymorphism was recorded in 60% (9/15) of codons. The scrapie-positive Banat’s White goat had G37G, W102W, T110T, G127G, I142I, H143H, N146N, R151R, R154R, P168P, S173S, R211R, I218I, Q222Q, and S240S. The K222 allele had a frequency of 6% (3/50) in Carpathian, 9.43% (5/53) in Banat’s White, and 15.09% (8/53) in French Alpine. Therefore, the polymorphisms detected in this sample of Romanian goat breeds are too rare to design a breeding program at the current time. Full article

(This article belongs to the Special Issue From QTL Mapping to QTG and QTN Identification)

17 pages, 1404 KiB

Open AccessEditor’s ChoiceArticle

Identification of New Toxicity Mechanisms in Drug-Induced Liver Injury through Systems Pharmacology

by Aurelio A. Moya-García, Andrés González-Jiménez, Fernando Moreno, Camilla Stephens, María Isabel Lucena and Juan A. G. Ranea

Genes 2022, 13(7), 1292; https://doi.org/10.3390/genes13071292 - 21 Jul 2022

Cited by 1 | Viewed by 2601

Abstract

Among adverse drug reactions, drug-induced liver injury presents particular challenges because of its complexity, and the underlying mechanisms are still not completely characterized. Our knowledge of the topic is limited and based on the assumption that a drug acts on one molecular target. [...] Read more.

Among adverse drug reactions, drug-induced liver injury presents particular challenges because of its complexity, and the underlying mechanisms are still not completely characterized. Our knowledge of the topic is limited and based on the assumption that a drug acts on one molecular target. We have leveraged drug polypharmacology, i.e., the ability of a drug to bind multiple targets and thus perturb several biological processes, to develop a systems pharmacology platform that integrates all drug–target interactions. Our analysis sheds light on the molecular mechanisms of drugs involved in drug-induced liver injury and provides new hypotheses to study this phenomenon. Full article

(This article belongs to the Special Issue Feature Papers in Technologies and Resources for Genetics)

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15 pages, 1644 KiB

Open AccessEditor’s ChoiceArticle

Heritability Analyses Uncover Shared Genetic Effects of Lung Function and Change over Time

by Donghe Li, Woojin Kim, Jahoon An, Soriul Kim, Seungku Lee, Ahra Do, Wonji Kim, Sanghun Lee, Dankyu Yoon, Kwangbae Lee, Seounguk Ha, Edwin K. Silverman, Michael Cho, Chol Shin and Sungho Won

Genes 2022, 13(7), 1261; https://doi.org/10.3390/genes13071261 - 15 Jul 2022

Cited by 1 | Viewed by 2320

Abstract

Genetic influence on lung functions has been identified in previous studies; however, the relative longitudinal effects of genetic factors and their interactions with smoking on lung function remain unclear. Here, we identified the longitudinal effects of genetic variants on lung function by determining [...] Read more.

Genetic influence on lung functions has been identified in previous studies; however, the relative longitudinal effects of genetic factors and their interactions with smoking on lung function remain unclear. Here, we identified the longitudinal effects of genetic variants on lung function by determining single nucleotide polymorphism (SNP) heritability and genetic correlations, and by analyzing interactions with smoking. Subject-specific means and annual change rates were calculated for eight spirometric measures obtained from 6622 Korean adults aged 40–69 years every two years for 14 years, and their heritabilities were estimated separately. Statistically significant (p < 0.05) heritability for the subject-specific means of all spirometric measures (8~32%) and change rates of forced expiratory volume in 1 s to forced vital capacity ratio (FEV₁/FVC; 16%) and post-bronchodilator FEV₁/FVC (17%) were detected. Significant genetic correlations of the change rate with the subject-specific mean were observed for FEV₁/FVC (

ρ_{g}

= 0.64) and post-bronchodilator FEV₁/FVC (

ρ_{g}

= 0.47). Furthermore, post-bronchodilator FEV₁/FVC showed significant heritability of SNP-by-smoking interaction (

h_{G X S}^{2}

= 0.4) for the annual change rate. The GWAS also detected genome-wide significant SNPs for FEV₁ (rs4793538), FEV₁/FVC (rs2704589, rs62201158, and rs9391733), and post-bronchodilator FEV₁/FVC (rs2445936). We found statistically significant evidence of heritability role on the change in lung function, and this was shared with the effects on cross-sectional measurements. We also found some evidence of interaction with smoking for the change of lung function. Full article

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

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12 pages, 948 KiB

Open AccessEditor’s ChoiceArticle

Multi-Cell-Type Openness-Weighted Association Studies for Trait-Associated Genomic Segments Prioritization

by Shuang Song, Hongyi Sun, Jun S. Liu and Lin Hou

Genes 2022, 13(7), 1220; https://doi.org/10.3390/genes13071220 - 8 Jul 2022

Viewed by 2090

Abstract

Openness-weighted association study (OWAS) is a method that leverages the in silico prediction of chromatin accessibility to prioritize genome-wide association studies (GWAS) signals, and can provide novel insights into the roles of non-coding variants in complex diseases. A prerequisite to apply OWAS is [...] Read more.

Openness-weighted association study (OWAS) is a method that leverages the in silico prediction of chromatin accessibility to prioritize genome-wide association studies (GWAS) signals, and can provide novel insights into the roles of non-coding variants in complex diseases. A prerequisite to apply OWAS is to choose a trait-related cell type beforehand. However, for most complex traits, the trait-relevant cell types remain elusive. In addition, many complex traits involve multiple related cell types. To address these issues, we develop OWAS-joint, an efficient framework that aggregates predicted chromatin accessibility across multiple cell types, to prioritize disease-associated genomic segments. In simulation studies, we demonstrate that OWAS-joint achieves a greater statistical power compared to OWAS. Moreover, the heritability explained by OWAS-joint segments is higher than or comparable to OWAS segments. OWAS-joint segments also have high replication rates in independent replication cohorts. Applying the method to six complex human traits, we demonstrate the advantages of OWAS-joint over a single-cell-type OWAS approach. We highlight that OWAS-joint enhances the biological interpretation of disease mechanisms, especially for non-coding regions. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

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15 pages, 2145 KiB

Open AccessEditor’s ChoiceArticle

Pilot Study Showing Feasibility of Phosphoproteomic Profiling of Pathway-Level Molecular Alterations in Barrett’s Esophagus

by Jarrod Moore, Ryan Hekman, Benjamin C. Blum, Matthew Lawton, Sylvain Lehoux, Matthew Stachler, Douglas Pleskow, Mandeep S. Sawhney, Richard D. Cummings, Andrew Emili and Alia Qureshi

Genes 2022, 13(7), 1215; https://doi.org/10.3390/genes13071215 - 7 Jul 2022

Viewed by 2747

Abstract

(1) Background: Barrett’s esophagus is a major risk factor for esophageal adenocarcinoma. In this pilot study, we employed precision mass spectrometry to map global (phospho)protein perturbations in Barrett’s esophagus lesions and adjacent normal tissue to glean insights into disease progression. (2) Methods: Biopsies [...] Read more.

(1) Background: Barrett’s esophagus is a major risk factor for esophageal adenocarcinoma. In this pilot study, we employed precision mass spectrometry to map global (phospho)protein perturbations in Barrett’s esophagus lesions and adjacent normal tissue to glean insights into disease progression. (2) Methods: Biopsies were collected from two small but independent cohorts. Comparative analyses were performed between Barrett’s esophagus samples and adjacent matched (normal) tissues from patients with known pathology, while specimens from healthy patients served as additional controls. (3) Results: We identified and quantified 6810 proteins and 6395 phosphosites in the discovery cohort, revealing hundreds of statistically significant differences in protein abundances and phosphorylation states. We identified a robust proteomic signature that accurately classified the disease status of samples from the independent patient cohorts. Pathway-level analysis of the phosphoproteomic profiles revealed the dysregulation of specific cellular processes, including DNA repair, in Barrett’s esophagus relative to paired controls. Comparative analysis with previously published transcriptomic profiles provided independent evidence in support of these preliminary findings. (4) Conclusions: This pilot study establishes the feasibility of using unbiased quantitative phosphoproteomics to identify molecular perturbations associated with disease progression in Barrett’s esophagus to define potentially clinically actionable targets warranting further assessment. Full article

(This article belongs to the Special Issue Protein Interactions, Pathways, and Networks in Health and Disease)

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13 pages, 3223 KiB

Open AccessEditor’s ChoiceArticle

BcTFIIIA Negatively Regulates Turnip Mosaic Virus Infection through Interaction with Viral CP and VPg Proteins in Pak Choi (Brassica campestris ssp. chinensis)

by Rujia Zhang, Changwei Zhang, Shanwu Lyu, Huiyuan Wu, Mengguo Yuan, Zhiyuan Fang, Fangfang Li and Xilin Hou

Genes 2022, 13(7), 1209; https://doi.org/10.3390/genes13071209 - 6 Jul 2022

Cited by 1 | Viewed by 2253

Abstract

TFIIIA is a zinc-finger transcription factor that is involved in post-transcriptional regulation during development. Here, the BcTFIIIA gene was isolated from pak choi. Sequence analysis showed that BcTFIIIA encodes 383 amino acids (aa) with an open reading frame (ORF) of 1152 base pairs [...] Read more.

TFIIIA is a zinc-finger transcription factor that is involved in post-transcriptional regulation during development. Here, the BcTFIIIA gene was isolated from pak choi. Sequence analysis showed that BcTFIIIA encodes 383 amino acids (aa) with an open reading frame (ORF) of 1152 base pairs (bp). We investigated the subcellular location of BcTFIIIA and found the localized protein in the nucleus. BcTFIIIA was suppressed when the pak choi was infected by the turnip mosaic virus (TuMV). The BcTFIIIA mRNA expression level in a resistant variety was higher than that in a sensitive variety, as determined by qRT-PCR analysis. Yeast two hybrid (Y2H) assay and bimolecular fluorescence complementation (BiFC) suggested that BcTFIIIA interacts with TuMV CP and VPg in vivo, respectively, and in vitro. A virus-induced gene silencing (VIGS) experiment showed that the silencing of BcTFIIIA gene expression in pak choi promoted the accumulation of TuMV. These results suggest that BcTFIIIA negatively regulates viral infection through the interaction with TuMV CP and VPg. Full article

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

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7 pages, 1591 KiB

Open AccessEditor’s ChoiceCase Report

Methionine Adenosyltransferase I/III Deficiency Detected by Newborn Screening

by Vanessa Hübner, Luciana Hannibal, Nils Janzen, Sarah Catharina Grünert and Peter Freisinger

Genes 2022, 13(7), 1163; https://doi.org/10.3390/genes13071163 - 27 Jun 2022

Viewed by 2607

Abstract

Methionine adenosyltransferase I/III deficiency is an inborn error of metabolism due to mutations in the MAT1A gene. It is the most common cause of hypermethioninemia in newborn screening. Heterozygotes are often asymptomatic. In contrast, homozygous or compound heterozygous individuals can develop severe neurological [...] Read more.

Methionine adenosyltransferase I/III deficiency is an inborn error of metabolism due to mutations in the MAT1A gene. It is the most common cause of hypermethioninemia in newborn screening. Heterozygotes are often asymptomatic. In contrast, homozygous or compound heterozygous individuals can develop severe neurological symptoms. Less than 70 cases with biallelic variants have been reported worldwide. A methionine-restricted diet is recommended if methionine levels are above 500–600 µmol/L. In this study, we report on a female patient identified with elevated methionine concentrations in a pilot newborn screening program. The patient carries a previously described variant c.1132G>A (p.Gly378Ser) in homozygosity. It is located at the C-terminus of MAT1A. In silico analysis suggests impaired protein stability by β-turn disruption. On a methionine-restricted diet, her serum methionine concentration ranged between 49–605 µmol/L (median 358 µmol/L). Her clinical course was characterized by early-onset muscular hypotonia, mild developmental delay, delayed myelination and mild periventricular diffusion interference in MRI. At 21 months, the girl showed age-appropriate neurological development, but progressive diffusion disturbances in MRI. Little is known about the long-term outcome of this disorder and the necessity of treatment. Our case demonstrates that neurological symptoms can be transient and even patients with initial neurologic manifestations can show normal development under dietary management. Full article

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

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11 pages, 1410 KiB

Open AccessEditor’s ChoiceArticle

Structural Analysis of microRNAs in Myeloid Cancer Reveals Consensus Motifs

by Senol Dogan, Emrulla Spahiu and Anis Cilic

Genes 2022, 13(7), 1152; https://doi.org/10.3390/genes13071152 - 26 Jun 2022

Cited by 1 | Viewed by 3027

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs that function in post-transcriptional gene silencing and mRNA regulation. Although the number of nucleotides of miRNAs ranges from 17 to 27, they are mostly made up of 22 nucleotides. The expression of miRNAs changes significantly in cancer, [...] Read more.

MicroRNAs (miRNAs) are short non-coding RNAs that function in post-transcriptional gene silencing and mRNA regulation. Although the number of nucleotides of miRNAs ranges from 17 to 27, they are mostly made up of 22 nucleotides. The expression of miRNAs changes significantly in cancer, causing protein alterations in cancer cells by preventing some genes from being translated into proteins. In this research, a structural analysis of 587 miRNAs that are differentially expressed in myeloid cancer was carried out. Length distribution studies revealed a mean and median of 22 nucleotides, with an average of 21.69 and a variance of 1.65. We performed nucleotide analysis for each position where Uracil was the most observed nucleotide and Adenine the least observed one with 27.8% and 22.6%, respectively. There was a higher frequency of Adenine at the beginning of the sequences when compared to Uracil, which was more frequent at the end of miRNA sequences. The purine content of each implicated miRNA was also assessed. A novel motif analysis script was written to detect the most frequent 3–7 nucleotide (3–7n) long motifs in the miRNA dataset. We detected CUG (42%) as the most frequent 3n motif, CUGC (15%) as a 4n motif, AGUGC (6%) as a 5n motif, AAGUGC (4%) as a 6n motif, and UUUAGAG (4%) as a 7n motif. Thus, in the second part of our study, we further characterized the motifs by analyzing whether these motifs align at certain consensus sequences in our miRNA dataset, whether certain motifs target the same genes, and whether these motifs are conserved within other species. This thorough structural study of miRNA sequences provides a novel strategy to study the implications of miRNAs in health and disease. A better understanding of miRNA structure is crucial to developing therapeutic settings. Full article

(This article belongs to the Section RNA)

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15 pages, 3548 KiB

Open AccessEditor’s ChoiceArticle

Research on Potential Network Markers and Signaling Pathways in Type 2 Diabetes Based on Conditional Cell-Specific Network

by Yuke Xie, Zhizhong Cui, Nan Wang and Peiluan Li

Genes 2022, 13(7), 1155; https://doi.org/10.3390/genes13071155 - 26 Jun 2022

Cited by 2 | Viewed by 2509

Abstract

Traditional methods concerning type 2 diabetes (T2D) are limited to grouped cells instead of each single cell, and thus the heterogeneity of single cells is erased. Therefore, it is still challenging to study T2D based on a single-cell and network perspective. In this [...] Read more.

Traditional methods concerning type 2 diabetes (T2D) are limited to grouped cells instead of each single cell, and thus the heterogeneity of single cells is erased. Therefore, it is still challenging to study T2D based on a single-cell and network perspective. In this study, we construct a conditional cell-specific network (CCSN) for each single cell for the GSE86469 dataset which is a single-cell transcriptional set from nondiabetic (ND) and T2D human islet samples, and obtain a conditional network degree matrix (CNDM). Since beta cells are the key cells leading to T2D, we search for hub genes in CCSN of beta cells and find that ATP6AP2 is essential for regulation and storage of insulin, and the renin-angiotensin system involving ATP6AP2 is related to most pathological processes leading to diabetic nephropathy. The communication between beta cells and other endocrine cells is performed and three gene pairs with obvious interaction are found. In addition, different expression genes (DEGs) are found based on CNDM and the gene expression matrix (GEM), respectively. Finally, ‘dark’ genes are identified, and enrichment analysis shows that NFATC2 is involved in the VEGF signaling pathway and indirectly affects the production of Prostacyclin (PGI₂), which may be a potential biomarker for diabetic nephropathy. Full article

(This article belongs to the Special Issue From Basic to Translational Bioinformatics of Human Infectious Diseases)

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14 pages, 2658 KiB

Open AccessEditor’s ChoiceArticle

QTL Mapping for Age-Related Eye Pigmentation in the Pink-Eyed Dilution Castaneus Mutant Mouse

by Takaya Nakano, Momoko Takenaka, Makoto Sugiyama and Akira Ishikawa

Genes 2022, 13(7), 1138; https://doi.org/10.3390/genes13071138 - 24 Jun 2022

Viewed by 2785

Abstract

Pink-eyed dilution castaneus (Oca2^p-cas) is a mutant gene on mouse chromosome 7 that arose spontaneously in wild Mus musculus castaneus. Homozygotes for Oca2^p-cas exhibit pink eyes and a light gray coat throughout life. In an ordinary [...] Read more.

Pink-eyed dilution castaneus (Oca2^p-cas) is a mutant gene on mouse chromosome 7 that arose spontaneously in wild Mus musculus castaneus. Homozygotes for Oca2^p-cas exhibit pink eyes and a light gray coat throughout life. In an ordinary mutant strain carrying Oca2^p-cas, we previously discovered a novel spontaneous mutation that gradually increases melanin pigmentation in the eyes and coat with aging, and we developed a novel mutant strain that was fixed for the novel phenotype. The purpose of this study was to map major quantitative trait loci (QTLs) for the novel pigmentation phenotype and for expression levels of four important melanogenesis genes, microphthalmia-associated transcription factor (Mitf), tyrosinase (Tyr), tyrosinase-related protein-1 (Tyrp1) and dopachrome tautomerase (Dct). We developed 69 DNA markers and created 303 F2 mice from two reciprocal crosses between novel and ordinary mutant strains. The QTL analysis using a selective genotyping strategy revealed a significant QTL for eye pigmentation between 34 and 64 Mb on chromosome 13. This QTL explained approximately 20% of the phenotypic variance. The QTL allele derived from the novel strain increased pigmentation. Although eye pigmentation was positively correlated with Dct expression, no expression QTLs were found, suggesting that the pigmentation QTL on chromosome 13 may not be directly in the pathway of any of the four melanogenesis genes. This study is the first step toward identifying a causal gene for the novel spontaneous phenotype in mice and is expected to discover a new regulatory mechanism for complex melanin biosynthesis during aging. Full article

(This article belongs to the Special Issue From QTL Mapping to QTG and QTN Identification)

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9 pages, 212 KiB

Open AccessEditor’s ChoiceReview

From First to Second: How Stickler’s Diagnostic Genetics Has Evolved to Match Sequencing Technologies

by Howard Martin, Allan J. Richards and Martin P. Snead

Genes 2022, 13(7), 1123; https://doi.org/10.3390/genes13071123 - 23 Jun 2022

Viewed by 1706

Abstract

Diagnostic genetics within the United Kingdom National Health Service (NHS) has undergone many stepwise improvements in technology since the completion of the human genome project in 2003. Although Sanger sequencing has remained a cornerstone of the diagnostic sequencing arena, the human genome reference [...] Read more.

Diagnostic genetics within the United Kingdom National Health Service (NHS) has undergone many stepwise improvements in technology since the completion of the human genome project in 2003. Although Sanger sequencing has remained a cornerstone of the diagnostic sequencing arena, the human genome reference sequence has enabled next-generation sequencing (more accurately named ‘second-generation sequencing’), to rapidly surpass it in scale and potential. This mini review discusses such developments from the viewpoint of the Stickler’s higher specialist service, detailing the considerations and improvements to diagnostic sequencing implemented since 2003. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

17 pages, 9746 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Immune-Based Molecular Subtypes and Prognostic Model in Prostate Adenocarcinoma

by Li Guo, Yihao Kang, Daoliang Xia, Yujie Ren, Xueni Yang, Yangyang Xiang, Lihua Tang, Dekang Ren, Jiafeng Yu, Jun Wang and Tingming Liang

Genes 2022, 13(6), 1087; https://doi.org/10.3390/genes13061087 - 18 Jun 2022

Cited by 1 | Viewed by 2774

Abstract

Prostate adenocarcinoma (PRAD), also named prostate cancer, the most common visceral malignancy, is diagnosed in male individuals. Herein, in order to obtain immune-based subtypes, we performed an integrative analysis to characterize molecular subtypes based on immune-related genes, and further discuss the potential features [...] Read more.

Prostate adenocarcinoma (PRAD), also named prostate cancer, the most common visceral malignancy, is diagnosed in male individuals. Herein, in order to obtain immune-based subtypes, we performed an integrative analysis to characterize molecular subtypes based on immune-related genes, and further discuss the potential features and differences between identified subtypes. Simultaneously, we also construct an immune-based risk model to assess cancer prognosis. Our findings showed that the two subtypes, C1 and C2, could be characterized, and the two subtypes showed different characteristics that could clearly describe the heterogeneity of immune microenvironments. The C2 subtype presented a better survival rate than that in the C1 subtype. Further, we constructed an immune-based prognostic model based on four screened abnormally expressed genes, and they were selected as predictors of the robust prognostic model (AUC = 0.968). Our studies provide reference for characterization of molecular subtypes and immunotherapeutic agents against prostate cancer, and the developed robust and useful immune-based prognostic model can contribute to cancer prognosis and provide reference for the individualized treatment plan and health resource utilization. These findings further promote the development and application of precision medicine in prostate cancer. Full article

(This article belongs to the Topic Big Data in Healthcare, Bioinformatics and Precision Medicine)

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3 pages, 182 KiB

Open AccessEditor’s ChoiceEditorial

Male Reproduction: Regulation, Differentiation and Epigenetics

by Massimo Venditti and Sergio Minucci

Genes 2022, 13(6), 1001; https://doi.org/10.3390/genes13061001 - 2 Jun 2022

Viewed by 1795

Abstract

The production of good-quality spermatozoa (SPZ) is one of the most intricate and far from being completely understood developmental processes during postnatal life [...] Full article

(This article belongs to the Special Issue Male Reproduction: Regulation, Differentiation and Epigenetics)

9 pages, 1094 KiB

Open AccessEditor’s ChoiceArticle

Genetic Determination of the Amount of White Spotting: A Case Study in Siberian Cats

by Agnieszka Górska, Wioleta Drobik-Czwarno, Agata Górska and Joanna Bryś

Genes 2022, 13(6), 1006; https://doi.org/10.3390/genes13061006 - 2 Jun 2022

Viewed by 8229

Abstract

The current hypothesis, along with the opinion of the breeders, is that a cat with two copies of the white spotting allele (SS) has white on more than half of its body, while a cat with only one copy (Ss [...] Read more.

The current hypothesis, along with the opinion of the breeders, is that a cat with two copies of the white spotting allele (SS) has white on more than half of its body, while a cat with only one copy (Ss) has white on less than half of its body. The present study was based on the analysis of two large pedigree databases of Siberian cats (23,905 individuals in PawPeds and 21,650 individuals in Felis Polonia database). The distribution of the amount of white spotting in the offspring of cats with different amounts of white was investigated. Significant differences compared to expected distributions were observed. In many cases the amount of white in cats that were supposed to be homozygous was less than 50% of the body, while in many supposedly heterozygous cats a very large amount of white (over 50%) was observed. This phenomenon was also presented on the verified examples of the specific families excluding possible errors in determining the amount of white by the breeder. The collected evidence suggests that there are other factors involved in the inheritance of the amount of white in cats and the current hypothesis should be revised. Full article

(This article belongs to the Special Issue Animal Domestication and Breeding)

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13 pages, 2754 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide RNA Sequencing Analysis in Human Dermal Fibroblasts Exposed to Low-Dose Ultraviolet A Radiation

by Jinyun Wang, Satoshi Yano, Kun Xie, Yoshihisa Ohata and Taichi Hara

Genes 2022, 13(6), 974; https://doi.org/10.3390/genes13060974 - 29 May 2022

Cited by 2 | Viewed by 4456

Abstract

Ultraviolet A (UVA) radiation can pass through the epidermis and reach the dermal skin layer, contributing to photoaging, DNA damage, and photocarcinogenesis in dermal fibroblasts. High-dose UVA exposure induces erythema, whereas low-dose, long-term UVA exposure causes skin damage and cell senescence. Biomarkers for [...] Read more.

Ultraviolet A (UVA) radiation can pass through the epidermis and reach the dermal skin layer, contributing to photoaging, DNA damage, and photocarcinogenesis in dermal fibroblasts. High-dose UVA exposure induces erythema, whereas low-dose, long-term UVA exposure causes skin damage and cell senescence. Biomarkers for evaluating damage caused by low-dose UVA in fibroblasts are lacking, making it difficult to develop therapeutic agents for skin aging and aging-associated diseases. We performed RNA-sequencing to investigate gene and pathway alterations in low-dose UVA-irradiated human skin-derived NB1RGB primary fibroblasts. Differentially expressed genes were identified and subjected to Gene Ontology and reactome pathway analysis, which revealed enrichment in genes in the senescence-associated secretory phenotype, apoptosis, respiratory electron transport, and transcriptional regulation by tumor suppressor p53 pathways. Insulin-like growth factor binding protein 7 (IGFBP7) showed the lowest p-value in RNA-sequencing analysis and was associated with the senescence-associated secretory phenotype. Protein–protein interaction analysis revealed that Fos proto-oncogene had a high-confidence network with IGFBP7 as transcription factor of the IGFBP7 gene among SASP hit genes, which were validated using RT-qPCR. Because of their high sensitivity to low-dose UVA radiation, Fos and IGFBP7 show potential as biomarkers for evaluating the effect of low-dose UVA radiation on dermal fibroblasts. Full article

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

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26 pages, 3468 KiB

Open AccessEditor’s ChoiceArticle

Characterization, Selection, and Trans-Species Polymorphism in the MHC Class II of Heermann’s Gull (Charadriiformes)

by Misael Daniel Mancilla-Morales, Enriqueta Velarde, Araceli Contreras-Rodríguez, Zulema Gómez-Lunar, Jesús A. Rosas-Rodríguez, Joseph Heras, José G. Soñanez-Organis and Enrico A. Ruiz

Genes 2022, 13(5), 917; https://doi.org/10.3390/genes13050917 - 20 May 2022

Viewed by 3542

Abstract

The major histocompatibility complex (MHC) enables vertebrates to cope with pathogens and maintain healthy populations, thus making it a unique set of loci for addressing ecology and evolutionary biology questions. The aim of our study was to examine the variability of Heermann’s Gull [...] Read more.

The major histocompatibility complex (MHC) enables vertebrates to cope with pathogens and maintain healthy populations, thus making it a unique set of loci for addressing ecology and evolutionary biology questions. The aim of our study was to examine the variability of Heermann’s Gull MHC class II (MHCIIB) and compare these loci with other Charadriiformes. Fifty-nine MHCIIB haplotypes were recovered from sixty-eight Heermann’s Gulls by cloning, of them, twelve were identified as putative true alleles, forty-five as unique alleles, and two as pseudogenes. Intra and interspecific relationships indicated at least two loci in Heermann’s Gull MHCIIB and trans-species polymorphism among Charadriiformes (coinciding with the documented evidence of two ancient avian MHCIIB lineages, except in the Charadriidae family). Additionally, sites under diversifying selection revealed a better match with peptide-binding sites inferred in birds than those described in humans. Despite the negative anthropogenic activity reported on Isla Rasa, Heermann’s Gull showed MHCIIB variability consistent with population expansion, possibly due to a sudden growth following conservation efforts. Duplication must play an essential role in shaping Charadriiformes MHCIIB variability, buffering selective pressures through balancing selection. These findings suggest that MHC copy number and protected islands can contribute to seabird conservation. Full article

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

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13 pages, 793 KiB

Open AccessEditor’s ChoiceArticle

Array Comparative Genomic Hybridisation and Droplet Digital PCR Uncover Recurrent Copy Number Variation of the TTN Segmental Duplication Region

by Lydia Sagath, Vilma-Lotta Lehtokari, Katarina Pelin and Kirsi Kiiski

Genes 2022, 13(5), 905; https://doi.org/10.3390/genes13050905 - 19 May 2022

Cited by 1 | Viewed by 2510

Abstract

Intragenic segmental duplication regions are potential hotspots for recurrent copy number variation and possible pathogenic aberrations. Two large sarcomeric genes, nebulin and titin, both contain such segmental duplication regions. Using our custom Comparative Genomic Hybridisation array, we have previously shown that a gain [...] Read more.

Intragenic segmental duplication regions are potential hotspots for recurrent copy number variation and possible pathogenic aberrations. Two large sarcomeric genes, nebulin and titin, both contain such segmental duplication regions. Using our custom Comparative Genomic Hybridisation array, we have previously shown that a gain or loss of more than one copy of the repeated block of the nebulin triplicate region constitutes a recessive pathogenic mutation. Using targeted array-CGH, similar copy number variants can be detected in the segmental duplication region of titin. Due to the limitations of the array-CGH methodology and the repetitiveness of the region, the exact copy numbers of the blocks could not be determined. Therefore, we developed complementary custom Droplet Digital PCR assays for the titin segmental duplication region to confirm true variation. Our combined methods show that the titin segmental duplication region is subject to recurrent copy number variation. Gains and losses were detected in samples from healthy individuals as well as in samples from patients with different muscle disorders. The copy number variation observed in our cohort is likely benign, but pathogenic copy number variants in the segmental duplication region of titin cannot be excluded. Further investigations are needed, however, this region should no longer be neglected in genetic analyses. Full article

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

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24 pages, 332 KiB

Open AccessEditor’s ChoiceArticle

The Skin We Live in: Pigmentation Traits and Tanning Behaviour in British Young Adults, an Observational and Genetically-Informed Study

by Carolina Bonilla and Cilia Mejia-Lancheros

Genes 2022, 13(5), 896; https://doi.org/10.3390/genes13050896 - 17 May 2022

Cited by 1 | Viewed by 2987

Abstract

Skin cancer incidence has been increasing worldwide, representing a particularly high burden for populations of European ancestry. Outdoor and indoor tanning using ultraviolet (UV) radiation devices are major risk factors for skin cancer. While tanning behaviours can be modified by targeted interventions to [...] Read more.

Skin cancer incidence has been increasing worldwide, representing a particularly high burden for populations of European ancestry. Outdoor and indoor tanning using ultraviolet (UV) radiation devices are major risk factors for skin cancer. While tanning behaviours can be modified by targeted interventions to reduce skin cancer rates, there is insufficient evidence on the motivations for tanning preferences and their relationship with pigmentation phenotypes. The present observational and genetically-informed study investigates motives for tanning and the role that pigmentation phenotypes play on outdoor and indoor tanning behaviour in British young adults. This study included 3722 participants from the Avon Longitudinal Study of Parents and Children in South West England, with data on pigmentation features, tanning ability and preferences, and SNP genotypes. Liking to tan and outdoor tanning were strongly influenced by pigmentary traits and tanning ability. However, the association of these phenotypes with UV indoor tanning was weaker. Our results provide evidence to support the implementation of skin cancer preventative interventions that consider individual biological characteristics and motives for undergoing outdoor and indoor tanning. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases)

5 pages, 205 KiB

Open AccessEditor’s ChoiceEditorial

Genetics of Hearing Impairment

by Hannie Kremer and Ignacio del Castillo

Genes 2022, 13(5), 852; https://doi.org/10.3390/genes13050852 - 11 May 2022

Cited by 1 | Viewed by 2311

Abstract

The inner ear is a complex structure at the cellular and molecular levels [...] Full article

(This article belongs to the Special Issue Genetics of Hearing Impairment)

26 pages, 2954 KiB

Open AccessEditor’s ChoiceArticle

Gene-Based Methods for Estimating the Degree of the Skewness of X Chromosome Inactivation

by Meng-Kai Li, Yu-Xin Yuan, Bin Zhu, Kai-Wen Wang, Wing Kam Fung and Ji-Yuan Zhou

Genes 2022, 13(5), 827; https://doi.org/10.3390/genes13050827 - 6 May 2022

Viewed by 2540

Abstract

Skewed X chromosome inactivation (XCI-S) has been reported to be associated with some X-linked diseases, and currently several methods have been proposed to estimate the degree of the XCI-S (denoted as

γ

) for a single locus. However, no method has been available [...] Read more.

Skewed X chromosome inactivation (XCI-S) has been reported to be associated with some X-linked diseases, and currently several methods have been proposed to estimate the degree of the XCI-S (denoted as

γ

) for a single locus. However, no method has been available to estimate

γ

for genes. Therefore, in this paper, we first propose the point estimate and the penalized point estimate of

γ

for genes, and then derive its confidence intervals based on the Fieller’s and penalized Fieller’s methods, respectively. Further, we consider the constraint condition of

γ \in [0, 2]

and propose the Bayesian methods to obtain the point estimates and the credible intervals of

γ

, where a truncated normal prior and a uniform prior are respectively used (denoted as GBN and GBU). The simulation results show that the Bayesian methods can avoid the extreme point estimates (0 or 2), the empty sets, the noninformative intervals (

[0, 2]

) and the discontinuous intervals to occur. GBN performs best in both the point estimation and the interval estimation. Finally, we apply the proposed methods to the Minnesota Center for Twin and Family Research data for their practical use. In summary, in practical applications, we recommend using GBN to estimate

γ

of genes. Full article

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

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13 pages, 24956 KiB

Open AccessEditor’s ChoiceArticle

Novel Role of AaMYBC1 in Regulating Actinidia arguta Vine Architecture by Elongating Internode Based on Multi-Omics Analysis of Transgenic Tobacco

by Yukuo Li, Hailei Huang, Muhammad Abid, Hong Gu, Zhongping Cheng, Jinbao Fang and Xiujuan Qi

Genes 2022, 13(5), 817; https://doi.org/10.3390/genes13050817 - 3 May 2022

Cited by 1 | Viewed by 2263

Abstract

The internode length affects the status of fruiting branches and shapes the vine architecture. MYB TFs (transcription factors) have been widely studied and reported to control many biological processes including secondary metabolism, abiotic stresses, growth and development, etc. However, the roles of MYB [...] Read more.

The internode length affects the status of fruiting branches and shapes the vine architecture. MYB TFs (transcription factors) have been widely studied and reported to control many biological processes including secondary metabolism, abiotic stresses, growth and development, etc. However, the roles of MYB TFs in regulating internode length remain poorly understood. Here, we demonstrated that a secondary metabolism-related R2R3-MYB TF AaMYBC1 from Actinidia arguta was involved in the regulation of internode length by combined analysis of transcriptome and metabolome of transgenic tobacco plants. The metabolome analysis of OE (over-expressed tobacco) and WT (wild-typed tobacco) showed that there were a total of 1000 metabolites, 176 of which had significant differences. A key metabolite pme1651 annotated as indole 3-acetic acid belonged to phytohormone that was involved in internode length regulation. The RNA-seq analysis presented 446 differentially expressed genes (DEGs) between OE and WT, 14 of which were common DEGs in KEGG and GO enrichment. Through the combined analysis of metabolome and transcriptome in transgenic and wild-type tobacco, three key genes including two SAUR and a GH3 gene were possibly involved in internode elongation. Finally, a regulatory module was deduced to show the role of AaMYBC1 in internode elongation. Our results proposed a molecular mechanism of AaMYBC1 regulating internode length by mediated auxin signaling, implying the potential role in regulating the vine architecture. Full article

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

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18 pages, 9698 KiB

Open AccessEditor’s ChoiceArticle

Molecular Evolutionary Rate Predicts Intraspecific Genetic Polymorphism and Species-Specific Selection

by Jiaqi Wu, Takahiro Yonezawa and Hirohisa Kishino

Genes 2022, 13(4), 708; https://doi.org/10.3390/genes13040708 - 17 Apr 2022

Viewed by 2954

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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27 pages, 19141 KiB

Open AccessEditor’s ChoiceArticle

A Penalization Method for Estimating Heterogeneous Covariate Effects in Cancer Genomic Data

by Ziye Luo, Yuzhao Zhang and Yifan Sun

Genes 2022, 13(4), 702; https://doi.org/10.3390/genes13040702 - 15 Apr 2022

Viewed by 2192

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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17 pages, 4303 KiB

Open AccessEditor’s ChoiceArticle

hMSH5 Regulates NHEJ and Averts Excessive Nucleotide Alterations at Repair Joints

by Aneesa T. Al-Soodani, Xiling Wu, Nicole C. Kelp, Alexander J. Brown, Steven A. Roberts and Chengtao Her

Genes 2022, 13(4), 673; https://doi.org/10.3390/genes13040673 - 11 Apr 2022

Cited by 1 | Viewed by 3097

Abstract

Inappropriate repair of DNA double-strand breaks (DSBs) leads to genomic instability, cell death, or malignant transformation. Cells minimize these detrimental effects by selectively activating suitable DSB repair pathways in accordance with their underlying cellular context. Here, we report that hMSH5 down-regulates NHEJ and [...] Read more.

Inappropriate repair of DNA double-strand breaks (DSBs) leads to genomic instability, cell death, or malignant transformation. Cells minimize these detrimental effects by selectively activating suitable DSB repair pathways in accordance with their underlying cellular context. Here, we report that hMSH5 down-regulates NHEJ and restricts the extent of DSB end processing before rejoining, thereby reducing “excessive” deletions and insertions at repair joints. RNAi-mediated knockdown of hMSH5 led to large nucleotide deletions and longer insertions at the repair joints, while at the same time reducing the average length of microhomology (MH) at repair joints. Conversely, hMSH5 overexpression reduced end-joining activity and increased RPA foci formation (i.e., more stable ssDNA at DSB ends). Furthermore, silencing of hMSH5 delayed 53BP1 chromatin spreading, leading to increased end resection at DSB ends. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Microorganisms, Plants and Mammalian Systems)

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9 pages, 1052 KiB

Open AccessEditor’s ChoiceArticle

Integrated Quantitative Neuro-Transcriptome Analysis of Several Brain Areas in Human Trisomy 21

by Alejandra Rodríguez-Ortiz, Julio César Montoya-Villegas, Felipe García-Vallejo and Yecid Mina-Paz

Genes 2022, 13(4), 628; https://doi.org/10.3390/genes13040628 - 1 Apr 2022

Viewed by 2330

Abstract

Background: Although Down syndrome (DS) is the most frequent human chromosomal disorder and it causes mainly intellectual disability, its clinical presentation is complex and variable. Objective: We aimed to analyze and compare the transcriptome disruption in several brain areas from individuals with DS [...] Read more.

Background: Although Down syndrome (DS) is the most frequent human chromosomal disorder and it causes mainly intellectual disability, its clinical presentation is complex and variable. Objective: We aimed to analyze and compare the transcriptome disruption in several brain areas from individuals with DS and euploid controls as a new approach to consider a global systemic differential disruption of gene expression beyond chromosome 21. Methods: We used data from a DNA microarray experiment with ID GSE59630 previously deposited in the GEO DataSet of NCBI database. The array contained log2 values of 17,537 human genes expressed in several aeras of the human brain. We calculated the differential gene expression (Z-ratio) of all genes. Results: We found several differences in gene expression along the DS brain transcriptome, not only in the genes located at chromosome 21 but in other chromosomes. Moreover, we registered the lowest Z-ratio correlation between the age ranks of 16–22 weeks of gestation and 39–42 years (R² = 0.06) and the highest Z-ratio correlation between the age ranks of 30–39 years and 40–42 years (R² = 0.89). The analysis per brain areas showed that the hippocampus and the cerebellar cortex had the most different gene expression pattern when compared to the brain as a whole. Conclusions: Our results support the hypothesis of a systemic imbalance of brain protein homeostasis, or proteostasis network of cognitive and neuroplasticity process, as new model to explain the important effect on the neurophenotype of trisomy that occur not only in the loci of chromosome 21 but also in genes located in other chromosomes. Full article

(This article belongs to the Special Issue Epigenetics in Brain Development and Neurodevelopmental Disorders)

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9 pages, 1170 KiB

Open AccessEditor’s ChoiceCommunication

Effectiveness of Two Universal Angiosperm Probe Sets Tested In Silico for Caryophyllids Taxa with Emphasis on Cacti Species

by Delil A. Chincoya and Sofía Solórzano

Genes 2022, 13(4), 570; https://doi.org/10.3390/genes13040570 - 24 Mar 2022

Viewed by 2441

Abstract

In angiosperms, huge advances in massive DNA sequencing technologies have impacted phylogenetic studies. Probe sets have been developed with the purpose of recovering hundreds of orthologous loci of targeted DNA sequences (TDS) across different plant lineages. We tested in silico the effectiveness of [...] Read more.

In angiosperms, huge advances in massive DNA sequencing technologies have impacted phylogenetic studies. Probe sets have been developed with the purpose of recovering hundreds of orthologous loci of targeted DNA sequences (TDS) across different plant lineages. We tested in silico the effectiveness of two universal probe sets in the whole available genomes of Caryophyllids, emphasizing phylogenetic issues in cacti species. A total of 870 TDS (517 TDS from Angiosperm v.1 and 353 from Angiosperms353) were individually tested in nine cacti species and Amaranthus hypochondriacus (external group) with ≥17 Gbp of available DNA data. The effectiveness was measured by the total number of orthologous loci recovered and their length, the percentage of loci discarded by paralogy, and the proportion of informative sites (PIS) in the alignments. The results showed that, on average, Angiosperms353 was better than Angiosperm v.1 for cacti species, since the former obtained an average of 275.6 loci that represent 123,687 bp, 2.48% of paralogous loci, and 4.32% of PIS in alignments, whereas the latter recovered 148.4 loci (37,683 bp), 10.38% of paralogous loci, and 3.49% of PIS. We recommend the use of predesigned universal probe sets for Caryophyllids, since these recover a high number of orthologous loci that resolve phylogenetic relationships. Full article

(This article belongs to the Special Issue Cactaceae Genetics and Genomics)

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9 pages, 1547 KiB

Open AccessEditor’s ChoiceBrief Report

Identification of Frameshift Variants in POLH Gene Causing Xeroderma Pigmentosum in Two Consanguineous Pakistani Families

by Ghazala Y. Zamani, Ranjha Khan, Noreen Karim, Zubair M. Ahmed and Muhammad Naeem

Genes 2022, 13(3), 543; https://doi.org/10.3390/genes13030543 - 19 Mar 2022

Viewed by 3285

Abstract

Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder characterized by severe sensitivity of skin to sunlight and an increased risk of skin cancer. XP variant (XPV), a milder subtype, is caused by variants in the POLH gene. POLH encodes an error-prone [...] Read more.

Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder characterized by severe sensitivity of skin to sunlight and an increased risk of skin cancer. XP variant (XPV), a milder subtype, is caused by variants in the POLH gene. POLH encodes an error-prone DNA-polymerase eta (pol eta) which performs translesion synthesis past ultraviolet photoproducts. The current study documents the clinical and genetic investigations of two large consanguineous Pakistani families affected with XPV. In family 1, whole exome sequencing (WES) revealed a novel frameshift variant, c.1723dupG (p.(Val575Glyfs*4)), of POLH, which is predicted to cause frameshift and premature truncation of the encoded enzyme. Indeed, our ex vivo studies in HEK293T cells confirmed the truncation of the encoded protein due to the c.1723dupG variant. In family 2, Sanger sequencing of POLH exons, revealed a recurrent nonsense variant, c.437dupA (p.Tyr146*). POLH forms a hetero-tetrameric POLZ complex with REV3L, REV7, POLD2 and POLD3. Next, we performed in silico analysis of POLH and other POLZ complex genes expression in publicly available single cell mRNAseq datasets from adult human healthy and aging skin. We found overlapping expression of POLH, REV3L and POLD2 in multiple cell types including differentiated and undifferentiated keratinocytes, pericytes and melanocytes in healthy skin. However, in aging human skin, POLH expression is reduced in compare to its POLZ complex partners. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of POLH-related XPV. Full article

(This article belongs to the Special Issue Molecular Basis of Rare Diseases)

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16 pages, 1480 KiB

Open AccessEditor’s ChoiceArticle

Transcriptomics of Wet Skin Biopsies Predict Early Radiation-Induced Hematological Damage in a Mouse Model

by Abdulnaser Alkhalil, John Clifford, Stacy Ann Miller, Aarti Gautam, Marti Jett, Rasha Hammamieh, Lauren T. Moffatt and Jeffrey W. Shupp

Genes 2022, 13(3), 538; https://doi.org/10.3390/genes13030538 - 18 Mar 2022

Viewed by 2862

Abstract

The lack of an easy and fast radiation-exposure testing method with a dosimetric ability complicates triage and treatment in response to a nuclear detonation, radioactive material release, or clandestine exposure. The potential of transcriptomics in radiation diagnosis and prognosis were assessed here using [...] Read more.

The lack of an easy and fast radiation-exposure testing method with a dosimetric ability complicates triage and treatment in response to a nuclear detonation, radioactive material release, or clandestine exposure. The potential of transcriptomics in radiation diagnosis and prognosis were assessed here using wet skin (blood/skin) biopsies obtained at hour 2 and days 4, 7, 21, and 28 from a mouse radiation model. Analysis of significantly differentially transcribed genes (SDTG; p ≤ 0.05 and FC ≥ 2) during the first post-exposure week identified the glycoprotein 6 (GP-VI) signaling, the dendritic cell maturation, and the intrinsic prothrombin activation pathways as the top modulated pathways with stable inactivation after lethal exposures (20 Gy) and intermittent activation after sublethal (1, 3, 6 Gy) exposure time points (TPs). Interestingly, these pathways were inactivated in the late TPs after sublethal exposure in concordance with a delayed deleterious effect. Modulated transcription of a variety of collagen types, laminin, and peptidase genes underlay the modulated functions of these hematologically important pathways. Several other SDTGs related to platelet and leukocyte development and functions were identified. These results outlined genetic determinants that were crucial to clinically documented radiation-induced hematological and skin damage with potential countermeasure applications. Full article

(This article belongs to the Collection Feature Papers in ‘Animal Genetics and Genomics’)

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10 pages, 2059 KiB

Open AccessEditor’s ChoiceArticle

Crlz-1 Homozygous Null Knockout Mouse Embryos Are Lethally Stopped in Their Early Development

by Seung-Young Choi, Joo-Hyun Pi, So-Eun Jeong and Chang-Joong Kang

Genes 2022, 13(3), 511; https://doi.org/10.3390/genes13030511 - 14 Mar 2022

Viewed by 2569

Abstract

Although the conditional gene knockout (KO) is a better choice for observing its phenotype in a specific cell, tissue, and/or organ, the simple null gene KO could nevertheless be attempted initially to scan its overall phenotypes at the level of the whole-body system, [...] Read more.

Although the conditional gene knockout (KO) is a better choice for observing its phenotype in a specific cell, tissue, and/or organ, the simple null gene KO could nevertheless be attempted initially to scan its overall phenotypes at the level of the whole-body system, especially for a new gene such as Crlz-1. Therefore, with a hope to glean phenotypic clues for Crlz-1 at the whole-body system, we attempted to generate its null KO mice. Contrary to our original desire, Crlz-1 homozygous null KO mice were not born. However, in the chasing of their homozygous KO embryos, they were found to be lethally impaired from early development, remaining in a state of small globular mass without ever leading to a body shape, indicating the critical role of Crlz-1 as a Wnt target gene for the proliferation and/or differentiation of cells during early mouse embryonic development. Full article

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

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8 pages, 3208 KiB

Open AccessEditor’s ChoiceCommunication

First Description of Inheritance of a Postzygotic OPA1 Mosaic Variant

by Svenja Alter, Navid Farassat, Sebastian Küchlin, Wolf A. Lagrèze and Judith Fischer

Genes 2022, 13(3), 478; https://doi.org/10.3390/genes13030478 - 8 Mar 2022

Viewed by 2290

Abstract

Optic atrophy 1 (MIM #165500) is caused by pathogenic variants in the gene OPA1 (OPA1 MITOCHONDRIAL DYNAMIN-LIKE GTPase, MIM *605290) and is inherited in an autosomal dominant manner. We describe a 6-year-old male patient with severe early onset manifestation of optic [...] Read more.

Optic atrophy 1 (MIM #165500) is caused by pathogenic variants in the gene OPA1 (OPA1 MITOCHONDRIAL DYNAMIN-LIKE GTPase, MIM *605290) and is inherited in an autosomal dominant manner. We describe a 6-year-old male patient with severe early onset manifestation of optic atrophy, whose parents are subjectively asymptomatic. OPA1-sequence analysis revealed the heterozygous missense variant NM_015560.3:c.806C>T, p.(Ser269Phe) in the patient. Segregation analysis of the parents showed that the mother carried a low-grade postzygotic mosaic of this variant, which apparently also involves germline cells. In line with this, ophthalmological investigation of the mother showed subclinical manifestation of optic atrophy 1. This is the first report of an OPA1 postzygotic mosaic that was inherited to offspring. Full article

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

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25 pages, 3377 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

by Chenguang Zhao, Tong Liu and Zheng Wang

Genes 2022, 13(3), 480; https://doi.org/10.3390/genes13030480 - 8 Mar 2022

Cited by 1 | Viewed by 2877

Abstract

Topologically associating domains (TADs) are the structural and functional units of the genome. However, the functions of protein-coding genes existing in the same or different TADs have not been fully investigated. We compared the functional similarities of protein-coding genes existing in the same [...] Read more.

Topologically associating domains (TADs) are the structural and functional units of the genome. However, the functions of protein-coding genes existing in the same or different TADs have not been fully investigated. We compared the functional similarities of protein-coding genes existing in the same TAD and between different TADs, and also in the same gap region (the region between two consecutive TADs) and between different gap regions. We found that the protein-coding genes from the same TAD or gap region are more likely to share similar protein functions, and this trend is more obvious with TADs than the gap regions. We further created two types of gene–gene spatial interaction networks: the first type is based on Hi-C contacts, whereas the second type is based on both Hi-C contacts and the relationship of being in the same TAD. A graph auto-encoder was applied to learn the network topology, reconstruct the two types of networks, and predict the functions of the central genes/nodes based on the functions of the neighboring genes/nodes. It was found that better performance was achieved with the second type of network. Furthermore, we detected long-range spatially-interactive regions based on Hi-C contacts and calculated the functional similarities of the gene pairs from these regions. Full article

(This article belongs to the Special Issue 3D Reconstruction of Genome Structures)

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9 pages, 2880 KiB

Open AccessEditor’s ChoiceArticle

enChIP-Seq Analyzer: A Software Program to Analyze and Interpret enChIP-Seq Data for the Detection of Physical Interactions between Genomic Regions

by Ashita Sarudate, Toshitsugu Fujita, Takahiro Nakayama and Hodaka Fujii

Genes 2022, 13(3), 472; https://doi.org/10.3390/genes13030472 - 7 Mar 2022

Viewed by 2512

Abstract

Accumulating evidence suggests that the physical interactions between genomic regions play critical roles in the regulation of genome functions, such as transcription and epigenetic regulation. Various methods to detect the physical interactions between genomic regions have been developed. We recently developed a method [...] Read more.

Accumulating evidence suggests that the physical interactions between genomic regions play critical roles in the regulation of genome functions, such as transcription and epigenetic regulation. Various methods to detect the physical interactions between genomic regions have been developed. We recently developed a method to search for genomic regions interacting with a locus of interest in a non-biased manner that combines pull-down of the locus using engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) and next-generation sequencing (NGS) analysis (enChIP-Seq). The clustered regularly interspaced short palindromic repeats (CRISPR) system, consisting of a nuclease-dead form of Cas9 (dCas9) and a guide RNA (gRNA), or transcription activator-like (TAL) proteins, can be used for enChIP. In enChIP-Seq, it is necessary to compare multiple datasets of enChIP-Seq data to unambiguously detect specific interactions. However, it is not always easy to analyze enChIP-Seq datasets to subtract non-specific interactions or identify common interactions. To facilitate such analysis, we developed the enChIP-Seq analyzer software. It enables easy extraction of common signals as well as subtraction of non-specific signals observed in negative control samples, thereby streamlining extraction of specific enChIP-Seq signals. enChIP-Seq analyzer will help users analyze enChIP-Seq data and identify physical interactions between genomic regions. Full article

(This article belongs to the Section Bioinformatics)

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22 pages, 1056 KiB

Open AccessEditor’s ChoiceArticle

Simulation Research on the Methods of Multi-Gene Region Association Analysis Based on a Functional Linear Model

by Shijing Li, Fujie Zhou, Jiayu Shen, Hui Zhang and Yongxian Wen

Genes 2022, 13(3), 455; https://doi.org/10.3390/genes13030455 - 2 Mar 2022

Viewed by 2326

Abstract

Genome-wide association analysis is an important approach to identify genetic variants associated with complex traits. Complex traits are not only affected by single gene loci, but also by the interaction of multiple gene loci. Studies of association between gene regions and quantitative traits [...] Read more.

Genome-wide association analysis is an important approach to identify genetic variants associated with complex traits. Complex traits are not only affected by single gene loci, but also by the interaction of multiple gene loci. Studies of association between gene regions and quantitative traits are of great significance in revealing the genetic mechanism of biological development. There have been a lot of studies on single-gene region association analysis, but the application of functional linear models in multi-gene region association analysis is still less. In this paper, a functional multi-gene region association analysis test method is proposed based on the functional linear model. From the three directions of common multi-gene region method, multi-gene region weighted method and multi-gene region loci weighted method, that test method is studied combined with computer simulation. The following conclusions are obtained through computer simulation: (a) The functional multi-gene region association analysis test method has higher power than the functional single gene region association analysis test method; (b) The functional multi-gene region weighted method performs better than the common functional multi-gene region method; (c) the functional multi-gene region loci weighted method is the best method for association analysis on three directions of the common multi-gene region method; (d) the performance of the Step method and Multi-gene region loci weighted Step for multi-gene regions is the best in general. Functional multi-gene region association analysis test method can theoretically provide a feasible method for the study of complex traits affected by multiple genes. Full article

(This article belongs to the Section Bioinformatics)

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3 pages, 179 KiB

Open AccessEditor’s ChoiceEditorial

Investigations on Nuclear DNA Content and DNA Synthesis in Plants and Fungi Using Flow Cytometry and Fluorescence Microscopy

by Elwira Sliwinska

Genes 2022, 13(3), 417; https://doi.org/10.3390/genes13030417 - 25 Feb 2022

Viewed by 1751

Abstract

The twenty-first century has been an era of extensive genome exploration and modifications, using advanced methods such as genome sequencing and editing [...] Full article

(This article belongs to the Special Issue Investigations on Nuclear DNA Content and DNA Synthesis in Plants and Fungi Using Flow Cytometry and Fluorescence Microscopy)

20 pages, 10456 KiB

Open AccessEditor’s ChoiceArticle

Cloning of the Human MORG1 Promoter: Differential Regulation by Hypoxia and Prolyl-Hydroxylase Inhibitors

by Tzvetanka Bondeva and Gunter Wolf

Genes 2022, 13(3), 427; https://doi.org/10.3390/genes13030427 - 25 Feb 2022

Viewed by 2043

Abstract

MAPK-organizer 1 (MORG1) is a molecular scaffold for prolyl-hydroxylase-3 containing a domain (PHD3) protein linking MORG1 to mechanisms of adaptation in hypoxic conditions. In this paper, we report the cloning of the promoter region of the murine and human MORG1 gene. Among other [...] Read more.

MAPK-organizer 1 (MORG1) is a molecular scaffold for prolyl-hydroxylase-3 containing a domain (PHD3) protein linking MORG1 to mechanisms of adaptation in hypoxic conditions. In this paper, we report the cloning of the promoter region of the murine and human MORG1 gene. Among other transcriptional factors binding sites, we identified that both (mouse and human) promoter regions contained several putative hypoxia-inducible factor binding motifs. Analyses of the human MORG1 promoter by reporter assays revealed that hypoxia and pharmacological inhibitors of prolyl-hydroxylases under in vitro conditions in HEK 293 cells differentially regulate the MORG1 promoter reporter activity. The exposure of the cells to 10% hypoxia showed inhibition of MORG1 promotor activity at 6 and 12 h, but stimulation after 24 h while treated with prolyl-hydroxylase inhibitors led to a time-independent MORG1 promoter activation. Mutational analyses of the individual HIF binding sites on human MORG1 promoter suggest that the binding sites work in a complex corporation because single mutations were not sufficient to abolish completely the MORG1 reporter activation by PHD inhibitors. Our data provide the first evidence that not only MORG1 regulate HIF stabilization through a PHD complex, but also that, vice versa, HIFs control MORG1 expression directly or indirectly by a complex regulatory mechanism. Full article

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

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15 pages, 13317 KiB

Open AccessEditor’s ChoiceArticle

Characterization and Functional Study of FAM49B Reveals Its Effect on Cell Proliferation in HEK293T Cells

by Yijian Chen, Yuyan Jiang, Jihui Lao, Yankuan Zhou, Lida Su and Xiao Huang

Genes 2022, 13(2), 388; https://doi.org/10.3390/genes13020388 - 21 Feb 2022

Cited by 2 | Viewed by 3074

Abstract

FAM49B/Fam49b is a member of the Fam49 (Family with sequence similarity 49) gene family, which is characterized by the conserved domain, DUF1394 (Domain of Unknown Function 1394). It has also been named CYRI-B (CYFIP related RAC1 interactor B), implicating its important function of [...] Read more.

FAM49B/Fam49b is a member of the Fam49 (Family with sequence similarity 49) gene family, which is characterized by the conserved domain, DUF1394 (Domain of Unknown Function 1394). It has also been named CYRI-B (CYFIP related RAC1 interactor B), implicating its important function of regulating RAC1-driven cytoskeleton remolding. In this study, to further investigate its functions and mechanisms affecting cell behaviors, HEK293T cells (where FAM49B is highly expressed) were used to establish a FAM49B knockout cell line by CRISPR/Cas9 genome editing technology. Our data have clearly revealed that there are triple alleles of FAM49B in the genome of HEK293T cells. Meanwhile, the proliferation deficiency of the FAM49B KO HEK293T cell line and the significantly changed cell proliferation related gene expression profiles, such as CCND1, have been uncovered. At the same time, the existence of isoform 3 has been confirmed in HEK293T cells. Our studies have suggested that FAM49B may also affect cell proliferation via Cyclins, besides its influence on the cytoskeleton. Full article

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

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