Genes

13 pages, 14918 KiB

Open AccessEditor’s ChoiceArticle

Do Noncoding and Coding Sites in Angiosperm Chloroplast DNA Have Different Mutation Processes?

by Brian R. Morton

Genes 2023, 14(1), 148; https://doi.org/10.3390/genes14010148 - 5 Jan 2023

Cited by 1 | Viewed by 2012

Fourfold degenerate sites within coding regions and intergenic sites have both been used as estimates of neutral evolution. In chloroplast DNA, the pattern of substitution at intergenic sites is strongly dependent on the composition of the surrounding hexanucleotide composed of the three base [...] Read more.

Fourfold degenerate sites within coding regions and intergenic sites have both been used as estimates of neutral evolution. In chloroplast DNA, the pattern of substitution at intergenic sites is strongly dependent on the composition of the surrounding hexanucleotide composed of the three base pairs on each side, which suggests that the mutation process is highly context-dependent in this genome. This study examines the context-dependency of substitutions at fourfold degenerate sites in protein-coding regions and compares the pattern to what has been observed at intergenic sites. Overall, there is strong similarity between the two types of sites, but there are some intriguing differences. One of these is that substitutions of G and C are significantly higher at fourfold degenerate sites across a range of contexts. In fact, A → T and T → A substitutions are the only substitution types that occur at a lower rate at fourfold degenerate sites. The data are not consistent with selective constraints being responsible for the difference in substitution patterns between intergenic and fourfold degenerate sites. Rather, it is suggested that the difference may be a result of different epigenetic modifications that result in slightly different mutation patterns in coding and intergenic DNA. Full article

(This article belongs to the Special Issue Plant Plastid Genome)

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20 pages, 1622 KiB

Open AccessEditor’s ChoiceReview

Interacting Networks of the Hypothalamic–Pituitary–Ovarian Axis Regulate Layer Hens Performance

by Jinbo Zhao, Hongbin Pan, Yong Liu, Yang He, Hongmei Shi and Changrong Ge

Genes 2023, 14(1), 141; https://doi.org/10.3390/genes14010141 - 4 Jan 2023

Cited by 24 | Viewed by 4579

Abstract

Egg production is a vital biological and economic trait for poultry breeding. The ‘hypothalamic–pituitary–ovarian (HPO) axis’ determines the egg production, which affects the layer hens industry income. At the organism level, the HPO axis is influenced by the factors related to metabolic and [...] Read more.

Egg production is a vital biological and economic trait for poultry breeding. The ‘hypothalamic–pituitary–ovarian (HPO) axis’ determines the egg production, which affects the layer hens industry income. At the organism level, the HPO axis is influenced by the factors related to metabolic and nutritional status, environment, and genetics, whereas at the cellular and molecular levels, the HPO axis is influenced by the factors related to endocrine and metabolic regulation, cytokines, key genes, signaling pathways, post-transcriptional processing, and epigenetic modifications. MiRNAs and lncRNAs play a critical role in follicle selection and development, atresia, and ovulation in layer hens; in particular, miRNA is known to affect the development and atresia of follicles by regulating apoptosis and autophagy of granulosa cells. The current review elaborates on the regulation of the HPO axis and its role in the laying performance of hens at the organism, cellular, and molecular levels. In addition, this review provides an overview of the interactive network regulation mechanism of the HPO axis in layer hens, as well as comprehensive knowledge for successfully utilizing their genetic resources. Full article

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

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13 pages, 3023 KiB

Open AccessEditor’s ChoiceArticle

Transcriptomic Profiling Reveals an Enhancer RNA Signature for Recurrence Prediction in Colorectal Cancer

by Divya Sahu, Chen-Ching Lin and Ajay Goel

Genes 2023, 14(1), 137; https://doi.org/10.3390/genes14010137 - 3 Jan 2023

Cited by 1 | Viewed by 2583

Abstract

Background: Colorectal cancer (CRC) is one of the most fatal malignancies worldwide, and this is in part due to high rates of tumor recurrence in these patients. Currently, TNM staging remains the gold standard for predicting prognosis and recurrence in CRC patients; however, [...] Read more.

Background: Colorectal cancer (CRC) is one of the most fatal malignancies worldwide, and this is in part due to high rates of tumor recurrence in these patients. Currently, TNM staging remains the gold standard for predicting prognosis and recurrence in CRC patients; however, this approach is inadequate for identifying high-risk patients with the highest likelihood of disease recurrence. Recent evidence has revealed that enhancer RNAs (eRNAs) represent a higher level of cellular regulation, and their expression is frequently dysregulated in several cancers, including CRC. However, the clinical significance of eRNAs as recurrence predictor biomarkers in CRC remains unexplored, which is the primary aim of this study. Results: We performed a systematic analysis of eRNA expression profiles in colon cancer (CC) and rectal cancer (RC) patients from the TCGA dataset. By using rigorous biomarker discovery approaches by splitting the entire dataset into a training and testing cohort, we identified a 22-eRNA panel in CC and a 19-eRNA panel in RC for predicting tumor recurrence. The Kaplan–Meier analysis showed that biomarker panels robustly stratified low and high-risk CC (p = 7.29 × 10⁻⁵) and RC (p = 6.81 × 10⁻³) patients with recurrence. Multivariate and LASSO Cox regression models indicated that both biomarker panels were independent predictors of recurrence and significantly superior to TNM staging in CC (HR = 11.89, p = 9.54 × 10⁻⁴) and RC (HR = 3.91, p = 3.52 × 10⁻²). Notably, the ROC curves demonstrated that both panels exhibited excellent recurrence prediction accuracy in CC (AUC = 0.833; 95% CI: 0.74–0.93) and RC (AUC = 0.834; 95% CI: 0.72–0.92) patients. Subsequently, a combination signature that included the eRNA panels and TNM staging achieved an even greater predictive accuracy in patients with CC (AUC = 0.85). Conclusions: Herein, we report a novel eRNA signature for predicting recurrence in patients with CRC. Further experimental validation in independent clinical cohorts, these biomarkers can potentially improve current risk stratification approaches for guiding precision oncology treatments in patients suffering from this lethal malignancy. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics 2023)

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20 pages, 1685 KiB

Open AccessEditor’s ChoiceReview

Transgenerational Epigenetic Inheritance of Traumatic Experience in Mammals

by Jana Švorcová

Genes 2023, 14(1), 120; https://doi.org/10.3390/genes14010120 - 1 Jan 2023

Cited by 22 | Viewed by 17757

Abstract

In recent years, we have seen an increasing amount of evidence pointing to the existence of a non-genetic heredity of the effects of events such as separation from parents, threat to life, or other traumatising experiences such as famine. This heredity is often [...] Read more.

In recent years, we have seen an increasing amount of evidence pointing to the existence of a non-genetic heredity of the effects of events such as separation from parents, threat to life, or other traumatising experiences such as famine. This heredity is often mediated by epigenetic regulations of gene expression and may be transferred even across several generations. In this review, we focus on studies which involve transgenerational epigenetic inheritance (TEI), with a short detour to intergenerational studies focused on the inheritance of trauma or stressful experiences. The reviewed studies show a plethora of universal changes which stress exposure initiates on multiple levels of organisation ranging from hormonal production and the hypothalamic-pituitary-adrenal (HPA) axis modulation all the way to cognition, behaviour, or propensity to certain psychiatric or metabolic disorders. This review will also provide an overview of relevant methodology and difficulties linked to implementation of epigenetic studies. A better understanding of these processes may help us elucidate the evolutionary pathways which are at work in the course of emergence of the diseases and disorders associated with exposure to trauma, either direct or in a previous generation. Full article

(This article belongs to the Special Issue Mechanisms of Transgenerational Epigenetic Inheritance)

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10 pages, 854 KiB

Open AccessEditor’s ChoiceArticle

ITS1 Barcode and Phytochemical Analysis by Gas Chromatography–Mass Spectrometry of Corynaea crassa Hook. f (Balanophoraceae) from Ecuador and Peru

by Alexandra López-Barrera, Efrén Santos-Ordóñez, Ricardo Pacheco-Coello, Liliana Villao-Uzho, Migdalia Miranda, Yamilet Gutiérrez, Iván Chóez-Guaranda and Segundo Guillermo Ruiz-Reyes

Genes 2023, 14(1), 88; https://doi.org/10.3390/genes14010088 - 28 Dec 2022

Cited by 1 | Viewed by 2620

Abstract

The use of medicinal plants is the basis of traditional healthcare. Recently, the use of herbal medicine has been increasing among consumers due to availability, economy, and less side effect. For instance, the hemiparasite plant Corynaea crassa has medicinal properties and could be [...] Read more.

The use of medicinal plants is the basis of traditional healthcare. Recently, the use of herbal medicine has been increasing among consumers due to availability, economy, and less side effect. For instance, the hemiparasite plant Corynaea crassa has medicinal properties and could be found in some regions of America, from Costa Rica to Bolivia. Phytochemical and genetic characterization of medicinal plants is needed for proper identification of metabolites responsible for medicinal properties and for genotyping, respectively. Moreover, characterization of medicinal plants through the use of DNA barcodes is an important tool for phylogenetic analysis and identification of species; furthermore, complemented with phytochemical analysis, both are useful for identification of plant species and quality control of medicinal products. The objective of this study was to analyze the species of C. crassa collected in Ecuador and Peru from the phylogenetic and phytochemical point of view. Polymerase chain reaction (PCR) was performed for amplification of the internal transcribed spacer 1 (ITS1) region after DNA extraction of samples of C. crassa. Blast analysis was performed in the GenBank database with the ITS1 sequences obtained from two accessions of C. crassa from Ecuador (GenBank accession numbers OM471920 and OM471919 for isolates CIBE-17 and CIBE-18, respectively) and three from Peru (GenBank accession numbers OM471921, OM471922, and OM471923 for isolates CIBE-13, CIBE-14, and CIBE-15, respectively). The accessions available in the GenBank were used for phylogenetic analysis. For the phytochemical analysis, hydroalcoholic extracts were obtained by maceration using 80% ethanol as solvent, followed by a derivatization process and analysis by gas chromatography–mass spectrometry. Based on the phylogenetic analysis of the C. crassa samples, the ITS1 sequence could be used to differentiate C. crassa of different locations. The samples of C. crassa from Ecuador and Peru are more similar between them than with other clades including Helosis spp. The phytochemical study revealed differences in the presence and relative abundance of some metabolites; mainly eugenol, 1,4-lactone arabinonic acid, dimethoxyrabelomycin and azelaic acid, which are reported for the first time for the species under study and the genus Corynaea. These results are the first findings on the combined analysis using genetic and phytochemical analysis for C. crassa, which could be used as a useful tool for quality control of the C. crassa species in medicinal products. Full article

(This article belongs to the Special Issue Molecular Markers in Plant Genetics and Breeding)

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16 pages, 2613 KiB

Open AccessEditor’s ChoiceArticle

Are the Organellar Genomes Useful for Fine Scale Population Structure Analysis of Endangered Plants?—A Case Study of Pulsatilla patens (L.) Mill

by Kamil Szandar, Sawicki Jakub, Łukasz Paukszto, Katarzyna Krawczyk and Monika Szczecińska

Genes 2023, 14(1), 67; https://doi.org/10.3390/genes14010067 - 25 Dec 2022

Cited by 2 | Viewed by 2503

Abstract

Pulsatilla patens is a rare and endangered species in Europe and its population resources have significantly decreased over the past decades. Previous genetic studies of this species made it possible to estimate the genetic diversity of the European population and to describe the [...] Read more.

Pulsatilla patens is a rare and endangered species in Europe and its population resources have significantly decreased over the past decades. Previous genetic studies of this species made it possible to estimate the genetic diversity of the European population and to describe the structure of chloroplast and mitochondrial genomes. The main aim of these studies was to characterize the variability of chloroplast and mitochondrial genomes in more detail at the intra-population and inter-population levels. Our study presents new organelle genome reference sequences that allow the design of novel markers that can be the starting point for testing hypotheses, past and modern biogeography of rare and endangered species P. patens, and adaptive responses of this species to changing environments. The study included sixteen individuals from five populations located in Northeastern Poland. Comparative analysis of 16 P. patens plastomes from 5 populations enabled us to identify 160 point mutations, including 64 substitutions and 96 InDels. The most numerous detected SNPs and Indels (75%) were accumulated in three intergenic spacers: ndhD—ccsA, rps4—rps16, and trnL(UAG)—ndhF. The mitogenome dataset, which was more than twice as large as the plastome (331 kbp vs. 151 kbp), revealed eight times fewer SNPs (8 vs. 64) and six times fewer InDels (16 vs. 96). Both chloroplast and mitochondrial genome identified the same number of haplotypes—11 out of 16 individuals, but both organellar genomes slightly differ in haplotype clustering. Despite the much lower variation, mitogenomic data provide additional resolution in the haplotype detection of P. patens, enabling molecular identification of individuals, which were unrecognizable based on the plastome dataset. Full article

(This article belongs to the Topic Plant Chloroplast Genome and Evolution)

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4 pages, 194 KiB

Open AccessEditor’s ChoiceEditorial

Special Issue “Feature Papers in Population and Evolutionary Genetics and Genomics”

by Maria-Anna Kyrgiafini and Zissis Mamuris

Genes 2023, 14(1), 38; https://doi.org/10.3390/genes14010038 - 23 Dec 2022

Viewed by 1334

Abstract

Theodosius Dobzhansky famously wrote in 1973 that “nothing in biology makes sense except in the light of evolution” [...] Full article

(This article belongs to the Special Issue Feature Papers in Population and Evolutionary Genetics and Genomics)

10 pages, 876 KiB

Open AccessEditor’s ChoiceCommunication

Genotype Distribution of the ACTN3 p.R577X Polymorphism in Elite Badminton Players: A Preliminary Study

by Javier Abián-Vicén, Pablo Abián, Alfredo Bravo-Sánchez, Inés Piñas-Bonilla, Beatriz Lara and Juan Del Coso

Genes 2023, 14(1), 50; https://doi.org/10.3390/genes14010050 - 23 Dec 2022

Cited by 3 | Viewed by 3695

Abstract

α-Actinin-3 is a protein with a structural role at the sarcomeric Z-line in skeletal muscle. As it is only present in fast-type muscle fibers, α-actinin-3 is considered a key mechanical component to produce high-intensity muscle contractions and to withstand external tension applied to [...] Read more.

α-Actinin-3 is a protein with a structural role at the sarcomeric Z-line in skeletal muscle. As it is only present in fast-type muscle fibers, α-actinin-3 is considered a key mechanical component to produce high-intensity muscle contractions and to withstand external tension applied to the skeletal muscle. α-Actinin-3 is encoded by the gene ACTN3, which has a single-nucleotide polymorphism (p.R577X; rs1815739) that affects the expression of α-actinin-3 due to the presence of a stop codon. Individuals homozygous for the 577R allele (i.e., RR genotype) and RX heterozygotes express functional α-actinin-3, while those homozygous for the 577X (i.e., XX genotype) express a non-functional protein. There is ample evidence to support the associations between the ACTN3 genotype and athletic performance, with higher frequencies of the 577R allele in elite and professional sprint and power athletes than in control populations. This suggests a beneficial influence of possessing functional α-actinin-3 to become an elite athlete in power-based disciplines. However, no previous investigation has determined the frequency of the ACTN3 genotypes in elite badminton players, despite this sport being characterized by high-intensity actions of intermittent nature such as changes of direction, accelerations, jumps and smashes. The purpose of this study was to analyze ACTN3 R577X genotype frequencies in professional badminton players to establish whether this polymorphism is associated with elite athlete status. A total of 53 European Caucasian professional badminton players competing in the 2018 European Badminton Championships volunteered to participate in the study. Thirty-one were men (26.2 ± 4.4 years) and twenty-two were women (23.4 ± 4.5 years). Chi-squared tests were used to analyze the differences in the distribution of ACTN3 genotypes (RR, RX and XX) between categories and sexes. The ACTN3 RR genotype was the most frequent in the sample of professional badminton players (RR = 49.1%, RX = 22.6% and XX = 28.3%). None of the badminton players ranked in the world’s top ten possessed the XX genotype (RX = 60%, RR = 40%). The distribution of the ACTN3 genotypes was similar between male and female professional badminton players (men: RR = 45.2%, RX = 25.8% and XX = 29.0%; women: RR = 54.5%, RX = 18.2% and XX = 27.3%; χ² = 0.58; p = 0.750). The distribution of the ACTN3 genotypes in badminton players was different from the 1000 genome database for the European population (χ² = 15.5; p < 0.001), with an overrepresentation of the RR genotype (p < 0.05) and an underrepresentation of the RX genotype (p < 0.01). In conclusion, the expression of functional α-actinin-3, associated with RR and RX genotypes in the ACTN3 gene may confer an advantage for reaching the status of elite athlete in badminton, and especially the world’s top-ten ranking. Large-scale studies with different ethnic backgrounds are needed to confirm the association of the R allele of ACTN3 with badminton performance. Full article

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

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12 pages, 1523 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Predictors of Smoking in Older Adults and an Epigenetic Validation of Self-Report

by Jeffrey D. Long, Michael P. Gehlsen, Joanna Moody, Gracie Weeks and Robert Philibert

Genes 2023, 14(1), 25; https://doi.org/10.3390/genes14010025 - 22 Dec 2022

Cited by 1 | Viewed by 2099

Abstract

There are several established predictors of smoking, but it is unknown if these predictors operate similarly for young and old smokers. We examined clinical data from the National Lung Screening Trial (NLST) to determine the predictive ability of gender, body mass index (BMI), [...] Read more.

There are several established predictors of smoking, but it is unknown if these predictors operate similarly for young and old smokers. We examined clinical data from the National Lung Screening Trial (NLST) to determine the predictive ability of gender, body mass index (BMI), marital status, and race on smoking behavior, with emphasis on gender interactions. In addition, we validated the self-report of smoking behaviors for a subgroup that had available epigenetic data in the form of cg05575921 methylation. Participants were

N = 9572

current or former smokers from the NLST biofluids database, age 55–74, minimum of 30 pack years, and mostly White. A subgroup of

N = 3084

who had DNA were used for the self-report validation analysis. The predictor analysis was based on the larger group and used penalized logistic regression to predict the self-report of being a former or current smoker at baseline. Cg05575921 methylation showed a moderate ability to discriminate among former and current smokers, AUC = 0.85 (95% confidence interval = [0.83, 0.86]). The final selected variables for the prediction model were BMI, gender, BMI by gender, age, divorced (vs. married), education, and race. The gender by BMI interaction was such that males had a higher probability of current smoking for lower BMI, but this switched to females having higher current smoking for overweight to obese. There is evidence that the self-reported smoking behavior in NLST is moderately accurate. The results of the primary analysis are consistent with the general smoking literature, and our results provide additional specificity regarding the gender by BMI interaction. Body weight issues might play a role in smoking cessation for older established smokers in a similar manner as younger smokers. It could be that women have less success with cessation when their BMI increases. Full article

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

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15 pages, 2062 KiB

Open AccessEditor’s ChoiceArticle

Sex Differences in Response to Marek’s Disease: Mapping Quantitative Trait Loci Regions (QTLRs) to the Z Chromosome

by Ehud Lipkin, Jacqueline Smith, Morris Soller, David W. Burt and Janet E. Fulton

Genes 2023, 14(1), 20; https://doi.org/10.3390/genes14010020 - 21 Dec 2022

Cited by 3 | Viewed by 2468

Abstract

Marek’s Disease (MD) has a significant impact on both the global poultry economy and animal welfare. The disease pathology can include neurological damage and tumour formation. Sexual dimorphism in immunity and known higher susceptibility of females to MD makes the chicken Z chromosome [...] Read more.

Marek’s Disease (MD) has a significant impact on both the global poultry economy and animal welfare. The disease pathology can include neurological damage and tumour formation. Sexual dimorphism in immunity and known higher susceptibility of females to MD makes the chicken Z chromosome (GGZ) a particularly attractive target to study the chicken MD response. Previously, we used a Hy-Line F₆ population from a full-sib advanced intercross line to map MD QTL regions (QTLRs) on all chicken autosomes. Here, we mapped MD QTLRs on GGZ in the previously utilized F₆ population with individual genotypes and phenotypes, and in eight elite commercial egg production lines with daughter-tested sires and selective DNA pooling (SDP). Four MD QTLRs were found from each analysis. Some of these QTLRs overlap regions from previous reports. All QTLRs were tested by individuals from the same eight lines used in the SDP and genotyped with markers located within and around the QTLRs. All QTLRs were confirmed. The results exemplify the complexity of MD resistance in chickens and the complex distribution of p-values and Linkage Disequilibrium (LD) pattern and their effect on localization of the causative elements. Considering the fragments and interdigitated LD blocks while using LD to aid localization of causative elements, one must look beyond the non-significant markers, for possible distant markers and blocks in high LD with the significant block. The QTLRs found here may explain at least part of the gender differences in MD tolerance, and provide targets for mitigating the effects of MD. Full article

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

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15 pages, 2019 KiB

Open AccessEditor’s ChoiceReview

Roles of Polycomb Complexes in the Reconstruction of 3D Genome Architecture during Preimplantation Embryonic Development

by Longtao Yu, Hengxiang Shen and Xiaowen Lyu

Genes 2022, 13(12), 2382; https://doi.org/10.3390/genes13122382 - 16 Dec 2022

Cited by 1 | Viewed by 2913

Abstract

The appropriate deployment of developmental programs depends on complex genetic information encoded by genomic DNA sequences and their positioning and contacts in the three-dimensional (3D) space within the nucleus. Current studies using novel techniques including, but not limited to, Hi-C, ChIA-PET, and Hi-ChIP [...] Read more.

The appropriate deployment of developmental programs depends on complex genetic information encoded by genomic DNA sequences and their positioning and contacts in the three-dimensional (3D) space within the nucleus. Current studies using novel techniques including, but not limited to, Hi-C, ChIA-PET, and Hi-ChIP reveal that regulatory elements (Res), such as enhancers and promoters, may participate in the precise regulation of expression of tissue-specific genes important for both embryogenesis and organogenesis by recruiting Polycomb Group (PcG) complexes. PcG complexes usually poise the transcription of developmental genes by forming Polycomb bodies to compact poised enhancers and promoters marked by H3K27me3 in the 3D space. Additionally, recent studies have also uncovered their roles in transcriptional activation. To better understand the full complexities in the mechanisms of how PcG complexes regulate transcription and long-range 3D contacts of enhancers and promoters during developmental programs, we outline novel insights regarding PcG-associated dramatic changes in the 3D chromatin conformation in developmental programs of early embryos and naïve-ground-state transitions of pluripotent embryonic stem cells (ESCs), and highlight the distinct roles of unique and common subunits of canonical and non-canonical PcG complexes in shaping genome architectures and transcriptional programs. Full article

(This article belongs to the Special Issue Dynamics of 3D Genome Organization)

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12 pages, 2444 KiB

Open AccessEditor’s ChoiceArticle

PCYT1A Missense Variant in Vizslas with Disproportionate Dwarfism

by Odette Ludwig-Peisker, Emily Ansel, Daniela Schweizer, Vidhya Jagannathan, Robert Loechel and Tosso Leeb

Genes 2022, 13(12), 2354; https://doi.org/10.3390/genes13122354 - 13 Dec 2022

Cited by 2 | Viewed by 3861

Abstract

Disproportionate dwarfism phenotypes represent a heterogeneous subset of skeletal dysplasias and have been described in many species including humans and dogs. In this study, we investigated Vizsla dogs that were affected by disproportionate dwarfism that we propose to designate as skeletal dysplasia 3 [...] Read more.

Disproportionate dwarfism phenotypes represent a heterogeneous subset of skeletal dysplasias and have been described in many species including humans and dogs. In this study, we investigated Vizsla dogs that were affected by disproportionate dwarfism that we propose to designate as skeletal dysplasia 3 (SD3). The most striking skeletal changes comprised a marked shortening and deformation of the humerus and femur. An extended pedigree with six affected dogs suggested autosomal recessive inheritance. Combined linkage and homozygosity mapping localized a potential genetic defect to a ~4 Mb interval on chromosome 33. We sequenced the genome of an affected dog, and comparison with 926 control genomes revealed a single, private protein-changing variant in the critical interval, PCYT1A:XM_038583131.1:c.673T>C, predicted to cause an exchange of a highly conserved amino acid, XP_038439059.1:p.(Y225H). We observed perfect co-segregation of the genotypes with the phenotype in the studied family. When genotyping additional Vizslas, we encountered a single dog with disproportionate dwarfism that did not carry the mutant PCYT1A allele, which we hypothesize was due to heterogeneity. In the remaining 130 dogs, we observed perfect genotype–phenotype association, and none of the unaffected dogs were homozygous for the mutant PCYT1A allele. PCYT1A loss-of-function variants cause spondylometaphyseal dysplasia with cone–rod dystrophy (SMD-CRD) in humans. The skeletal changes in Vizslas were comparable to human patients. So far, no ocular phenotype has been recognized in dwarf Vizslas. We propose the PCYT1A missense variant as a candidate causative variant for SD3. Our data facilitate genetic testing of Vizslas to prevent the unintentional breeding of further affected puppies. Full article

(This article belongs to the Special Issue Advances in Canine Genetics)

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19 pages, 4239 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Evolutionary Relationships and Divergence of Filamin Gene Family Involved in Development and Stress in Cotton (Gossypium hirsutum L.)

by Mingyang Wang, Lanxin Wu, Shouhong Zhu, Wei Chen, Jinbo Yao, Yan Li, Tengyu Li, Haihong Shang and Yongshan Zhang

Genes 2022, 13(12), 2313; https://doi.org/10.3390/genes13122313 - 8 Dec 2022

Viewed by 1881

Abstract

Filamin protein is characterized by an N-terminal actin-binding domain that is followed by 24 Ig (immunoglobulin)-like repeats, which act as hubs for interactions with a variety of proteins. In humans, this family has been found to be involved in cancer cell invasion and [...] Read more.

Filamin protein is characterized by an N-terminal actin-binding domain that is followed by 24 Ig (immunoglobulin)-like repeats, which act as hubs for interactions with a variety of proteins. In humans, this family has been found to be involved in cancer cell invasion and metastasis and can be involved in a variety of growth signal transduction processes, but it is less studied in plants. Therefore, in this study, 54 Filamin gene family members from 23 plant species were investigated and divided into two subfamilies: FLMN and GEX2. Subcellular localization showed that most of the Filamin gene family members were located in the cell membrane. A total of 47 Filamin gene pairs were identified, most of which were whole-genome copies. Through the analyses of cis-acting elements, expression patterns and quantitative fluorescence, it was found that GH_ A02G0519 and GH_ D02G0539 are mainly expressed in the reproductive organs of upland cotton, and their interacting proteins are also related to the fertilization process, whereas GH_A02G0216 and GH_D02G0235 were related to stress. Thus, it is speculated that two genes of the GEX2 subfamily (GH_A02G0519 and GH_D02G0539) may be involved in the reproductive development of cotton and may affect the fertilization process of cotton. This study provides a theoretical basis for the further study of the cotton Filamin gene family. Full article

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

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14 pages, 1762 KiB

Open AccessEditor’s ChoiceArticle

Unaffected Li-Fraumeni Syndrome Carrier Parent Demonstrates Allele-Specific mRNA Stabilization of Wild-Type TP53 Compared to Affected Offspring

by Jeffrey S. Buzby, Shirley A. Williams and Diane J. Nugent

Genes 2022, 13(12), 2302; https://doi.org/10.3390/genes13122302 - 7 Dec 2022

Viewed by 2172

Abstract

Li-Fraumeni Syndrome (LFS) is an autosomal dominant disorder where an oncogenic TP53 germline mutation is inherited by offspring of a carrier parent. p53 is a key tumor suppressor regulating cell cycle arrest in response to DNA damage. Unexpectedly, some mutant TP53 carriers remain [...] Read more.

Li-Fraumeni Syndrome (LFS) is an autosomal dominant disorder where an oncogenic TP53 germline mutation is inherited by offspring of a carrier parent. p53 is a key tumor suppressor regulating cell cycle arrest in response to DNA damage. Unexpectedly, some mutant TP53 carriers remain unaffected, while their children develop cancer early in life. To begin unravelling this paradox, the response of dermal fibroblasts (dFb) isolated from a child with LFS was compared to those from her unaffected father after UV exposure. Phospho-Chk1[S345], a key activator of cell cycle arrest, was increased by UV induction in the LFS patient compared to their unaffected parent dFb. This result, along with previous findings of reduced CDKN1A/p21 UV induction in affected dFb, suggest that cell cycle dysregulation may contribute to cancer onset in the affected LFS subject but not the unaffected parent. Mutant p53 protein and its promoter binding affinity were also higher in dFb from the LFS patient compared to their unaffected parent. These results were as predicted based on decreased mutant TP53 allele-specific mRNA expression previously found in unaffected dFb. Investigation of the potential mechanism regulating this TP53 allele-specific expression found that, while epigenetic promoter methylation was not detectable, TP53 wild-type mRNA was specifically stabilized in the unaffected dFb. Hence, the allele-specific stabilization of wild-type TP53 mRNA may allow an unaffected parent to counteract genotoxic stress by means more characteristic of homozygous wild-type TP53 individuals than their affected offspring, providing protection from the oncogenesis associated with LFS. Full article

(This article belongs to the Special Issue Carcinogenesis as an Evolutionary Process)

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15 pages, 1628 KiB

Open AccessEditor’s ChoiceArticle

Characterizing Macrophages Diversity in COVID-19 Patients Using Deep Learning

by Mario A. Flores, Karla Paniagua, Wenjian Huang, Ricardo Ramirez, Leonardo Falcon, Andy Liu, Yidong Chen, Yufei Huang and Yufang Jin

Genes 2022, 13(12), 2264; https://doi.org/10.3390/genes13122264 - 1 Dec 2022

Cited by 2 | Viewed by 2979

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for coronavirus disease 2019 (COVID-19), has affected the lives of billions and killed millions of infected people. This virus has been demonstrated to have different outcomes among individuals, with some of [...] Read more.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for coronavirus disease 2019 (COVID-19), has affected the lives of billions and killed millions of infected people. This virus has been demonstrated to have different outcomes among individuals, with some of them presenting a mild infection, while others present severe symptoms or even death. The identification of the molecular states related to the severity of a COVID-19 infection has become of the utmost importance to understanding the differences in critical immune response. In this study, we computationally processed a set of publicly available single-cell RNA-Seq (scRNA-Seq) data of 12 Bronchoalveolar Lavage Fluid (BALF) samples diagnosed as having a mild, severe, or no infection, and generated a high-quality dataset that consists of 63,734 cells, each with 23,916 genes. We extended the cell-type and sub-type composition identification and our analysis showed significant differences in cell-type composition in mild and severe groups compared to the normal. Importantly, inflammatory responses were dramatically elevated in the severe group, which was evidenced by the significant increase in macrophages, from 10.56% in the normal group to 20.97% in the mild group and 34.15% in the severe group. As an indicator of immune defense, populations of T cells accounted for 24.76% in the mild group and decreased to 7.35% in the severe group. To verify these findings, we developed several artificial neural networks (ANNs) and graph convolutional neural network (GCNN) models. We showed that the GCNN models reach a prediction accuracy of the infection of 91.16% using data from subtypes of macrophages. Overall, our study indicates significant differences in the gene expression profiles of inflammatory response and immune cells of severely infected patients. Full article

(This article belongs to the Special Issue Selected Papers from the International Conference on Intelligent Biology and Medicine (ICIBM 2022))

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12 pages, 1243 KiB

Open AccessEditor’s ChoiceArticle

Assessment of Rare Genetic Variants to Identify Candidate Modifier Genes Underlying Neurological Manifestations in Neurofibromatosis 1 Patients

by Jie Tang, Niu Li, Guoqiang Li, Jian Wang, Tingting Yu and Ruen Yao

Genes 2022, 13(12), 2218; https://doi.org/10.3390/genes13122218 - 26 Nov 2022

Viewed by 1998

Abstract

Neurological phenotypes such as intellectual disability occur in almost half of patients with neurofibromatosis 1 (NF1). Current genotype–phenotype studies have failed to reveal the mechanism underlying this clinical variability. Despite the presence of pathogenic variants of NF1, modifier genes likely determine the occurrence [...] Read more.

Neurological phenotypes such as intellectual disability occur in almost half of patients with neurofibromatosis 1 (NF1). Current genotype–phenotype studies have failed to reveal the mechanism underlying this clinical variability. Despite the presence of pathogenic variants of NF1, modifier genes likely determine the occurrence and severity of neurological phenotypes. Exome sequencing data were used to identify genetic variants in 13 NF1 patients and 457 healthy controls, and this information was used to identify candidate modifier genes underlying neurological phenotypes based on an optimal sequence kernel association test. Thirty-six genes were identified as significant modifying factors in patients with neurological phenotypes and all are highly expressed in the nervous system. A review of the literature confirmed that 19 genes including CUL7, DPH1, and BCO1 are clearly associated with the alteration of neurological functioning and development. Our study revealed the enrichment of rare variants of 19 genes closely related to neurological development and functioning in NF1 patients with neurological phenotypes, indicating possible modifier genes and variants affecting neurodevelopment. Further studies on rare genetic variants of candidate modifier genes may help explain the clinical heterogeneity of NF1. Full article

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

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14 pages, 4564 KiB

Open AccessEditor’s ChoiceArticle

Dbf4 Zn-Finger Motif Is Specifically Required for Stimulation of Ctf19-Activated Origins in Saccharomyces cerevisiae

by Meghan V. Petrie, Haiyang Zhang, Emily M. Arnold, Yan Gan and Oscar M. Aparicio

Genes 2022, 13(12), 2202; https://doi.org/10.3390/genes13122202 - 24 Nov 2022

Viewed by 2130

Abstract

Eukaryotic genomes are replicated in spatiotemporal patterns that are stereotypical for individual genomes and developmental profiles. In the model system Saccharomyces cerevisiae, two primary mechanisms determine the preferential activation of replication origins during early S phase, thereby largely defining the consequent replication [...] Read more.

Eukaryotic genomes are replicated in spatiotemporal patterns that are stereotypical for individual genomes and developmental profiles. In the model system Saccharomyces cerevisiae, two primary mechanisms determine the preferential activation of replication origins during early S phase, thereby largely defining the consequent replication profiles of these cells. Both mechanisms are thought to act through specific recruitment of a rate-limiting initiation factor, Dbf4-dependent kinase (DDK), to a subset of licensed replication origins. Fkh1/2 is responsible for stimulation of most early-firing origins, except for centromere (CEN)-proximal origins that recruit DDK via the kinetochore protein Ctf19, which is required for their early firing. The C-terminus of Dbf4 has been implicated in its recruitment to origins via both the Fkh1/2 and Ctf19 mechanisms. Here, we show that the Zn-finger motif within the C-terminus is specifically required for Dbf4 recruitment to CENs to stimulate CEN-proximal/Ctf19-dependent origins, whereas stimulation of origins via the Fkh1/2 pathway remains largely intact. These findings re-open the question of exactly how Fkh1/2 and DDK act together to stimulate replication origin initiation. Full article

(This article belongs to the Special Issue DNA Replication Kinetics)

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15 pages, 6420 KiB

Open AccessEditor’s ChoiceTechnical Note

A Multigraph-Based Representation of Hi-C Data

by Diána Makai, András Cseh, Adél Sepsi and Szabolcs Makai

Genes 2022, 13(12), 2189; https://doi.org/10.3390/genes13122189 - 23 Nov 2022

Viewed by 3103

Abstract

Chromatin–chromatin interactions and three-dimensional (3D) spatial structures are involved in transcriptional regulation and have a decisive role in DNA replication and repair. To understand how individual genes and their regulatory elements function within the larger genomic context, and how the genome reacts to [...] Read more.

Chromatin–chromatin interactions and three-dimensional (3D) spatial structures are involved in transcriptional regulation and have a decisive role in DNA replication and repair. To understand how individual genes and their regulatory elements function within the larger genomic context, and how the genome reacts to environmental stimuli, the linear sequence information needs to be interpreted in three-dimensional space, which is still a challenging task. Here, we propose a novel, heuristic approach to represent Hi-C datasets by a whole-genomic pseudo-structure in 3D space. The baseline of our approach is the construction of a multigraph from genomic-sequence data and Hi-C interaction data, then applying a modified force-directed layout algorithm. The resulting layout is a pseudo-structure. While pseudo-structures are not based on direct observation and their details are inherent to settings, surprisingly, they demonstrate interesting, overall similarities of known genome structures of both barley and rice, namely, the Rabl and Rosette-like conformation. It has an exciting potential to be extended by additional omics data (RNA-seq, Chip-seq, etc.), allowing to visualize the dynamics of the pseudo-structures across various tissues or developmental stages. Furthermore, this novel method would make it possible to revisit most Hi-C data accumulated in the public domain in the last decade. Full article

(This article belongs to the Special Issue Application of Bioinformatics in Plants)

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14 pages, 2547 KiB

Open AccessEditor’s ChoiceArticle

Anticipating the Next Chess Move: Blocking SARS-CoV-2 Replication and Simultaneously Disarming Viral Escape Mechanisms

by Samir Mansour Moraes Casseb, André Salim Khayat, Jorge Estefano Santana de Souza, Edivaldo Herculano Correa de Oliveira, Sidney Emanuel Batista Dos Santos, Pedro Fernando da Costa Vasconcelos and Paulo Pimentel de Assumpção

Genes 2022, 13(11), 2147; https://doi.org/10.3390/genes13112147 - 18 Nov 2022

Cited by 2 | Viewed by 2468

Abstract

The COVID-19 pandemic initiated a race to determine the best measures to control the disease and to save as many people as possible. Efforts to implement social distancing, the use of masks, and massive vaccination programs turned out to be essential in reducing [...] Read more.

The COVID-19 pandemic initiated a race to determine the best measures to control the disease and to save as many people as possible. Efforts to implement social distancing, the use of masks, and massive vaccination programs turned out to be essential in reducing the devastating effects of the pandemic. Nevertheless, the high mutation rates of SARS-CoV-2 challenge the vaccination strategy and maintain the threat of new outbreaks due to the risk of infection surges and even lethal variations able to resist the effects of vaccines and upset the balance. Most of the new therapies tested against SARS-CoV-2 came from already available formulations developed to treat other diseases, so they were not specifically developed for SARS-CoV-2. In parallel, the knowledge produced regarding the molecular mechanisms involved in this disease was vast due to massive efforts worldwide. Taking advantage of such a vast molecular understanding of virus genomes and disease mechanisms, a targeted molecular therapy based on siRNA specifically developed to reach exclusive SARS-CoV-2 genomic sequences was tested in a non-transformed human cell model. Since coronavirus can escape from siRNA by producing siRNA inhibitors, a complex strategy to simultaneously strike both the viral infectious mechanism and the capability of evading siRNA therapy was developed. The combined administration of the chosen produced siRNA proved to be highly effective in successfully reducing viral load and keeping virus replication under control, even after many days of treatment, unlike the combinations of siRNAs lacking this anti-anti-siRNA capability. Additionally, the developed therapy did not harm the normal cells, which was demonstrated because, instead of testing the siRNA in nonhuman cells or in transformed human cells, a non-transformed human thyroid cell was specifically chosen for the experiment. The proposed siRNA combination could reduce the viral load and allow the cellular recovery, presenting a potential innovation for consideration as an additional strategy to counter or cope COVID-19. Full article

(This article belongs to the Section Viral Genomics)

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8 pages, 1944 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Congenital Nail Disorders among Children with Suspected Ectodermal Dysplasias

by Sigrun Maier-Wohlfart, Carmen Aicher, Ines Willershausen, Nicolai Peschel, Udo Meißner, Lina Gölz and Holm Schneider

Genes 2022, 13(11), 2119; https://doi.org/10.3390/genes13112119 - 15 Nov 2022

Cited by 2 | Viewed by 6440

Abstract

We report on a cohort of 204 children referred between January 2017 and January 2022 to the German Center for Ectodermal Dysplasias, Erlangen. The most frequent reasons for referral were tooth malformations and lack of multiple teeth leading to the suspicion of an [...] Read more.

We report on a cohort of 204 children referred between January 2017 and January 2022 to the German Center for Ectodermal Dysplasias, Erlangen. The most frequent reasons for referral were tooth malformations and lack of multiple teeth leading to the suspicion of an ectodermal dysplasia. Many patients also suffered from being unable to perspire. Nail abnormalities, in contrast, represented a much rarer finding, albeit the impact on some individuals was large. As ectodermal dysplasias are congenital genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands, we analyzed congenital nail disorders detected in these patients. Dystrophic or otherwise abnormal nails were evident in 17 of 18 subjects with pathogenic WNT10A or GJB6 variants but in none of 161 children with EDA variants underlying X-linked hypohidrotic ectodermal dysplasia. However, 2 of 17 children who carry mutations in EDAR or EDARADD, two other genes involved in the ectodysplasin A signaling pathway, showed nail abnormalities, such as brittle or hypoplastic nails. TP63 variants were regularly associated with nail disorders. In one girl, anonychia congenita caused by a compound heterozygous variant of the R-spondin-4 gene (RSPO4) was diagnosed. Thus, nail dysplasia is rarer among patients with ectodermal dysplasia than commonly thought. Full article

(This article belongs to the Special Issue Molecular Biology and Treatment of Genodermatoses)

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9 pages, 1642 KiB

Open AccessEditor’s ChoiceCommunication

Targeted Panel Sequencing Identifies an Intronic c.5225-3C>G Variant of the FBN1 Gene Causing Sporadic Marfan Syndrome with Annuloaortic Ectasia

by Kyung Hwa Kim, Tae Yun Kim, Soon Jin Kim, Yong Gon Cho, Joonhong Park and Woori Jang

Genes 2022, 13(11), 2108; https://doi.org/10.3390/genes13112108 - 13 Nov 2022

Cited by 1 | Viewed by 2401

Abstract

Marfan syndrome (MFS) is a hereditary connective tissue disease whose clinical severity varies widely. Mutations of the FBN1 gene encoding fibrillin-1 are the most common genetic cause of Marfanoid habitus; however, about 10% of MFS patients are unaware of their genetic defects. Herein, [...] Read more.

Marfan syndrome (MFS) is a hereditary connective tissue disease whose clinical severity varies widely. Mutations of the FBN1 gene encoding fibrillin-1 are the most common genetic cause of Marfanoid habitus; however, about 10% of MFS patients are unaware of their genetic defects. Herein, we report a Korean patient with MFS and annuloaortic ectasia caused by an intronic c.5225-3C>G variant of the FBN1 gene identified by targeted panel sequencing. The reverse transcription analysis of FBN1 revealed that the intron 43 sequence from positions c.5297-1516 to c.5297-1 was retained at the coding sequence as a consequence of the c.5225-3C>G variant enhancing a cryptic splice acceptor site (c.5297-1518_5297-1517AG) in intron 43. The retained sequence of the part of intron 43 caused the same effect as insertion mutation (NM_000138.5:c.5297_c.5298ins5297-1516_5297-1), resulting in a frameshift mutation resulting in p.Ile1767Trpfs*3. The patient underwent an urgent modified Bentall operation with a 29 mm mechanical valve for annuloaortic ectasia and severe aortic valve regurgitation. This report emphasizes the need for functional investigations into the diagnostic workflows of certain diseases or gene panels with suspected high rates of intronic variants and potential pathogenic effects. Hence, further descriptions of individuals with intronic variants causing alternative splicing expected to have pathogenic effects at different transcript levels are crucial for improving our understanding. Full article

(This article belongs to the Special Issue Next Generation Sequencing in Clinical Diagnostics)

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3 pages, 185 KiB

Open AccessEditor’s ChoiceEditorial

Special Issue: Genetics of Psychiatric Disease and the Basics of Neurobiology

by Laia Rodriguez-Revenga and Maria Isabel Alvarez-Mora

Genes 2022, 13(11), 2008; https://doi.org/10.3390/genes13112008 - 2 Nov 2022

Viewed by 1487

Abstract

A psychiatric disorder is a mental illness involving significant disturbances in thinking, emotional regulation or behavior [...] Full article

(This article belongs to the Special Issue Genetics of Psychiatric Disease and the Basics of Neurobiology)

16 pages, 1270 KiB

Open AccessEditor’s ChoiceArticle

Genetic Hearing Loss Affects Cochlear Processing

by Cris Lanting, Ad Snik, Joop Leijendeckers, Arjan Bosman and Ronald Pennings

Genes 2022, 13(11), 1923; https://doi.org/10.3390/genes13111923 - 22 Oct 2022

Viewed by 1693

Abstract

The relationship between speech recognition and hereditary hearing loss is not straightforward. Underlying genetic defects might determine an impaired cochlear processing of sound. We obtained data from nine groups of patients with a specific type of genetic hearing loss. For each group, the [...] Read more.

The relationship between speech recognition and hereditary hearing loss is not straightforward. Underlying genetic defects might determine an impaired cochlear processing of sound. We obtained data from nine groups of patients with a specific type of genetic hearing loss. For each group, the affected cochlear site-of-lesion was determined based on previously published animal studies. Retrospectively obtained speech recognition scores in noise were related to several aspects of supra-threshold cochlear processing as assessed by psychophysical measurements. The differences in speech perception in noise between these patient groups could be explained by these factors and partially by the hypothesized affected structure of the cochlea, suggesting that speech recognition in noise was associated with a genetics-related malfunctioning of the cochlea. In particular, regression models indicate that loudness growth and spectral resolution best describe the cochlear distortions and are thus a good biomarker for speech understanding in noise. Full article

(This article belongs to the Special Issue Functional Otogenetics)

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10 pages, 273 KiB

Open AccessEditor’s ChoiceArticle

Posttransplant Complications and Genetic Loci Involved in Telomere Maintenance in Heart Transplant Patients

by Dana Dlouha, Jevgenija Vymetalova, Sarka Novakova, Pavlina Huckova, Vera Lanska and Jaroslav Alois Hubacek

Genes 2022, 13(10), 1855; https://doi.org/10.3390/genes13101855 - 14 Oct 2022

Cited by 1 | Viewed by 1646

Abstract

Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart [...] Read more.

Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart transplant patients. DNA was isolated from paired aortic samples of 383 heart recipients (age 50.7 ± 11.9 years) and corresponding donors (age 38.7 ± 12.0 years). Variants within the TERC (rs12696304), TERF2IP (rs3784929 and rs8053257), and OBCF1 (rs4387287) genes were genotyped, and telomere length was measured using qPCR. We identified similar frequencies of genotypes in heart donors and recipients. Antibody-mediated rejection (AMR) was more common (p < 0.05) in carriers of at least one G allele within the TERF2IP locus (rs3784929). Chronic graft dysfunction (CGD) was associated with the TERC (rs12696304) GG donor genotype (p = 0.05). The genetic risk score did not determine posttransplant complication risk prediction. No associations between the analyzed polymorphisms and telomere length were detected in either donor or recipient DNA. In conclusion, possible associations between donor TERF2IP (rs3784929) and AMR and between TERC (rs12696304) and CGD were found. SNPs within the examined genes were not associated with telomere length in transplanted patients. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

11 pages, 2226 KiB

Open AccessEditor’s ChoiceArticle

Spatial and Temporal Expression Characteristics of the HBB Gene Family in Six Different Pig Breeds

by Xin Guo, Zhiguo Liu, Yulian Mu, Lei Huang, Kui Li and Jing Zhang

Genes 2022, 13(10), 1822; https://doi.org/10.3390/genes13101822 - 9 Oct 2022

Viewed by 3365

Abstract

β-Thalassemia induces hemolytic anemia caused by mutations in the β-chain gene locus. As humans progress from embryo to adulthood, hemoglobin recombines twice. To test whether similar hemoglobin reassembly occurs in pigs, bioinformatics tools were used to predict the pig hemoglobin-encoding gene. We then [...] Read more.

β-Thalassemia induces hemolytic anemia caused by mutations in the β-chain gene locus. As humans progress from embryo to adulthood, hemoglobin recombines twice. To test whether similar hemoglobin reassembly occurs in pigs, bioinformatics tools were used to predict the pig hemoglobin-encoding gene. We then systematically analyzed the expression patterns of the HBB gene family in three developmental stages (weaning, sexual maturity and physical maturity) of six different pig breeds (Landrace, Yorkshire, Wuzhishan, Songliao black, Meishan and Tibetan). The results showed that the new hemoglobin coding gene ‘HBB-like’ was found in pigs, while the HBG gene did not exist in pigs, indicating that human-like reassembly might not exist in pigs. The HBB and HBB-like genes shared highly similar amino acid sequences and gene sequences. The genes on the β-chain were highly similar between humans and pigs and the amino acid sequences of human and pig HBB genes at position 26 and positions 41–42 were identical. qPCR results showed that there were significant differences in the spatiotemporal expression patterns of the four genes (HBA, HBB, HBB-like and HBE) across breeds. Our results provide a foundation for follow-up studies assessing the relationship between the gene-encoding hemoglobin and β-thalassemia disease, as well as the construction of a gene-edited β-thalassemia miniature pig model to assess β-thalassemia treatments. Full article

(This article belongs to the Topic Animal Models of Human Disease)

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12 pages, 1477 KiB

Open AccessEditor’s ChoiceArticle

Expression Activity of Artificial Promoters for Disease Resistance in Transgenic Eucalyptus urophylla

by Zhenchi Huang, Qingchun Xu, Xiaolan Fang and Zhihua Wu

Genes 2022, 13(10), 1813; https://doi.org/10.3390/genes13101813 - 7 Oct 2022

Cited by 2 | Viewed by 2203

Abstract

The transcriptional properties of artificial promoters are closely related to the type and arrangement position of cis-elements. GWSF (374-bp) was an effective SPIP with four cis-element dimers. There were four pathogen-inducible cis-elements in the GWSF promoter (GST1-boxes, W-boxes, S-boxes, and F-boxes) and a [...] Read more.

The transcriptional properties of artificial promoters are closely related to the type and arrangement position of cis-elements. GWSF (374-bp) was an effective SPIP with four cis-element dimers. There were four pathogen-inducible cis-elements in the GWSF promoter (GST1-boxes, W-boxes, S-boxes, and F-boxes) and a minimal cauliflower mosaic virus 35S promoter. V-element dimers were inserted into the upstream (VGWSF), midstream (GWVSF), and downstream (GWSFV) regions of the original GWSF promoter sequence to examine their affect on the position. The expression activity of promoters was analyzed and estimated using the histochemical staining of leaf discs of eucalyptus with transient expression, an image digitization method to extract the color features, and the induction treatment by a plant pathogenic microorganism/inducer and qPCR assays. The histochemical staining results of the adventitious buds indicated that the promoters had been successfully integrated into the E. urophylla genome and that they drove the expression of the gus gene. There was a noticeable difference in the intensity of color between the adventitious buds on the same callus block, as well as the intensity of color within the same adventitious bud. According to the established two-factor model of blue value, there was a greater difference between the levels of the genotype factor than the promoter factor in eucalyptus leaf discs. Further, the basal and inducible transcriptional levels of the three improved promoters were investigated by qPCR. With the basal transcriptional level of the GWSF promoter normalized to one, the relative basal levels of VGWSF, GWVSF, and GWSFV were 1.40, 1.45, and 4.15, respectively. The qPCR results were consistent with the staining results of GUS histochemical staining. The three improved promoters all had the properties of being induced by salicylic acid, Ralstonia solanacearum, and Phytophthora capsici. The three improved promoters demonstrated a significantly higher TMV induction activity: their induction activity from high to low was GWSFV > GWVSF > VGWSF. The findings will be beneficial to the construction and optimization of artificial promoters for transgenic plants. Full article

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

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15 pages, 6066 KiB

Open AccessEditor’s ChoiceArticle

The Identification and Characterization of the KNOX Gene Family as an Active Regulator of Leaf Development in Trifolium repens

by Jinwan Fan, Gang Nie, Jieyu Ma, Ruchang Hu, Jie He, Feifei Wu, Zhongfu Yang, Sainan Ma, Xin Zhang and Xinquan Zhang

Genes 2022, 13(10), 1778; https://doi.org/10.3390/genes13101778 - 1 Oct 2022

Viewed by 2946

Abstract

Leaves are the primary and critical feed for herbivores. They directly determine the yield and quality of legume forage. Trifolium repens (T. repens) is an indispensable legume species, widely cultivated in temperate pastures due to its nutritional value and nitrogen fixation. [...] Read more.

Leaves are the primary and critical feed for herbivores. They directly determine the yield and quality of legume forage. Trifolium repens (T. repens) is an indispensable legume species, widely cultivated in temperate pastures due to its nutritional value and nitrogen fixation. Although the leaves of T. repens are typical trifoliate, they have unusual patterns to adapt to herbivore feeding. The number of leaflets in T. repens affects its production and utilization. The KNOX gene family encodes transcriptional regulators that are vital in regulating and developing leaves. Identification and characterization of TrKNOX gene family as an active regulator of leaf development in T. repens were studied. A total of 21 TrKNOX genes were identified from the T. repens genome database and classified into three subgroups (Class I, Class II, and Class M) based on phylogenetic analysis. Nineteen of the genes identified had four conserved domains, except for KNOX5 and KNOX9, which belong to Class M. Varying expression levels of TrKNOX genes were observed at different developmental stages and complexities of leaves. KNOX9 was observed to upregulate the leaf complexity of T. repens. Research on TrKNOX genes could be novel and further assist in exploring their functions and cultivating high-quality T. repens varieties. Full article

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

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6 pages, 989 KiB

Open AccessEditor’s ChoiceEssay

The Crazy Biology

by Philippe Monget

Genes 2022, 13(10), 1769; https://doi.org/10.3390/genes13101769 - 30 Sep 2022

Viewed by 1995

Abstract

Since the end of the 1980s and the advent of molecular biology, then the beginning of the 2000s with the sequencing of whole genomes, modern tools have never ceased to amaze us and provide answers to questions that we didn’t even dare ask [...] Read more.

Since the end of the 1980s and the advent of molecular biology, then the beginning of the 2000s with the sequencing of whole genomes, modern tools have never ceased to amaze us and provide answers to questions that we didn’t even dare ask ourselves before: Why do elephants have fewer cancers than humans? Why do humans have such big brains? How does a eukaryotic cell recognize a “foreign” DNA sequence? Are there molecular crossroads of incompatible functions? Can cells count each other? These fascinating questions have made biology in recent years almost crazy. Full article

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

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13 pages, 1560 KiB

Open AccessEditor’s ChoiceArticle

TWEAK and TNFα, Both TNF Ligand Family Members and Multiple Sclerosis-Related Cytokines, Induce Distinct Gene Response in Human Brain Microvascular Endothelial Cells

by Delphine Stephan, Anais Roger, Jehanne Aghzadi, Sylvie Carmona, Christophe Picard, Jean-Philippe Dales and Sophie Desplat-Jégo

Genes 2022, 13(10), 1714; https://doi.org/10.3390/genes13101714 - 24 Sep 2022

Cited by 4 | Viewed by 2448

Abstract

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family involved in various diseases including brain inflammatory pathologies such as multiple sclerosis. It has been demonstrated that TWEAK can induce cerebrovascular permeability in an in vitro model [...] Read more.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family involved in various diseases including brain inflammatory pathologies such as multiple sclerosis. It has been demonstrated that TWEAK can induce cerebrovascular permeability in an in vitro model of the blood–brain barrier. The molecular mechanisms playing a role in TWEAK versus TNFα signaling on cerebral microvascular endothelial cells are not well defined. Therefore, we aimed to identify gene expression changes in cultures of human brain microvascular endothelial cells (hCMEC/D3) to address changes initiated by TWEAK exposure. Taken together, our studies highlighted that gene involved in leukocyte extravasation, notably claudin-5, were differentially modulated by TWEAK and TNFα. We identified differential gene expression of hCMEC/D3 cells at three timepoints following TWEAK versus TNFα stimulation and also found distinct modulations of several canonical pathways including the actin cytoskeleton, vascular endothelial growth factor (VEGF), Rho family GTPases, and phosphatase and tensin homolog (PTEN) pathways. To our knowledge, this is the first study to interrogate and compare the effects of TWEAK versus TNFα on gene expression in brain microvascular endothelial cells. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Multiple Sclerosis)

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13 pages, 1808 KiB

Open AccessEditor’s ChoiceArticle

Differentially Methylated DNA Regions and Left Ventricular Hypertrophy in African Americans: A HyperGEN Study

by Alana C. Jones, Amit Patki, Steven A. Claas, Hemant K. Tiwari, Ninad S. Chaudhary, Devin M. Absher, Leslie A. Lange, Ethan M. Lange, Wei Zhao, Scott M. Ratliff, Sharon L. R. Kardia, Jennifer A. Smith, Marguerite R. Irvin and Donna K. Arnett

Genes 2022, 13(10), 1700; https://doi.org/10.3390/genes13101700 - 22 Sep 2022

Cited by 1 | Viewed by 2700

Abstract

Left ventricular (LV) hypertrophy (LVH) is an independent risk factor for cardiovascular disease, and African Americans experience a disparate high risk of LVH. Genetic studies have identified potential candidate genes and variants related to the condition. Epigenetic modifications may continue to help unravel [...] Read more.

Left ventricular (LV) hypertrophy (LVH) is an independent risk factor for cardiovascular disease, and African Americans experience a disparate high risk of LVH. Genetic studies have identified potential candidate genes and variants related to the condition. Epigenetic modifications may continue to help unravel disease mechanisms. We used methylation and echocardiography data from 636 African Americans selected from the Hypertension Genetic Epidemiology Network (HyperGEN) to identify differentially methylated regions (DMRs) associated with LVH. DNA extracted from whole blood was assayed on Illumina Methyl450 arrays. We fit linear mixed models to examine associations between co-methylated regions and LV traits, and we then conducted single CpG analyses within significant DMRs. We identified associations between DMRs and ejection fraction (XKR6), LV internal diastolic dimension (TRAK1), LV mass index (GSE1, RPS15 A, PSMD7), and relative wall thickness (DNHD1). In single CpG analysis, CpG sites annotated to TRAK1 and DNHD1 were significant. These CpGs were not associated with LV traits in replication cohorts but the direction of effect for DNHD1 was consistent across cohorts. Of note, DNHD1, GSE1, and PSMD7 may contribute to cardiac structural function. Future studies should evaluate relationships between regional DNA methylation patterns and the development of LVH. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Contributions to Hypertension and Blood Pressure Response to Interventions)

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8 pages, 602 KiB

Open AccessEditor’s ChoiceArticle

Population Genetic Data of 30 Insertion-Deletion Markers in the Polish Population

by Monica Abreu-Glowacka, Witold Pepinski, Eliza Michalak, Magdalena Konarzewska, Krzysztof Zak, Malgorzata Skawronska, Anna Niemcunowicz-Janica, Ireneusz Soltyszewski, Pawel Krajewski and Czeslaw Zaba

Genes 2022, 13(10), 1683; https://doi.org/10.3390/genes13101683 - 20 Sep 2022

Cited by 1 | Viewed by 2040

Abstract

(1) Background: Insertion-deletion (InDel) markers show the advantages of both short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs) and are considered alternative markers in forensic genetics. (2) Methods: Allelic frequencies and corresponding forensic efficiency parameters of 30 autosomal polymorphic InDel loci included [...] Read more.

(1) Background: Insertion-deletion (InDel) markers show the advantages of both short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs) and are considered alternative markers in forensic genetics. (2) Methods: Allelic frequencies and corresponding forensic efficiency parameters of 30 autosomal polymorphic InDel loci included in the Investigator DIPplex kit (Qiagen) were obtained in a sample of 631 unrelated Polish individuals. Allelic frequency data were compared with those reported for selected populations (3) Results: All the loci conformed with Hardy-Weinberg equilibrium after applying a Bonferroni correction and no pair-wise significant linkage disequilibrium was detected. (4) Conclusions: DIPplex Kit differences were high among populations worldwide. The InDel markers are highly discriminating for human identification purposes in the Polish population. Full article

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

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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 3382

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 2934

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 2110

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 2341

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 2032

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 2657

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 2792

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 2656

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 2544

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 3103

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 2 | Viewed by 1756

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 3045

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 2543

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 3112

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 2028

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 2679

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 2 | Viewed by 2378

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 2131

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 2809

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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