Genes

25 pages, 8475 KiB

Open AccessEditor’s ChoiceReview

Whole-Body Regeneration in Sponges: Diversity, Fine Mechanisms, and Future Prospects

by Alexander Ereskovsky, Ilya E. Borisenko, Fyodor V. Bolshakov and Andrey I. Lavrov

Genes 2021, 12(4), 506; https://doi.org/10.3390/genes12040506 - 29 Mar 2021

Cited by 25 | Viewed by 5260

While virtually all animals show certain abilities for regeneration after an injury, these abilities vary greatly among metazoans. Porifera (Sponges) is basal metazoans characterized by a wide variety of different regenerative processes, including whole-body regeneration (WBR). Considering phylogenetic position and unique body organization, [...] Read more.

While virtually all animals show certain abilities for regeneration after an injury, these abilities vary greatly among metazoans. Porifera (Sponges) is basal metazoans characterized by a wide variety of different regenerative processes, including whole-body regeneration (WBR). Considering phylogenetic position and unique body organization, sponges are highly promising models, as they can shed light on the origin and early evolution of regeneration in general and WBR in particular. The present review summarizes available data on the morphogenetic and cellular mechanisms accompanying different types of WBR in sponges. Sponges show a high diversity of WBR, which principally could be divided into (1) WBR from a body fragment and (2) WBR by aggregation of dissociated cells. Sponges belonging to different phylogenetic clades and even to different species and/or differing in the anatomical structure undergo different morphogeneses after similar operations. A common characteristic feature of WBR in sponges is the instability of the main body axis: a change of the organism polarity is described during all types of WBR. The cellular mechanisms of WBR are different across sponge classes, while cell dedifferentiations and transdifferentiations are involved in regeneration processes in all sponges. Data considering molecular regulation of WBR in sponges are extremely scarce. However, the possibility to achieve various types of WBR ensured by common morphogenetic and cellular basis in a single species makes sponges highly accessible for future comprehensive physiological, biochemical, and molecular studies of regeneration processes. Full article

(This article belongs to the Special Issue The Molecular Genetics and Major Concepts Underlying Whole Body Regeneration in the Animal World)

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23 pages, 2745 KiB

Open AccessEditor’s ChoiceReview

Diverse Regulation but Conserved Function: SOX9 in Vertebrate Sex Determination

by Brittany Vining, Zhenhua Ming, Stefan Bagheri-Fam and Vincent Harley

Genes 2021, 12(4), 486; https://doi.org/10.3390/genes12040486 - 26 Mar 2021

Cited by 28 | Viewed by 7338

Abstract

Sex determination occurs early during embryogenesis among vertebrates. It involves the differentiation of the bipotential gonad to ovaries or testes by a fascinating diversity of molecular switches. In most mammals, the switch is SRY (sex determining region Y); in other vertebrates it could [...] Read more.

Sex determination occurs early during embryogenesis among vertebrates. It involves the differentiation of the bipotential gonad to ovaries or testes by a fascinating diversity of molecular switches. In most mammals, the switch is SRY (sex determining region Y); in other vertebrates it could be one of a variety of genes including Dmrt1 or dmy. Downstream of the switch gene, SOX9 upregulation is a central event in testes development, controlled by gonad-specific enhancers across the 2 Mb SOX9 locus. SOX9 is a ‘hub’ gene of gonadal development, regulated positively in males and negatively in females. Despite this diversity, SOX9 protein sequence and function among vertebrates remains highly conserved. This article explores the cellular, morphological, and genetic mechanisms initiated by SOX9 for male gonad differentiation. Full article

(This article belongs to the Special Issue Evolution and Development of Testis)

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17 pages, 2263 KiB

Open AccessEditor’s ChoiceReview

The Diversity and Evolution of Sex Chromosomes in Frogs

by Wen-Juan Ma and Paris Veltsos

Genes 2021, 12(4), 483; https://doi.org/10.3390/genes12040483 - 26 Mar 2021

Cited by 23 | Viewed by 5870

Abstract

Frogs are ideal organisms for studying sex chromosome evolution because of their diversity in sex chromosome differentiation and sex-determination systems. We review 222 anuran frogs, spanning ~220 Myr of divergence, with characterized sex chromosomes, and discuss their evolution, phylogenetic distribution and transitions between [...] Read more.

Frogs are ideal organisms for studying sex chromosome evolution because of their diversity in sex chromosome differentiation and sex-determination systems. We review 222 anuran frogs, spanning ~220 Myr of divergence, with characterized sex chromosomes, and discuss their evolution, phylogenetic distribution and transitions between homomorphic and heteromorphic states, as well as between sex-determination systems. Most (~75%) anurans have homomorphic sex chromosomes, with XY systems being three times more common than ZW systems. Most remaining anurans (~25%) have heteromorphic sex chromosomes, with XY and ZW systems almost equally represented. There are Y-autosome fusions in 11 species, and no W-/Z-/X-autosome fusions are known. The phylogeny represents at least 19 transitions between sex-determination systems and at least 16 cases of independent evolution of heteromorphic sex chromosomes from homomorphy, the likely ancestral state. Five lineages mostly have heteromorphic sex chromosomes, which might have evolved due to demographic and sexual selection attributes of those lineages. Males do not recombine over most of their genome, regardless of which is the heterogametic sex. Nevertheless, telomere-restricted recombination between ZW chromosomes has evolved at least once. More comparative genomic studies are needed to understand the evolutionary trajectories of sex chromosomes among frog lineages, especially in the ZW systems. Full article

(This article belongs to the Special Issue Vertebrate Karyotype Evolution: How Far Have We Come, and Where Are We Going?)

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33 pages, 854 KiB

Open AccessEditor’s ChoiceReview

Kabuki Syndrome—Clinical Review with Molecular Aspects

by Snir Boniel, Krystyna Szymańska, Robert Śmigiel and Krzysztof Szczałuba

Genes 2021, 12(4), 468; https://doi.org/10.3390/genes12040468 - 25 Mar 2021

Cited by 45 | Viewed by 17428

Abstract

Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large [...] Read more.

Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals. Full article

(This article belongs to the Collection Study on Genotypes and Phenotypes of Pediatric Clinical Rare Diseases)

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21 pages, 3869 KiB

Open AccessEditor’s ChoiceArticle

Regulation of DNA (de)Methylation Positively Impacts Seed Germination during Seed Development under Heat Stress

by Jaiana Malabarba, David Windels, Wenjia Xu and Jerome Verdier

Genes 2021, 12(3), 457; https://doi.org/10.3390/genes12030457 - 23 Mar 2021

Cited by 20 | Viewed by 4500

Abstract

Seed development needs the coordination of multiple molecular mechanisms to promote correct tissue development, seed filling, and the acquisition of germination capacity, desiccation tolerance, longevity, and dormancy. Heat stress can negatively impact these processes and upon the increase of global mean temperatures, global [...] Read more.

Seed development needs the coordination of multiple molecular mechanisms to promote correct tissue development, seed filling, and the acquisition of germination capacity, desiccation tolerance, longevity, and dormancy. Heat stress can negatively impact these processes and upon the increase of global mean temperatures, global food security is threatened. Here, we explored the impact of heat stress on seed physiology, morphology, gene expression, and methylation on three stages of seed development. Notably, Arabidopsis Col-0 plants under heat stress presented a decrease in germination capacity as well as a decrease in longevity. We observed that upon mild stress, gene expression and DNA methylation were moderately affected. Nevertheless, upon severe heat stress during seed development, gene expression was intensively modified, promoting heat stress response mechanisms including the activation of the ABA pathway. By analyzing candidate epigenetic markers using the mutants’ physiological assays, we observed that the lack of DNA demethylation by the ROS1 gene impaired seed germination by affecting germination-related gene expression. On the other hand, we also observed that upon severe stress, a large proportion of differentially methylated regions (DMRs) were located in the promoters and gene sequences of germination-related genes. To conclude, our results indicate that DNA (de)methylation could be a key regulatory process to ensure proper seed germination of seeds produced under heat stress. Full article

(This article belongs to the Special Issue Seeds and Epigenetics)

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24 pages, 1008 KiB

Open AccessEditor’s ChoiceReview

Decipher the Glioblastoma Microenvironment: The First Milestone for New Groundbreaking Therapeutic Strategies

by Giuseppe Nicolò Fanelli, Dario Grassini, Valerio Ortenzi, Francesco Pasqualetti, Nicola Montemurro, Paolo Perrini, Antonio Giuseppe Naccarato and Cristian Scatena

Genes 2021, 12(3), 445; https://doi.org/10.3390/genes12030445 - 20 Mar 2021

Cited by 65 | Viewed by 5885

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite the combination of novel therapeutical approaches, it remains a deadly malignancy with an abysmal prognosis. GBM is a polymorphic tumour from both molecular and histological points of view. It consists [...] Read more.

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite the combination of novel therapeutical approaches, it remains a deadly malignancy with an abysmal prognosis. GBM is a polymorphic tumour from both molecular and histological points of view. It consists of different malignant cells and various stromal cells, contributing to tumour initiation, progression, and treatment response. GBM’s microenvironment is multifaceted and is made up of soluble factors, extracellular matrix components, tissue-resident cell types (e.g., neurons, astrocytes, endothelial cells, pericytes, and fibroblasts) together with resident (e.g., microglia) or recruited (e.g., bone marrow-derived macrophages) immune cells. These latter constitute the so-called immune microenvironment, accounting for a substantial GBM’s tumour volume. Despite the abundance of immune cells, an intense state of tumour immunosuppression is promoted and developed; this represents the significant challenge for cancer cells’ immune-mediated destruction. Though literature data suggest that distinct GBM’s subtypes harbour differences in their microenvironment, its role in treatment response remains obscure. However, an in-depth investigation of GBM’s microenvironment may lead to novel therapeutic opportunities to improve patients’ outcomes. This review will elucidate the GBM’s microenvironment composition, highlighting the current state of the art in immunotherapy approaches. We will focus on novel strategies of active and passive immunotherapies, including vaccination, gene therapy, checkpoint blockade, and adoptive T-cell therapies. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Solid Tumors)

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16 pages, 1546 KiB

Open AccessEditor’s ChoiceReview

The PARP Way to Epigenetic Changes

by Simone Ummarino, Clinton Hausman and Annalisa Di Ruscio

Genes 2021, 12(3), 446; https://doi.org/10.3390/genes12030446 - 20 Mar 2021

Cited by 23 | Viewed by 4364

Abstract

ADP-ribosylation, is a reversible post-translational modification implicated in major biological functions. Poly ADP-ribose polymerases (PARP) are specialized enzymes that catalyze the addition of ADP ribose units from “nicotinamide adenine dinucleotide-donor molecules” to their target substrates. This reaction known as PARylation modulates essential cellular [...] Read more.

ADP-ribosylation, is a reversible post-translational modification implicated in major biological functions. Poly ADP-ribose polymerases (PARP) are specialized enzymes that catalyze the addition of ADP ribose units from “nicotinamide adenine dinucleotide-donor molecules” to their target substrates. This reaction known as PARylation modulates essential cellular processes including DNA damage response, chromatin remodeling, DNA methylation and gene expression. Herein, we discuss emerging roles of PARP1 in chromatin remodeling and epigenetic regulation, focusing on its therapeutic implications for cancer treatment and beyond. Full article

(This article belongs to the Special Issue Advances in Tumor Epigenetics Research)

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29 pages, 3524 KiB

Open AccessEditor’s ChoiceReview

Molecular Regulation of Lipogenesis, Adipogenesis and Fat Deposition in Chicken

by Sara Nematbakhsh, Chong Pei Pei, Jinap Selamat, Noordiana Nordin, Lokman Hakim Idris and Ahmad Faizal Abdull Razis

Genes 2021, 12(3), 414; https://doi.org/10.3390/genes12030414 - 13 Mar 2021

Cited by 45 | Viewed by 6214

Abstract

In the poultry industry, excessive fat deposition is considered an undesirable factor, affecting feed efficiency, meat production cost, meat quality, and consumer’s health. Efforts to reduce fat deposition in economically important animals, such as chicken, can be made through different strategies; including genetic [...] Read more.

In the poultry industry, excessive fat deposition is considered an undesirable factor, affecting feed efficiency, meat production cost, meat quality, and consumer’s health. Efforts to reduce fat deposition in economically important animals, such as chicken, can be made through different strategies; including genetic selection, feeding strategies, housing, and environmental strategies, as well as hormone supplementation. Recent investigations at the molecular level have revealed the significant role of the transcriptional and post-transcriptional regulatory networks and their interaction on modulating fat metabolism in chickens. At the transcriptional level, different transcription factors are known to regulate the expression of lipogenic and adipogenic genes through various signaling pathways, affecting chicken fat metabolism. Alternatively, at the post-transcriptional level, the regulatory mechanism of microRNAs (miRNAs) on lipid metabolism and deposition has added a promising dimension to understand the structural and functional regulatory mechanism of lipid metabolism in chicken. Therefore, this review focuses on the progress made in unraveling the molecular function of genes, transcription factors, and more notably significant miRNAs responsible for regulating adipogenesis, lipogenesis, and fat deposition in chicken. Moreover, a better understanding of the molecular regulation of lipid metabolism will give researchers novel insights to use functional molecular markers, such as miRNAs, for selection against excessive fat deposition to improve chicken production efficiency and meat quality. Full article

(This article belongs to the Special Issue Poultry Genetics, Breeding and Biotechnology)

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11 pages, 1976 KiB

Open AccessEditor’s ChoiceCommentary

Optical Genome Mapping as a Next-Generation Cytogenomic Tool for Detection of Structural and Copy Number Variations for Prenatal Genomic Analyses

by Nikhil Shri Sahajpal, Hayk Barseghyan, Ravindra Kolhe, Alex Hastie and Alka Chaubey

Genes 2021, 12(3), 398; https://doi.org/10.3390/genes12030398 - 11 Mar 2021

Cited by 53 | Viewed by 18118

Abstract

Global medical associations (ACOG, ISUOG, ACMG) recommend diagnostic prenatal testing for the detection and prevention of genetic disorders. Historically, cytogenetic methods such as karyotype analysis, fluorescent in situ hybridization (FISH) and chromosomal microarray (CMA) are utilized worldwide to diagnose common syndromes. However, the [...] Read more.

Global medical associations (ACOG, ISUOG, ACMG) recommend diagnostic prenatal testing for the detection and prevention of genetic disorders. Historically, cytogenetic methods such as karyotype analysis, fluorescent in situ hybridization (FISH) and chromosomal microarray (CMA) are utilized worldwide to diagnose common syndromes. However, the limitations of each of these methods, either performed in tandem or simultaneously, demonstrates the need of a revolutionary technology that can alleviate the need for multiple technologies. Optical genome mapping (OGM) is a novel method that fills this void by being able to detect all classes of structural variations (SVs), including copy number variations (CNVs). OGM is being adopted by laboratories as a tool for both postnatal constitutional genetic disorders and hematological malignancies. This commentary highlights the potential for OGM to become a standard of care in prenatal genetic testing based on its capability to comprehensively identify large balanced and unbalanced SVs (currently the strength of karyotyping and metaphase FISH), CNVs (by CMA), repeat contraction disorders (by Southern blotting) and multiple repeat expansion disorders (by PCR-based methods or Southern blotting). Next-generation sequencing (NGS) methods are excellent at detecting sequence variants, but they are unable to accurately resolve repeat regions of the genome, which limits their ability to detect all classes of SVs. Notably, multiple molecular methods are used to identify repeat expansion and contraction disorders in routine clinical laboratories around the world. With non-invasive prenatal testing (NIPT) becoming the standard of care screening assay for all global pregnancies, we anticipate that OGM can provide a high-resolution, cytogenomic assay to be employed following a positive NIPT screen or for high-risk pregnancies with an abnormal ultrasound. Accurate detection of all types of genetic disorders by OGM, such as liveborn aneuploidies, sex chromosome anomalies, microdeletion/microduplication syndromes, repeat expansion/contraction disorders is key to reducing the global burden of genetic disorders. Full article

(This article belongs to the Special Issue Advances in Prenatal Genetic Screening and Diagnosis Technologies)

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14 pages, 1461 KiB

Open AccessEditor’s ChoiceArticle

Maternal Vitamin and Mineral Supplementation and Rate of Maternal Weight Gain Affects Placental Expression of Energy Metabolism and Transport-Related Genes

by Wellison J. S. Diniz, Lawrence P. Reynolds, Pawel P. Borowicz, Alison K. Ward, Kevin K. Sedivec, Kacie L. McCarthy, Cierrah J. Kassetas, Friederike Baumgaertner, James D. Kirsch, Sheri T. Dorsam, Tammi L. Neville, J. Chris Forcherio, Ronald R. Scott, Joel S. Caton and Carl R. Dahlen

Genes 2021, 12(3), 385; https://doi.org/10.3390/genes12030385 - 09 Mar 2021

Cited by 24 | Viewed by 2914

Abstract

Maternal nutrients are essential for proper fetal and placental development and function. However, the effects of vitamin and mineral supplementation under two rates of maternal weight gain on placental genome-wide gene expression have not been investigated so far. Furthermore, biological processes and pathways [...] Read more.

Maternal nutrients are essential for proper fetal and placental development and function. However, the effects of vitamin and mineral supplementation under two rates of maternal weight gain on placental genome-wide gene expression have not been investigated so far. Furthermore, biological processes and pathways in the placenta that act in response to early maternal nutrition are yet to be elucidated. Herein, we examined the impact of maternal vitamin and mineral supplementation (from pre-breeding to day 83 post-breeding) and two rates of gain during the first 83 days of pregnancy on the gene expression of placental caruncles (CAR; maternal placenta) and cotyledons (COT; fetal placenta) of crossbred Angus beef heifers. We identified 267 unique differentially expressed genes (DEG). Among the DEGs from CAR, we identified ACAT2, SREBF2, and HMGCCS1 that underlie the cholesterol biosynthesis pathway. Furthermore, the transcription factors PAX2 and PAX8 were over-represented in biological processes related to kidney organogenesis. The DEGs from COT included SLC2A1, SLC2A3, SLC27A4, and INSIG1. Our over-representation analysis retrieved biological processes related to nutrient transport and ion homeostasis, whereas the pathways included insulin secretion, PPAR signaling, and biosynthesis of amino acids. Vitamin and mineral supplementation and rate of gain were associated with changes in gene expression, biological processes, and KEGG pathways in beef cattle placental tissues. Full article

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

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32 pages, 1466 KiB

Open AccessEditor’s ChoiceReview

The Role of Epigenetics in Congenital Heart Disease

by Tingsen Benson Lim, Sik Yin Roger Foo and Ching Kit Chen

Genes 2021, 12(3), 390; https://doi.org/10.3390/genes12030390 - 09 Mar 2021

Cited by 26 | Viewed by 9011

Abstract

Congenital heart disease (CHD) is the most common birth defect among newborns worldwide and contributes to significant infant morbidity and mortality. Owing to major advances in medical and surgical management, as well as improved prenatal diagnosis, the outcomes for these children with CHD [...] Read more.

Congenital heart disease (CHD) is the most common birth defect among newborns worldwide and contributes to significant infant morbidity and mortality. Owing to major advances in medical and surgical management, as well as improved prenatal diagnosis, the outcomes for these children with CHD have improved tremendously so much so that there are now more adults living with CHD than children. Advances in genomic technologies have discovered the genetic causes of a significant fraction of CHD, while at the same time pointing to remarkable complexity in CHD genetics. For this reason, the complex process of cardiogenesis, which is governed by multiple interlinked and dose-dependent pathways, is a well investigated process. In addition to the sequence of the genome, the contribution of epigenetics to cardiogenesis is increasingly recognized. Significant progress has been made dissecting the epigenome of the heart and identified associations with cardiovascular diseases. The role of epigenetic regulation in cardiac development/cardiogenesis, using tissue and animal models, has been well reviewed. Here, we curate the current literature based on studies in humans, which have revealed associated and/or causative epigenetic factors implicated in CHD. We sought to summarize the current knowledge on the functional role of epigenetics in cardiogenesis as well as in distinct CHDs, with an aim to provide scientists and clinicians an overview of the abnormal cardiogenic pathways affected by epigenetic mechanisms, for a better understanding of their impact on the developing fetal heart, particularly for readers interested in CHD research. Full article

(This article belongs to the Special Issue Advances in Prenatal Genetic Screening and Diagnosis Technologies)

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14 pages, 1814 KiB

Open AccessEditor’s ChoiceArticle

Whole Genome Sequencing in the Evaluation of Fetal Structural Anomalies: A Parallel Test with Chromosomal Microarray Plus Whole Exome Sequencing

by Jia Zhou, Ziying Yang, Jun Sun, Lipei Liu, Xinyao Zhou, Fengxia Liu, Ya Xing, Shuge Cui, Shiyi Xiong, Xiaoyu Liu, Yingjun Yang, Xiuxiu Wei, Gang Zou, Zhonghua Wang, Xing Wei, Yaoshen Wang, Yun Zhang, Saiying Yan, Fengyu Wu, Fanwei Zeng, Jian Wang, Tao Duan, Zhiyu Peng and Luming Sun Show full author list Hide full author list

Genes 2021, 12(3), 376; https://doi.org/10.3390/genes12030376 - 06 Mar 2021

Cited by 34 | Viewed by 4662

Abstract

Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome [...] Read more.

Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal structural anomalies. We performed trio WGS (≈40-fold) in parallel with CMA in 111 fetuses with structural or growth anomalies, and sequentially performed WES when CMA was negative (CMA plus WES). In comparison, WGS not only detected all pathogenic genetic variants in 22 diagnosed cases identified by CMA plus WES, yielding a diagnostic rate of 19.8% (22/110), but also provided additional and clinically significant information, including a case of balanced translocations and a case of intrauterine infection, which might not be detectable by CMA or WES. WGS also required less DNA (100 ng) as input and could provide a rapid turnaround time (TAT, 18 ± 6 days) compared with that (31 ± 8 days) of the CMA plus WES. Our results showed that WGS provided more comprehensive and precise genetic information with a rapid TAT and less DNA required than CMA plus WES, which enables it as an alternative prenatal diagnosis test for fetal structural anomalies. Full article

(This article belongs to the Special Issue Advances in Prenatal Genetic Screening and Diagnosis Technologies)

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22 pages, 1000 KiB

Open AccessEditor’s ChoiceReview

Circadian Clock Components Offer Targets for Crop Domestication and Improvement

by C. Robertson McClung

Genes 2021, 12(3), 374; https://doi.org/10.3390/genes12030374 - 06 Mar 2021

Cited by 23 | Viewed by 4201

Abstract

During plant domestication and improvement, farmers select for alleles present in wild species that improve performance in new selective environments associated with cultivation and use. The selected alleles become enriched and other alleles depleted in elite cultivars. One important aspect of crop improvement [...] Read more.

During plant domestication and improvement, farmers select for alleles present in wild species that improve performance in new selective environments associated with cultivation and use. The selected alleles become enriched and other alleles depleted in elite cultivars. One important aspect of crop improvement is expansion of the geographic area suitable for cultivation; this frequently includes growth at higher or lower latitudes, requiring the plant to adapt to novel photoperiodic environments. Many crops exhibit photoperiodic control of flowering and altered photoperiodic sensitivity is commonly required for optimal performance at novel latitudes. Alleles of a number of circadian clock genes have been selected for their effects on photoperiodic flowering in multiple crops. The circadian clock coordinates many additional aspects of plant growth, metabolism and physiology, including responses to abiotic and biotic stresses. Many of these clock-regulated processes contribute to plant performance. Examples of selection for altered clock function in tomato demonstrate that with domestication, the phasing of the clock is delayed with respect to the light–dark cycle and the period is lengthened; this modified clock is associated with increased chlorophyll content in long days. These and other data suggest the circadian clock is an attractive target during breeding for crop improvement. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Circadian Clock Function in Plants)

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17 pages, 366 KiB

Open AccessEditor’s ChoiceReview

Ophthalmologic Manifestations of Primary Sjögren’s Syndrome

by Anna Maria Roszkowska, Giovanni William Oliverio, Emanuela Aragona, Leandro Inferrera, Alice Antonella Severo, Federica Alessandrello, Rosaria Spinella, Elisa Imelde Postorino and Pasquale Aragona

Genes 2021, 12(3), 365; https://doi.org/10.3390/genes12030365 - 04 Mar 2021

Cited by 25 | Viewed by 3291

Abstract

Sjögren’s syndrome (SS) is a chronic, progressive, inflammatory, autoimmune disease, characterized by the lymphocyte infiltration of exocrine glands, especially the lacrimal and salivary, with their consequent destruction. The onset of primary SS (pSS) may remain misunderstood for several years. It usually presents with [...] Read more.

Sjögren’s syndrome (SS) is a chronic, progressive, inflammatory, autoimmune disease, characterized by the lymphocyte infiltration of exocrine glands, especially the lacrimal and salivary, with their consequent destruction. The onset of primary SS (pSS) may remain misunderstood for several years. It usually presents with different types of severity, e.g., dry eye and dry mouth symptoms, due to early involvement of the lacrimal and salivary glands, which may be associated with parotid enlargement and dry eye; keratoconjunctivitis sicca (KCS) is its most common ocular manifestation. It is still doubtful if the extent ocular surface manifestations are secondary to lacrimal or meibomian gland involvement or to the targeting of corneal and conjunctival autoantigens. SS is the most representative cause of aqueous deficient dry eye, and the primary role of the inflammatory process was evidenced. Recent scientific progress in understanding the numerous factors involved in the pathogenesis of pSS was registered, but the exact mechanisms involved still need to be clarified. The unquestionable role of both the innate and adaptive immune system, participating actively in the induction and evolution of the disease, was recognized. The ocular surface inflammation is a central mechanism in pSS leading to the decrease of lacrimal secretion and keratoconjunctival alterations. However, there are controversies about whether the ocular surface involvement is a direct autoimmune target or secondary to the inflammatory process in the lacrimal gland. In this review, we aimed to present actual knowledge relative to the pathogenesis of the pSS, considering the role of innate immunity, adaptive immunity, and genetics. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

20 pages, 772 KiB

Open AccessEditor’s ChoiceReview

Liquid Biopsies: Applications for Cancer Diagnosis and Monitoring

by Ivana Martins, Ilda Patrícia Ribeiro, Joana Jorge, Ana Cristina Gonçalves, Ana Bela Sarmento-Ribeiro, Joana Barbosa Melo and Isabel Marques Carreira

Genes 2021, 12(3), 349; https://doi.org/10.3390/genes12030349 - 27 Feb 2021

Cited by 87 | Viewed by 6604

Abstract

The minimally—or non-invasive detection of circulating tumor-derived components in biofluids, such as blood, liquid biopsy is a revolutionary approach with significant potential for the management of cancer. Genomic and transcriptomic alterations can be accurately detected through liquid biopsies, which provide a more comprehensive [...] Read more.

The minimally—or non-invasive detection of circulating tumor-derived components in biofluids, such as blood, liquid biopsy is a revolutionary approach with significant potential for the management of cancer. Genomic and transcriptomic alterations can be accurately detected through liquid biopsies, which provide a more comprehensive characterization of the heterogeneous tumor profile than tissue biopsies alone. Liquid biopsies could assist diagnosis, prognosis, and treatment selection, and hold great potential to complement current surveilling strategies to monitor disease evolution and treatment response in real-time. In particular, these are able to detect minimal residual disease, to predict progression, and to identify mechanisms of resistance, allowing to re-orient treatment strategies in a timelier manner. In this review we gathered current knowledge regarding the role and potential of liquid biopsies for the diagnosis and follow-up of cancer patients. The presented findings emphasize the strengths of liquid biopsies, revealing their chance of improving the diagnosis and monitoring of several tumor types in the near future. However, despite growing evidence supporting their value as a management tool in oncology, some limitations still need to be overcome for their implementation in the routine clinical setting. Full article

(This article belongs to the Special Issue Application of Genomic Technology in Disease Outcome Prediction)

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20 pages, 421 KiB

Open AccessEditor’s ChoicePerspective

The Regulation of RNA Modification Systems: The Next Frontier in Epitranscriptomics?

by Matthias R. Schaefer

Genes 2021, 12(3), 345; https://doi.org/10.3390/genes12030345 - 26 Feb 2021

Cited by 24 | Viewed by 3686

Abstract

RNA modifications, long considered to be molecular curiosities embellishing just abundant and non-coding RNAs, have now moved into the focus of both academic and applied research. Dedicated research efforts (epitranscriptomics) aim at deciphering the underlying principles by determining RNA modification landscapes and investigating [...] Read more.

RNA modifications, long considered to be molecular curiosities embellishing just abundant and non-coding RNAs, have now moved into the focus of both academic and applied research. Dedicated research efforts (epitranscriptomics) aim at deciphering the underlying principles by determining RNA modification landscapes and investigating the molecular mechanisms that establish, interpret and modulate the information potential of RNA beyond the combination of four canonical nucleotides. This has resulted in mapping various epitranscriptomes at high resolution and in cataloguing the effects caused by aberrant RNA modification circuitry. While the scope of the obtained insights has been complex and exciting, most of current epitranscriptomics appears to be stuck in the process of producing data, with very few efforts to disentangle cause from consequence when studying a specific RNA modification system. This article discusses various knowledge gaps in this field with the aim to raise one specific question: how are the enzymes regulated that dynamically install and modify RNA modifications? Furthermore, various technologies will be highlighted whose development and use might allow identifying specific and context-dependent regulators of epitranscriptomic mechanisms. Given the complexity of individual epitranscriptomes, determining their regulatory principles will become crucially important, especially when aiming at modifying specific aspects of an epitranscriptome both for experimental and, potentially, therapeutic purposes. Full article

(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)

18 pages, 11313 KiB

Open AccessEditor’s ChoiceArticle

Complete Mitochondrial DNA Genome of Nine Species of Sharks and Rays and Their Phylogenetic Placement among Modern Elasmobranchs

by Vasiliki Kousteni, Sofia Mazzoleni, Katerina Vasileiadou and Michail Rovatsos

Genes 2021, 12(3), 324; https://doi.org/10.3390/genes12030324 - 24 Feb 2021

Cited by 33 | Viewed by 5416

Abstract

Chondrichthyes occupy a key position in the phylogeny of vertebrates. The complete sequence of the mitochondrial genome (mitogenome) of four species of sharks and five species of rays was obtained by whole genome sequencing (DNA-seq) in the Illumina HiSeq2500 platform. The arrangement and [...] Read more.

Chondrichthyes occupy a key position in the phylogeny of vertebrates. The complete sequence of the mitochondrial genome (mitogenome) of four species of sharks and five species of rays was obtained by whole genome sequencing (DNA-seq) in the Illumina HiSeq2500 platform. The arrangement and features of the genes in the assembled mitogenomes were identical to those found in vertebrates. Both Maximum Likelihood (ML) and Bayesian Inference (BI) analyses were used to reconstruct the phylogenetic relationships among 172 species (including 163 mitogenomes retrieved from GenBank) based on the concatenated dataset of 13 individual protein coding genes. Both ML and BI analyses did not support the “Hypnosqualea” hypothesis and confirmed the monophyly of sharks and rays. The broad notion in shark phylogeny, namely the division of sharks into Galeomorphii and Squalomorphii and the monophyly of the eight shark orders, was also supported. The phylogenetic placement of all nine species sequenced in this study produced high statistical support values. The present study expands our knowledge on the systematics, genetic differentiation, and conservation genetics of the species studied, and contributes to our understanding of the evolutionary history of Chondrichthyes. Full article

(This article belongs to the Special Issue Molecular Evolution of the Mitochondrial DNA in Animals)

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19 pages, 1076 KiB

Open AccessEditor’s ChoiceReview

Post-Translational Mechanisms of Plant Circadian Regulation

by Jiapei Yan, Yeon Jeong Kim and David E. Somers

Genes 2021, 12(3), 325; https://doi.org/10.3390/genes12030325 - 24 Feb 2021

Cited by 24 | Viewed by 3951

Abstract

The molecular components of the circadian system possess the interesting feature of acting together to create a self-sustaining oscillator, while at the same time acting individually, and in complexes, to confer phase-specific circadian control over a wide range of physiological and developmental outputs. [...] Read more.

The molecular components of the circadian system possess the interesting feature of acting together to create a self-sustaining oscillator, while at the same time acting individually, and in complexes, to confer phase-specific circadian control over a wide range of physiological and developmental outputs. This means that many circadian oscillator proteins are simultaneously also part of the circadian output pathway. Most studies have focused on transcriptional control of circadian rhythms, but work in plants and metazoans has shown the importance of post-transcriptional and post-translational processes within the circadian system. Here we highlight recent work describing post-translational mechanisms that impact both the function of the oscillator and the clock-controlled outputs. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Circadian Clock Function in Plants)

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25 pages, 9434 KiB

Open AccessEditor’s ChoiceArticle

Comparative Analysis, Characterization and Evolutionary Study of Dirigent Gene Family in Cucurbitaceae and Expression of Novel Dirigent Peptide against Powdery Mildew Stress

by Vivek Yadav, Zhongyuan Wang, Xiaozhen Yang, Chunhua Wei, Xuan Changqing and Xian Zhang

Genes 2021, 12(3), 326; https://doi.org/10.3390/genes12030326 - 24 Feb 2021

Cited by 17 | Viewed by 2738

Abstract

Dirigent (DIR) proteins are induced under various stress conditions and involved in sterio- and regio-selective coupling of monolignol. A striking lack of information about dirigent genes in cucurbitaceae plants underscores the importance of functional characterization. In this study, 112 DIR genes were identified [...] Read more.

Dirigent (DIR) proteins are induced under various stress conditions and involved in sterio- and regio-selective coupling of monolignol. A striking lack of information about dirigent genes in cucurbitaceae plants underscores the importance of functional characterization. In this study, 112 DIR genes were identified in six species, and 61 genes from major cultivated species were analyzed. DIRs were analyzed using various bioinformatics tools and complemented by expression profiling. Phylogenetic analysis segregated the putative DIRs into six distinctively known subgroups. Chromosomal mapping revealed uneven distribution of genes, whereas synteny analysis exhibited that duplication events occurred during gene evolution. Gene structure analysis suggested the gain of introns during gene diversification. Gene ontology (GO) enrichment analysis indicates the participation of proteins in lignification and pathogen resistance activities. We also determined their organ-specific expression levels in three species revealing preferential expression in root and leaves. Furthermore, the number of CmDIR (CmDIR1, 6, 7 and 12) and ClDIR (ClDIR2, 5, 8, 9 and 17) genes exhibited higher expression in resistant cultivars after powdery mildew (PM) inoculation. In summary, based on the expression and in-silico analysis, we propose a role of DIRs in disease resistance mechanisms. Full article

(This article belongs to the Special Issue Powdery Mildew Resistance Genetics)

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16 pages, 1550 KiB

Open AccessEditor’s ChoiceReview

Sex Determination and Differentiation in Decapod and Cladoceran Crustaceans: An Overview of Endocrine Regulation

by Kenji Toyota, Hitoshi Miyakawa, Chizue Hiruta, Tomomi Sato, Hidekazu Katayama, Tsuyoshi Ohira and Taisen Iguchi

Genes 2021, 12(2), 305; https://doi.org/10.3390/genes12020305 - 21 Feb 2021

Cited by 27 | Viewed by 5196

Abstract

Mechanisms underlying sex determination and differentiation in animals are known to encompass a diverse array of molecular clues. Recent innovations in high-throughput sequencing and mass spectrometry technologies have been widely applied in non-model organisms without reference genomes. Crustaceans are no exception. They are [...] Read more.

Mechanisms underlying sex determination and differentiation in animals are known to encompass a diverse array of molecular clues. Recent innovations in high-throughput sequencing and mass spectrometry technologies have been widely applied in non-model organisms without reference genomes. Crustaceans are no exception. They are particularly diverse among the Arthropoda and contain a wide variety of commercially important fishery species such as shrimps, lobsters and crabs (Order Decapoda), and keystone species of aquatic ecosystems such as water fleas (Order Branchiopoda). In terms of decapod sex determination and differentiation, previous approaches have attempted to elucidate their molecular components, to establish mono-sex breeding technology. Here, we overview reports describing the physiological functions of sex hormones regulating masculinization and feminization, and gene discovery by transcriptomics in decapod species. Moreover, this review summarizes the recent progresses of studies on the juvenile hormone-driven sex determination system of the branchiopod genus Daphnia, and then compares sex determination and endocrine systems between decapods and branchiopods. This review provides not only substantial insights for aquaculture research, but also the opportunity to re-organize the current and future trends of this field. Full article

(This article belongs to the Special Issue The Evolution of Sexual Development in Arthropods)

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20 pages, 1678 KiB

Open AccessEditor’s ChoiceReview

Analysis of RNA Modifications by Second- and Third-Generation Deep Sequencing: 2020 Update

by Yuri Motorin and Virginie Marchand

Genes 2021, 12(2), 278; https://doi.org/10.3390/genes12020278 - 16 Feb 2021

Cited by 35 | Viewed by 6008

Abstract

The precise mapping and quantification of the numerous RNA modifications that are present in tRNAs, rRNAs, ncRNAs/miRNAs, and mRNAs remain a major challenge and a top priority of the epitranscriptomics field. After the keystone discoveries of massive m⁶A methylation in mRNAs, [...] Read more.

The precise mapping and quantification of the numerous RNA modifications that are present in tRNAs, rRNAs, ncRNAs/miRNAs, and mRNAs remain a major challenge and a top priority of the epitranscriptomics field. After the keystone discoveries of massive m⁶A methylation in mRNAs, dozens of deep sequencing-based methods and protocols were proposed for the analysis of various RNA modifications, allowing us to considerably extend the list of detectable modified residues. Many of the currently used methods rely on the particular reverse transcription signatures left by RNA modifications in cDNA; these signatures may be naturally present or induced by an appropriate enzymatic or chemical treatment. The newest approaches also include labeling at RNA abasic sites that result from the selective removal of RNA modification or the enhanced cleavage of the RNA ribose-phosphate chain (perhaps also protection from cleavage), followed by specific adapter ligation. Classical affinity/immunoprecipitation-based protocols use either antibodies against modified RNA bases or proteins/enzymes, recognizing RNA modifications. In this survey, we review the most recent achievements in this highly dynamic field, including promising attempts to map RNA modifications by the direct single-molecule sequencing of RNA by nanopores. Full article

(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)

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23 pages, 2058 KiB

Open AccessEditor’s ChoiceReview

HMGA2 as a Critical Regulator in Cancer Development

by Behzad Mansoori, Ali Mohammadi, Henrik J. Ditzel, Pascal H. G. Duijf, Vahid Khaze, Morten F. Gjerstorff and Behzad Baradaran

Genes 2021, 12(2), 269; https://doi.org/10.3390/genes12020269 - 13 Feb 2021

Cited by 90 | Viewed by 9172

Abstract

The high mobility group protein 2 (HMGA2) regulates gene expression by binding to AT-rich regions of DNA. Akin to other DNA architectural proteins, HMGA2 is highly expressed in embryonic stem cells during embryogenesis, while its expression is more limited at later stages of [...] Read more.

The high mobility group protein 2 (HMGA2) regulates gene expression by binding to AT-rich regions of DNA. Akin to other DNA architectural proteins, HMGA2 is highly expressed in embryonic stem cells during embryogenesis, while its expression is more limited at later stages of development and in adulthood. Importantly, HMGA2 is re-expressed in nearly all human malignancies, where it promotes tumorigenesis by multiple mechanisms. HMGA2 increases cancer cell proliferation by promoting cell cycle entry and inhibition of apoptosis. In addition, HMGA2 influences different DNA repair mechanisms and promotes epithelial-to-mesenchymal transition by activating signaling via the MAPK/ERK, TGFβ/Smad, PI3K/AKT/mTOR, NFkB, and STAT3 pathways. Moreover, HMGA2 supports a cancer stem cell phenotype and renders cancer cells resistant to chemotherapeutic agents. In this review, we discuss these oncogenic roles of HMGA2 in different types of cancers and propose that HMGA2 may be used for cancer diagnostic, prognostic, and therapeutic purposes. Full article

(This article belongs to the Special Issue Transcription Factors in Cancer Progression)

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17 pages, 3585 KiB

Open AccessEditor’s ChoiceArticle

miR-34a and miR-200c Have an Additive Tumor-Suppressive Effect on Breast Cancer Cells and Patient Prognosis

by Behzad Mansoori, Nicola Silvestris, Ali Mohammadi, Vahid Khaze, Elham Baghbani, Ahad Mokhtarzadeh, Dariush Shanehbandi, Afshin Derakhshani, Pascal H. G. Duijf and Behzad Baradaran

Genes 2021, 12(2), 267; https://doi.org/10.3390/genes12020267 - 12 Feb 2021

Cited by 26 | Viewed by 3173

Abstract

Breast cancer is the most common women’s malignancy in the world and, for subgroups of patients, treatment outcomes remain poor. Thus, more effective therapeutic strategies are urgently needed. MicroRNAs (miRNAs) have emerged as promising therapeutic tools and targets, as they play significant roles [...] Read more.

Breast cancer is the most common women’s malignancy in the world and, for subgroups of patients, treatment outcomes remain poor. Thus, more effective therapeutic strategies are urgently needed. MicroRNAs (miRNAs) have emerged as promising therapeutic tools and targets, as they play significant roles in regulating key cellular processes by suppressing gene expression. However, additive opportunities involving miRNAs have been underexplored. For example, both miR-34a and miR-200c individually suppress the development of different types of cancer, but the cellular effects of their combined actions remain unknown. Here, we show that miR-34a and miR-200c levels are reduced in breast tumors compared to adjacent normal tissues and that this additively predicts poor patient survival. In addition, in cell lines, miR-34a and miR-200c additively induce apoptosis and cell cycle arrest, while also inhibiting proliferation, invasion, migration, stemness and epithelial-to-mesenchymal transition (EMT). Mechanistically, both miRNA-34a and miR-200c directly target HIF1-α and subsequently downregulate VEGFR, MMP9 and CXCR4, although combined miRNA-34a and miR-200c delivery suppresses mouse xenograft tumor development as effectively as individual delivery. We establish a model, supported by in vitro and clinical data, which collectively suggest that the co-delivery of miR-34a and miR-200c represents a promising novel therapeutic strategy for breast cancer patients. Full article

(This article belongs to the Special Issue Transcription Factors in Cancer Progression)

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16 pages, 6533 KiB

Open AccessEditor’s ChoiceArticle

Two Expansin Genes, AtEXPA4 and AtEXPB5, Are Redundantly Required for Pollen Tube Growth and AtEXPA4 Is Involved in Primary Root Elongation in Arabidopsis thaliana

by Weimiao Liu, Liai Xu, Hui Lin and Jiashu Cao

Genes 2021, 12(2), 249; https://doi.org/10.3390/genes12020249 - 10 Feb 2021

Cited by 28 | Viewed by 2635

Abstract

The growth of plant cells is inseparable from relaxation and expansion of cell walls. Expansins are a class of cell wall binding proteins, which play important roles in the relaxation of cell walls. Although there are many members in expansin gene family, the [...] Read more.

The growth of plant cells is inseparable from relaxation and expansion of cell walls. Expansins are a class of cell wall binding proteins, which play important roles in the relaxation of cell walls. Although there are many members in expansin gene family, the functions of most expansin genes in plant growth and development are still poorly understood. In this study, the functions of two expansin genes, AtEXPA4 and AtEXPB5 were characterized in Arabidopsis thaliana. AtEXPA4 and AtEXPB5 displayed consistent expression patterns in mature pollen grains and pollen tubes, but AtEXPA4 also showed a high expression level in primary roots. Two single mutants, atexpa4 and atexpb5, showed normal reproductive development, whereas atexpa4atexpb5 double mutant was defective in pollen tube growth. Moreover, AtEXPA4 overexpression enhanced primary root elongation, on the contrary, knocking out AtEXPA4 made the growth of primary root slower. Our results indicated that AtEXPA4 and AtEXPB5 were redundantly involved in pollen tube growth and AtEXPA4 was required for primary root elongation. Full article

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

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31 pages, 2533 KiB

Open AccessEditor’s ChoiceReview

Molecular Aspects of Regeneration Mechanisms in Holothurians

by Igor Yu. Dolmatov

Genes 2021, 12(2), 250; https://doi.org/10.3390/genes12020250 - 10 Feb 2021

Cited by 26 | Viewed by 3183

Abstract

Holothurians, or sea cucumbers, belong to the phylum Echinodermata. They show good regenerative abilities. The present review provides an analysis of available data on the molecular aspects of regeneration mechanisms in holothurians. The genes and signaling pathways activated during the asexual reproduction and [...] Read more.

Holothurians, or sea cucumbers, belong to the phylum Echinodermata. They show good regenerative abilities. The present review provides an analysis of available data on the molecular aspects of regeneration mechanisms in holothurians. The genes and signaling pathways activated during the asexual reproduction and the formation of the anterior and posterior parts of the body, as well as the molecular mechanisms that provide regeneration of the nervous and digestive systems, are considered here. Damage causes a strong stress response, the signs of which are recorded even at late regeneration stages. In holothurian tissues, the concentrations of reactive oxygen species and antioxidant enzymes increase. Furthermore, the cellular and humoral components of the immune system are activated. Extracellular matrix remodeling and Wnt signaling play a major role in the regeneration in holothurians. All available morphological and molecular data show that the dedifferentiation of specialized cells in the remnant of the organ and the epithelial morphogenesis constitute the basis of regeneration in holothurians. However, depending on the type of damage, the mechanisms of regeneration may differ significantly in the spatial organization of regeneration process, the involvement of different cell types, and the depth of reprogramming of their genome (dedifferentiation or transdifferentiation). Full article

(This article belongs to the Special Issue The Molecular Genetics and Major Concepts Underlying Whole Body Regeneration in the Animal World)

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24 pages, 989 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

by Michela Di Nottia, Daniela Verrigni, Alessandra Torraco, Teresa Rizza, Enrico Bertini and Rosalba Carrozzo

Genes 2021, 12(2), 247; https://doi.org/10.3390/genes12020247 - 10 Feb 2021

Cited by 25 | Viewed by 4494

Abstract

Mitochondria do not exist as individual entities in the cell—conversely, they constitute an interconnected community governed by the constant and opposite process of fission and fusion. The mitochondrial fission leads to the formation of smaller mitochondria, promoting the biogenesis of new organelles. On [...] Read more.

Mitochondria do not exist as individual entities in the cell—conversely, they constitute an interconnected community governed by the constant and opposite process of fission and fusion. The mitochondrial fission leads to the formation of smaller mitochondria, promoting the biogenesis of new organelles. On the other hand, following the fusion process, mitochondria appear as longer and interconnected tubules, which enhance the communication with other organelles. Both fission and fusion are carried out by a small number of highly conserved guanosine triphosphatase proteins and their interactors. Disruption of this equilibrium has been associated with several pathological conditions, ranging from cancer to neurodegeneration, and mutations in genes involved in mitochondrial fission and fusion have been reported to be the cause of a subset of neurogenetic disorders. Full article

(This article belongs to the Special Issue Alterations in mtDNA and Mitochondrial Quality Control)

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18 pages, 4853 KiB

Open AccessEditor’s ChoiceArticle

Paracellular and Transcellular Leukocytes Diapedesis Are Divergent but Interconnected Evolutionary Events

by Michel-Edwar Mickael, Norwin Kubick, Pavel Klimovich, Patrick Henckell Flournoy, Irmina Bieńkowska and Mariusz Sacharczuk

Genes 2021, 12(2), 254; https://doi.org/10.3390/genes12020254 - 10 Feb 2021

Cited by 16 | Viewed by 3004

Abstract

Infiltration of the endothelial layer of the blood-brain barrier by leukocytes plays a critical role in health and disease. When passing through the endothelial layer during the diapedesis process lymphocytes can either follow a paracellular route or a transcellular one. There is a [...] Read more.

Infiltration of the endothelial layer of the blood-brain barrier by leukocytes plays a critical role in health and disease. When passing through the endothelial layer during the diapedesis process lymphocytes can either follow a paracellular route or a transcellular one. There is a debate whether these two processes constitute one mechanism, or they form two evolutionary distinct migration pathways. We used artificial intelligence, phylogenetic analysis, HH search, ancestor sequence reconstruction to investigate further this intriguing question. We found that the two systems share several ancient components, such as RhoA protein that plays a critical role in controlling actin movement in both mechanisms. However, some of the key components differ between these two transmigration processes. CAV1 genes emerged during Trichoplax adhaerens, and it was only reported in transcellular process. Paracellular process is dependent on PECAM1. PECAM1 emerged from FASL5 during Zebrafish divergence. Lastly, both systems employ late divergent genes such as ICAM1 and VECAM1. Taken together, our results suggest that these two systems constitute two different mechanical sensing mechanisms of immune cell infiltrations of the brain, yet these two systems are connected. We postulate that the mechanical properties of the cellular polarity is the main driving force determining the migration pathway. Our analysis indicates that both systems coevolved with immune cells, evolving to a higher level of complexity in association with the evolution of the immune system. Full article

(This article belongs to the Special Issue The Immune Response in the Time of Omics Research)

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13 pages, 3717 KiB

Open AccessEditor’s ChoiceArticle

Comparative Genomic Analysis of Lactiplantibacillus plantarum Isolated from Different Niches

by Bingyong Mao, Ruimin Yin, Xiaoshu Li, Shumao Cui, Hao Zhang, Jianxin Zhao and Wei Chen

Genes 2021, 12(2), 241; https://doi.org/10.3390/genes12020241 - 08 Feb 2021

Cited by 32 | Viewed by 3303

Abstract

Lactiplantibacillus plantarum can adapt to a variety of niches and is widely distributed in many sources. We used comparative genomics to explore the differences in the genome and in the physiological characteristics of L. plantarum isolated from pickles, fermented sauce, and human feces. [...] Read more.

Lactiplantibacillus plantarum can adapt to a variety of niches and is widely distributed in many sources. We used comparative genomics to explore the differences in the genome and in the physiological characteristics of L. plantarum isolated from pickles, fermented sauce, and human feces. The relationships between genotypes and phenotypes were analyzed to address the effects of isolation source on the genetic variation of L. plantarum. The comparative genomic results indicate that the numbers of unique genes in the different strains were niche-dependent. L. plantarum isolated from fecal sources generally had more strain-specific genes than L. plantarum isolated from pickles. The phylogenetic tree and average nucleotide identity (ANI) results indicate that L. plantarum in pickles and fermented sauce clustered independently, whereas the fecal L. plantarum was distributed more uniformly in the phylogenetic tree. The pan-genome curve indicated that the L. plantarum exhibited high genomic diversity. Based on the analysis of the carbohydrate active enzyme and carbohydrate-use abilities, we found that L. plantarum strains isolated from different sources exhibited different expression of the Glycoside Hydrolases (GH) and Glycosyl Transferases (GT) families and that the expression patterns of carbohydrate active enzymes were consistent with the evolution relationships of the strains. L. plantarum strains exhibited niche-specific characteristicsand the results provided better understating on genetics of this species. Full article

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

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33 pages, 2324 KiB

Open AccessEditor’s ChoiceReview

Epigenetics: New Insights into Mammary Gland Biology

by Elitsa Ivanova, Sandrine Le Guillou, Cathy Hue-Beauvais and Fabienne Le Provost

Genes 2021, 12(2), 231; https://doi.org/10.3390/genes12020231 - 05 Feb 2021

Cited by 21 | Viewed by 4142

Abstract

The mammary gland undergoes important anatomical and physiological changes from embryogenesis through puberty, pregnancy, lactation and involution. These steps are under the control of a complex network of molecular factors, in which epigenetic mechanisms play a role that is increasingly well described. Recently, [...] Read more.

The mammary gland undergoes important anatomical and physiological changes from embryogenesis through puberty, pregnancy, lactation and involution. These steps are under the control of a complex network of molecular factors, in which epigenetic mechanisms play a role that is increasingly well described. Recently, studies investigating epigenetic modifications and their impacts on gene expression in the mammary gland have been performed at different physiological stages and in different mammary cell types. This has led to the establishment of a role for epigenetic marks in milk component biosynthesis. This review aims to summarize the available knowledge regarding the involvement of the four main molecular mechanisms in epigenetics: DNA methylation, histone modifications, polycomb protein activity and non-coding RNA functions. Full article

(This article belongs to the Special Issue Gene Analysis of Mammary Gland Development and Breast Cancers)

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26 pages, 2066 KiB

Open AccessEditor’s ChoiceReview

The Genetic Basis of Tomato Aroma

by Matteo Martina, Yury Tikunov, Ezio Portis and Arnaud G. Bovy

Genes 2021, 12(2), 226; https://doi.org/10.3390/genes12020226 - 04 Feb 2021

Cited by 36 | Viewed by 7217

Abstract

Tomato (Solanum lycopersicum L.) aroma is determined by the interaction of volatile compounds (VOCs) released by the tomato fruits with receptors in the nose, leading to a sensorial impression, such as “sweet”, “smoky”, or “fruity” aroma. Of the more than 400 VOCs [...] Read more.

Tomato (Solanum lycopersicum L.) aroma is determined by the interaction of volatile compounds (VOCs) released by the tomato fruits with receptors in the nose, leading to a sensorial impression, such as “sweet”, “smoky”, or “fruity” aroma. Of the more than 400 VOCs released by tomato fruits, 21 have been reported as main contributors to the perceived tomato aroma. These VOCs can be grouped in five clusters, according to their biosynthetic origins. In the last decades, a vast array of scientific studies has investigated the genetic component of tomato aroma in modern tomato cultivars and their relatives. In this paper we aim to collect, compare, integrate and summarize the available literature on flavour-related QTLs in tomato. Three hundred and fifty nine (359) QTLs associated with tomato fruit VOCs were physically mapped on the genome and investigated for the presence of potential candidate genes. This review makes it possible to (i) pinpoint potential donors described in literature for specific traits, (ii) highlight important QTL regions by combining information from different populations, and (iii) pinpoint potential candidate genes. This overview aims to be a valuable resource for researchers aiming to elucidate the genetics underlying tomato flavour and for breeders who aim to improve tomato aroma. Full article

(This article belongs to the Special Issue Tomato Genetics)

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22 pages, 1211 KiB

Open AccessEditor’s ChoiceReview

Hashimoto’s Thyroiditis and Graves’ Disease in Genetic Syndromes in Pediatric Age

by Celeste Casto, Giorgia Pepe, Alessandra Li Pomi, Domenico Corica, Tommaso Aversa and Malgorzata Wasniewska

Genes 2021, 12(2), 222; https://doi.org/10.3390/genes12020222 - 04 Feb 2021

Cited by 21 | Viewed by 6141

Abstract

Autoimmune thyroid diseases (AITDs), including Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), are the most common cause of acquired thyroid disorder during childhood and adolescence. Our purpose was to assess the main features of AITDs when they occur in association with genetic syndromes. [...] Read more.

Autoimmune thyroid diseases (AITDs), including Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), are the most common cause of acquired thyroid disorder during childhood and adolescence. Our purpose was to assess the main features of AITDs when they occur in association with genetic syndromes. We conducted a systematic review of the literature, covering the last 20 years, through MEDLINE via PubMed and EMBASE databases, in order to identify studies focused on the relation between AITDs and genetic syndromes in children and adolescents. From the 1654 references initially identified, 90 articles were selected for our final evaluation. Turner syndrome, Down syndrome, Klinefelter syndrome, neurofibromatosis type 1, Noonan syndrome, 22q11.2 deletion syndrome, Prader–Willi syndrome, Williams syndrome and 18q deletion syndrome were evaluated. Our analysis confirmed that AITDs show peculiar phenotypic patterns when they occur in association with some genetic disorders, especially chromosomopathies. To improve clinical practice and healthcare in children and adolescents with genetic syndromes, an accurate screening and monitoring of thyroid function and autoimmunity should be performed. Furthermore, maintaining adequate thyroid hormone levels is important to avoid aggravating growth and cognitive deficits that are not infrequently present in the syndromes analyzed. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics)

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15 pages, 961 KiB

Open AccessEditor’s ChoiceReview

Eicosanoid Signaling in Insect Immunology: New Genes and Unresolved Issues

by Yonggyun Kim and David Stanley

Genes 2021, 12(2), 211; https://doi.org/10.3390/genes12020211 - 01 Feb 2021

Cited by 41 | Viewed by 3756

Abstract

This paper is focused on eicosanoid signaling in insect immunology. We begin with eicosanoid biosynthesis through the actions of phospholipase A₂, responsible for hydrolyzing the C18 polyunsaturated fatty acid, linoleic acid (18:2n-6), from cellular phospholipids, which is subsequently converted into arachidonic [...] Read more.

This paper is focused on eicosanoid signaling in insect immunology. We begin with eicosanoid biosynthesis through the actions of phospholipase A₂, responsible for hydrolyzing the C18 polyunsaturated fatty acid, linoleic acid (18:2n-6), from cellular phospholipids, which is subsequently converted into arachidonic acid (AA; 20:4n-6) via elongases and desaturases. The synthesized AA is then oxygenated into one of three groups of eicosanoids, prostaglandins (PGs), epoxyeicosatrienoic acids (EETs) and lipoxygenase products. We mark the distinction between mammalian cyclooxygenases and insect peroxynectins, both of which convert AA into PGs. One PG, PGI₂ (also called prostacyclin), is newly discovered in insects, as a negative regulator of immune reactions and a positive signal in juvenile development. Two new elements of insect PG biology are a PG dehydrogenase and a PG reductase, both of which enact necessary PG catabolism. EETs, which are produced from AA via cytochrome P450s, also act in immune signaling, acting as pro-inflammatory signals. Eicosanoids signal a wide range of cellular immune reactions to infections, invasions and wounding, including nodulation, cell spreading, hemocyte migration and releasing prophenoloxidase from oenocytoids, a class of lepidopteran hemocytes. We briefly review the relatively scant knowledge on insect PG receptors and note PGs also act in gut immunity and in humoral immunity. Detailed new information on PG actions in mosquito immunity against the malarial agent, Plasmodium berghei, has recently emerged and we treat this exciting new work. The new findings on eicosanoid actions in insect immunity have emerged from a very broad range of research at the genetic, cellular and organismal levels, all taking place at the international level. Full article

(This article belongs to the Special Issue Evolutionary Genetics of Insect Innate Immunity)

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21 pages, 696 KiB

Open AccessEditor’s ChoiceReview

Novel Approaches to Epigenetic Therapies: From Drug Combinations to Epigenetic Editing

by Aleksandra Majchrzak-Celińska, Anna Warych and Mikołaj Szoszkiewicz

Genes 2021, 12(2), 208; https://doi.org/10.3390/genes12020208 - 31 Jan 2021

Cited by 60 | Viewed by 6015

Abstract

Cancer development involves both genetic and epigenetic alterations. Aberrant epigenetic modifications are reversible, allowing excellent opportunities for therapeutic intervention. Nowadays, several epigenetic drugs are used worldwide to treat, e.g., myelodysplastic syndromes and leukemias. However, overcoming resistance and widening the therapeutic profiles are the [...] Read more.

Cancer development involves both genetic and epigenetic alterations. Aberrant epigenetic modifications are reversible, allowing excellent opportunities for therapeutic intervention. Nowadays, several epigenetic drugs are used worldwide to treat, e.g., myelodysplastic syndromes and leukemias. However, overcoming resistance and widening the therapeutic profiles are the most important challenges faced by traditional epigenetic drugs. Recently, novel approaches to epigenetic therapies have been proposed. Next-generation epigenetic drugs, with longer half-life and better bioavailability, are being developed and tested. Since epigenetic phenomena are interdependent, treatment modalities include co-administration of two different epigenetic drugs. In order to sensitize cancer cells to chemotherapy, epigenetic drugs are administered prior to chemotherapy, or both epigenetic drug and chemotherapy are used together to achieve synergistic effects and maximize treatment efficacy. The combinations of epigenetic drug with immunotherapy are being tested, because they have proved to enhance antitumor immune responses. The next approach involves targeting the metabolic causes of epigenetic changes, i.e., enzymes which, when mutated, produce oncometabolites. Finally, epigenome editing makes it possible to modify individual chromatin marks at a defined region with unprecedented specificity and efficiency. This review summarizes the above attempts in fulfilling the promise of epigenetic drugs in the effective cancer treatment. Full article

(This article belongs to the Special Issue Cancer Epigenetics-Recent Developments in Epigenetic Diagnostics and Therapy)

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27 pages, 4255 KiB

Open AccessEditor’s ChoiceArticle

Long-Term Waterlogging as Factor Contributing to Hypoxia Stress Tolerance Enhancement in Cucumber: Comparative Transcriptome Analysis of Waterlogging Sensitive and Tolerant Accessions

by Kinga Kęska, Michał Wojciech Szcześniak, Izabela Makałowska and Małgorzata Czernicka

Genes 2021, 12(2), 189; https://doi.org/10.3390/genes12020189 - 28 Jan 2021

Cited by 27 | Viewed by 3278

Abstract

Waterlogging (WL), excess water in the soil, is a phenomenon often occurring during plant cultivation causing low oxygen levels (hypoxia) in the soil. The aim of this study was to identify candidate genes involved in long-term waterlogging tolerance in cucumber using RNA sequencing. [...] Read more.

Waterlogging (WL), excess water in the soil, is a phenomenon often occurring during plant cultivation causing low oxygen levels (hypoxia) in the soil. The aim of this study was to identify candidate genes involved in long-term waterlogging tolerance in cucumber using RNA sequencing. Here, we also determined how waterlogging pre-treatment (priming) influenced long-term memory in WL tolerant (WL-T) and WL sensitive (WL-S) i.e., DH2 and DH4 accessions, respectively. This work uncovered various differentially expressed genes (DEGs) activated in the long-term recovery in both accessions. De novo assembly generated 36,712 transcripts with an average length of 2236 bp. The results revealed that long-term waterlogging had divergent impacts on gene expression in WL-T DH2 and WL-S DH4 cucumber accessions: after 7 days of waterlogging, more DEGs in comparison to control conditions were identified in WL-S DH4 (8927) than in WL-T DH2 (5957). Additionally, 11,619 and 5007 DEGs were identified after a second waterlogging treatment in the WL-S and WL-T accessions, respectively. We identified genes associated with WL in cucumber that were especially related to enhanced glycolysis, adventitious roots development, and amino acid metabolism. qRT-PCR assay for hypoxia marker genes i.e., alcohol dehydrogenase (adh), 1-aminocyclopropane-1-carboxylate oxidase (aco) and long chain acyl-CoA synthetase 6 (lacs6) confirmed differences in response to waterlogging stress between sensitive and tolerant cucumbers and effectiveness of priming to enhance stress tolerance. Full article

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

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14 pages, 5571 KiB

Open AccessEditor’s ChoiceReview

Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions

by Ryan O. Snodgrass, Timothy J. A. Chico and Helen M. Arthur

Genes 2021, 12(2), 174; https://doi.org/10.3390/genes12020174 - 27 Jan 2021

Cited by 29 | Viewed by 4283

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller [...] Read more.

Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies. Full article

(This article belongs to the Special Issue Genetic Disorders of the TGFβ Signaling Family)

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17 pages, 3810 KiB

Open AccessEditor’s ChoiceArticle

Identification of Key Pathways and Genes Related to the Development of Hair Follicle Cycle in Cashmere Goats

by Jianfang Wang, Jie Sui, Chao Mao, Xiaorui Li, Xingyi Chen, Chengcheng Liang, Xiaohui Wang, Si-Hu Wang and Cunling Jia

Genes 2021, 12(2), 180; https://doi.org/10.3390/genes12020180 - 27 Jan 2021

Cited by 24 | Viewed by 2904

Abstract

The development of hair follicle in cashmere goats shows significant periodic change, as with mice and humans. However, for cashmere goat with double-coat, the periodic change may be due to other regulatory molecules and signal pathways. To understand the mechanism of periodic development [...] Read more.

The development of hair follicle in cashmere goats shows significant periodic change, as with mice and humans. However, for cashmere goat with double-coat, the periodic change may be due to other regulatory molecules and signal pathways. To understand the mechanism of periodic development of hair follicle, we performed a weighted gene coexpression network analysis (WGCNA) to mine key genes and establish an interaction network by utilizing the NCBI public dataset. Ten coexpression modules, including 7689 protein-coding genes, were constructed by WGCNA, six of which are considered to be significantly related to the development of the hair follicle cycle. A functional enrichment analysis for each model showed that they are closely related to ECM- receptor interaction, focal adhesion, PI3K-Akt signaling pathway, estrogen signaling pathway, and so on. Combined with the analysis of differential expressed genes, 12 hub genes from coexpression modules were selected as candidate markers, i.e., COL1A1, C1QTNF6, COL1A2, AQP3, KRTAP3-1, KRTAP11-1, FA2H, NDUFS5, DERL2, MRPL14, ANTKMT and XAB2, which might be applied to improve cashmere production. Full article

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

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44 pages, 9690 KiB

Open AccessEditor’s ChoiceReview

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

by Tyler J. Creamer, Emily E. Bramel and Elena Gallo MacFarlane

Genes 2021, 12(2), 183; https://doi.org/10.3390/genes12020183 - 27 Jan 2021

Cited by 27 | Viewed by 6257

Abstract

Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain [...] Read more.

Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease. Full article

(This article belongs to the Special Issue Cardiovascular Genetics)

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20 pages, 3406 KiB

Open AccessEditor’s ChoiceArticle

Epigenetic Evolution of ACE2 and IL-6 Genes: Non-Canonical Interferon-Stimulated Genes Correlate to COVID-19 Susceptibility in Vertebrates

by Eric R. Sang, Yun Tian, Laura C. Miller and Yongming Sang

Genes 2021, 12(2), 154; https://doi.org/10.3390/genes12020154 - 25 Jan 2021

Cited by 29 | Viewed by 4809

Abstract

The current novel coronavirus disease (COVID-19) has spread globally within a matter of months. The virus establishes a success in balancing its deadliness and contagiousness, and causes substantial differences in susceptibility and disease progression in people of different ages, genders and pre-existing comorbidities. [...] Read more.

The current novel coronavirus disease (COVID-19) has spread globally within a matter of months. The virus establishes a success in balancing its deadliness and contagiousness, and causes substantial differences in susceptibility and disease progression in people of different ages, genders and pre-existing comorbidities. These host factors are subjected to epigenetic regulation; therefore, relevant analyses on some key genes underlying COVID-19 pathogenesis were performed to longitudinally decipher their epigenetic correlation to COVID-19 susceptibility. The genes of host angiotensin-converting enzyme 2 (ACE2, as the major virus receptor) and interleukin (IL)-6 (a key immuno-pathological factor triggering cytokine storm) were shown to evince active epigenetic evolution via histone modification and cis/trans-factors interaction across different vertebrate species. Extensive analyses revealed that ACE2 ad IL-6 genes are among a subset of non-canonical interferon-stimulated genes (non-ISGs), which have been designated for their unconventional responses to interferons (IFNs) and inflammatory stimuli through an epigenetic cascade. Furthermore, significantly higher positive histone modification markers and position weight matrix (PWM) scores of key cis-elements corresponding to inflammatory and IFN signaling, were discovered in both ACE2 and IL6 gene promoters across representative COVID-19-susceptible species compared to unsusceptible ones. The findings characterize ACE2 and IL-6 genes as non-ISGs that respond differently to inflammatory and IFN signaling from the canonical ISGs. The epigenetic properties ACE2 and IL-6 genes may serve as biomarkers to longitudinally predict COVID-19 susceptibility in vertebrates and partially explain COVID-19 inequality in people of different subgroups. Full article

(This article belongs to the Special Issue The Immune Response in the Time of Omics Research)

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15 pages, 2261 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of DNA Extraction Methods Developed for Forensic and Ancient DNA Applications Using Bone Samples of Different Age

by Catarina Xavier, Mayra Eduardoff, Barbara Bertoglio, Christina Amory, Cordula Berger, Andrea Casas-Vargas, Johannes Pallua and Walther Parson

Genes 2021, 12(2), 146; https://doi.org/10.3390/genes12020146 - 22 Jan 2021

Cited by 28 | Viewed by 9882

Abstract

The efficient extraction of DNA from challenging samples, such as bones, is critical for the success of downstream genotyping analysis in molecular genetic disciplines. Even though the ancient DNA community has developed several protocols targeting small DNA fragments that are typically present in [...] Read more.

The efficient extraction of DNA from challenging samples, such as bones, is critical for the success of downstream genotyping analysis in molecular genetic disciplines. Even though the ancient DNA community has developed several protocols targeting small DNA fragments that are typically present in decomposed or old specimens, only recently forensic geneticists have started to adopt those protocols. Here, we compare an ancient DNA extraction protocol (Dabney) with a bone extraction method (Loreille) typically used in forensics. Real-time quantitative PCR and forensically representative typing methods including fragment size analysis and sequencing were used to assess protocol performance. We used four bone samples of different age in replicates to study the effects of both extraction methods. Our results confirm Loreille’s overall increased gain of DNA when enough tissue is available and Dabney’s improved efficiency for retrieving shorter DNA fragments that is beneficial when highly degraded DNA is present. The results suggest that the choice of extraction method needs to be based on available sample, degradation state, and targeted genotyping method. We modified the Dabney protocol by pooling parallel lysates prior to purification to study gain and performance in single tube typing assays and found that up to six parallel lysates lead to an almost linear gain of extracted DNA. These data are promising for further forensic investigations as the adapted Dabney protocol combines increased sensitivity for degraded DNA with necessary total DNA amount for forensic applications. Full article

(This article belongs to the Special Issue Forensic Mitochondrial Genomics)

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13 pages, 1877 KiB

Open AccessEditor’s ChoiceArticle

The Desmin (DES) Mutation p.A337P Is Associated with Left-Ventricular Non-Compaction Cardiomyopathy

by Olga Kulikova, Andreas Brodehl, Anna Kiseleva, Roman Myasnikov, Alexey Meshkov, Caroline Stanasiuk, Anna Gärtner, Mikhail Divashuk, Evgeniia Sotnikova, Sergey Koretskiy, Maria Kharlap, Viktoria Kozlova, Elena Mershina, Polina Pilus, Valentin Sinitsyn, Hendrik Milting, Sergey Boytsov and Oxana Drapkina

Genes 2021, 12(1), 121; https://doi.org/10.3390/genes12010121 - 19 Jan 2021

Cited by 23 | Viewed by 3799

Abstract

Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing [...] Read more.

Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, DES-p.A337P was identified in the genomes of both patients, whereas only the index patient carried DSP-p.L1348X. DES encodes the muscle-specific intermediate filament protein desmin and DSP encodes desmoplakin, which is a cytolinker protein connecting desmosomes with the intermediate filaments. Because the majority of DES mutations cause severe filament assembly defects and because this mutation was found in both affected patients, we analyzed this DES mutation in vitro by cell transfection experiments in combination with confocal microscopy. Of note, desmin-p.A337P forms cytoplasmic aggregates in transfected SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells underlining its pathogenicity. In conclusion, we suggest including the DES gene in the genetic analysis for LVNC patients in the future, especially if clinical involvement of the skeletal muscle is present. Full article

(This article belongs to the Special Issue Cardiovascular Genetics)

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15 pages, 2357 KiB

Open AccessEditor’s ChoiceArticle

Weighted Single-Step GWAS Identified Candidate Genes Associated with Growth Traits in a Duroc Pig Population

by Donglin Ruan, Zhanwei Zhuang, Rongrong Ding, Yibin Qiu, Shenping Zhou, Jie Wu, Cineng Xu, Linjun Hong, Sixiu Huang, Enqin Zheng, Gengyuan Cai, Zhenfang Wu and Jie Yang

Genes 2021, 12(1), 117; https://doi.org/10.3390/genes12010117 - 19 Jan 2021

Cited by 25 | Viewed by 3734

Abstract

Growth traits are important economic traits of pigs that are controlled by several major genes and multiple minor genes. To better understand the genetic architecture of growth traits, we performed a weighted single-step genome-wide association study (wssGWAS) to identify genomic regions and candidate [...] Read more.

Growth traits are important economic traits of pigs that are controlled by several major genes and multiple minor genes. To better understand the genetic architecture of growth traits, we performed a weighted single-step genome-wide association study (wssGWAS) to identify genomic regions and candidate genes that are associated with days to 100 kg (AGE), average daily gain (ADG), backfat thickness (BF) and lean meat percentage (LMP) in a Duroc pig population. In this study, 3945 individuals with phenotypic and genealogical information, of which 2084 pigs were genotyped with a 50 K single-nucleotide polymorphism (SNP) array, were used for association analyses. We found that the most significant regions explained 2.56–3.07% of genetic variance for four traits, and the detected significant regions (>1%) explained 17.07%, 18.59%, 23.87% and 21.94% for four traits. Finally, 21 genes that have been reported to be associated with metabolism, bone growth, and fat deposition were treated as candidate genes for growth traits in pigs. Moreover, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses implied that the identified genes took part in bone formation, the immune system, and digestion. In conclusion, such full use of phenotypic, genotypic, and genealogical information will accelerate the genetic improvement of growth traits in pigs. Full article

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

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11 pages, 1411 KiB

Open AccessEditor’s ChoiceArticle

Sex Chromosome Turnover in Bent-Toed Geckos (Cyrtodactylus)

by Shannon E. Keating, Madison Blumer, L. Lee Grismer, Aung Lin, Stuart V. Nielsen, Myint Kyaw Thura, Perry L. Wood, Jr., Evan S. H. Quah and Tony Gamble

Genes 2021, 12(1), 116; https://doi.org/10.3390/genes12010116 - 19 Jan 2021

Cited by 19 | Viewed by 3454

Abstract

Lizards and snakes (squamates) are known for their varied sex determining systems, and gecko lizards are especially diverse, having evolved sex chromosomes independently multiple times. While sex chromosomes frequently turnover among gecko genera, intrageneric turnovers are known only from Gekko and Hemidactylus. [...] Read more.

Lizards and snakes (squamates) are known for their varied sex determining systems, and gecko lizards are especially diverse, having evolved sex chromosomes independently multiple times. While sex chromosomes frequently turnover among gecko genera, intrageneric turnovers are known only from Gekko and Hemidactylus. Here, we used RADseq to identify sex-specific markers in two species of Burmese bent-toed geckos. We uncovered XX/XY sex chromosomes in Cyrtodactylus chaunghanakwaensis and ZZ/ZW sex chromosomes in Cyrtodactylus pharbaungensis. This is the third instance of intrageneric turnover of sex chromosomes in geckos. Additionally, Cyrtodactylus are closely related to another genus with intrageneric turnover, Hemidactylus. Together, these data suggest that sex chromosome turnover may be common in this clade, setting them apart as exceptionally diverse in a group already known for diverse sex determination systems. Full article

(This article belongs to the Special Issue Vertebrate Karyotype Evolution: How Far Have We Come, and Where Are We Going?)

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21 pages, 1724 KiB

Open AccessEditor’s ChoiceReview

Suprabasin—A Review

by Miroslav Pribyl, Zdenek Hodny and Iva Kubikova

Genes 2021, 12(1), 108; https://doi.org/10.3390/genes12010108 - 18 Jan 2021

Cited by 17 | Viewed by 2872

Abstract

Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (SBSN). Originally described as a component of the cornified envelope, the function of stratified epithelia-expressed SBSN is unknown. Both the lack of knowledge about [...] Read more.

Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (SBSN). Originally described as a component of the cornified envelope, the function of stratified epithelia-expressed SBSN is unknown. Both the lack of knowledge about the gene role under physiological conditions and the emerging link of SBSN to various human diseases, including cancer, attract research interest. The association of SBSN expression with poor prognosis of patients suffering from oesophageal carcinoma, glioblastoma multiforme, and myelodysplastic syndromes suggests that SBSN may play a role in human tumourigenesis. Three SBSN isoforms code for the secreted proteins with putative function as signalling molecules, yet with poorly described effects. In this first review about SBSN, we summarised the current knowledge accumulated since its original description, and we discuss the potential mechanisms and roles of SBSN in both physiology and pathology. Full article

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

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26 pages, 10369 KiB

Open AccessEditor’s ChoiceArticle

Defining the Rhizobium leguminosarum Species Complex

by J. Peter W. Young, Sara Moeskjær, Alexey Afonin, Praveen Rahi, Marta Maluk, Euan K. James, Maria Izabel A. Cavassim, M. Harun-or Rashid, Aregu Amsalu Aserse, Benjamin J. Perry, En Tao Wang, Encarna Velázquez, Evgeny E. Andronov, Anastasia Tampakaki, José David Flores Félix, Raúl Rivas González, Sameh H. Youseif, Marc Lepetit, Stéphane Boivin, Beatriz Jorrin, Gregory J. Kenicer, Álvaro Peix, Michael F. Hynes, Martha Helena Ramírez-Bahena, Arvind Gulati and Chang-Fu Tian Show full author list Hide full author list

Genes 2021, 12(1), 111; https://doi.org/10.3390/genes12010111 - 18 Jan 2021

Cited by 44 | Viewed by 8832

Abstract

Bacteria currently included in Rhizobium leguminosarum are too diverse to be considered a single species, so we can refer to this as a species complex (the Rlc). We have found 429 publicly available genome sequences that fall within the Rlc and these show [...] Read more.

Bacteria currently included in Rhizobium leguminosarum are too diverse to be considered a single species, so we can refer to this as a species complex (the Rlc). We have found 429 publicly available genome sequences that fall within the Rlc and these show that the Rlc is a distinct entity, well separated from other species in the genus. Its sister taxon is R. anhuiense. We constructed a phylogeny based on concatenated sequences of 120 universal (core) genes, and calculated pairwise average nucleotide identity (ANI) between all genomes. From these analyses, we concluded that the Rlc includes 18 distinct genospecies, plus 7 unique strains that are not placed in these genospecies. Each genospecies is separated by a distinct gap in ANI values, usually at approximately 96% ANI, implying that it is a ‘natural’ unit. Five of the genospecies include the type strains of named species: R. laguerreae, R. sophorae, R. ruizarguesonis, “R. indicum” and R. leguminosarum itself. The 16S ribosomal RNA sequence is remarkably diverse within the Rlc, but does not distinguish the genospecies. Partial sequences of housekeeping genes, which have frequently been used to characterize isolate collections, can mostly be assigned unambiguously to a genospecies, but alleles within a genospecies do not always form a clade, so single genes are not a reliable guide to the true phylogeny of the strains. We conclude that access to a large number of genome sequences is a powerful tool for characterizing the diversity of bacteria, and that taxonomic conclusions should be based on all available genome sequences, not just those of type strains. Full article

(This article belongs to the Special Issue Genes at Ten)

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18 pages, 1902 KiB

Open AccessEditor’s ChoiceArticle

Real-Time Culture-Independent Microbial Profiling Onboard the International Space Station Using Nanopore Sequencing

by Sarah Stahl-Rommel, Miten Jain, Hang N. Nguyen, Richard R. Arnold, Serena M. Aunon-Chancellor, Gretta Marie Sharp, Christian L. Castro, Kristen K. John, Sissel Juul, Daniel J. Turner, David Stoddart, Benedict Paten, Mark Akeson, Aaron S. Burton and Sarah L. Castro-Wallace

Genes 2021, 12(1), 106; https://doi.org/10.3390/genes12010106 - 16 Jan 2021

Cited by 37 | Viewed by 9446

Abstract

For the past two decades, microbial monitoring of the International Space Station (ISS) has relied on culture-dependent methods that require return to Earth for analysis. This has a number of limitations, with the most significant being bias towards the detection of culturable organisms [...] Read more.

For the past two decades, microbial monitoring of the International Space Station (ISS) has relied on culture-dependent methods that require return to Earth for analysis. This has a number of limitations, with the most significant being bias towards the detection of culturable organisms and the inherent delay between sample collection and ground-based analysis. In recent years, portable and easy-to-use molecular-based tools, such as Oxford Nanopore Technologies’ MinION™ sequencer and miniPCR bio’s miniPCR™ thermal cycler, have been validated onboard the ISS. Here, we report on the development, validation, and implementation of a swab-to-sequencer method that provides a culture-independent solution to real-time microbial profiling onboard the ISS. Method development focused on analysis of swabs collected in a low-biomass environment with limited facility resources and stringent controls on allowed processes and reagents. ISS-optimized procedures included enzymatic DNA extraction from a swab tip, bead-based purifications, altered buffers, and the use of miniPCR and the MinION. Validation was conducted through extensive ground-based assessments comparing current standard culture-dependent and newly developed culture-independent methods. Similar microbial distributions were observed between the two methods; however, as expected, the culture-independent data revealed microbial profiles with greater diversity. Protocol optimization and verification was established during NASA Extreme Environment Mission Operations (NEEMO) analog missions 21 and 22, respectively. Unique microbial profiles obtained from analog testing validated the swab-to-sequencer method in an extreme environment. Finally, four independent swab-to-sequencer experiments were conducted onboard the ISS by two crewmembers. Microorganisms identified from ISS swabs were consistent with historical culture-based data, and primarily consisted of commonly observed human-associated microbes. This simplified method has been streamlined for high ease-of-use for a non-trained crew to complete in an extreme environment, thereby enabling environmental and human health diagnostics in real-time as future missions take us beyond low-Earth orbit. Full article

(This article belongs to the Special Issue MetaGenomics Sequencing In Situ)

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14 pages, 2181 KiB

Open AccessEditor’s ChoiceArticle

Metagenome Analysis of a Hydrocarbon-Degrading Bacterial Consortium Reveals the Specific Roles of BTEX Biodegraders

by Michael O. Eze

Genes 2021, 12(1), 98; https://doi.org/10.3390/genes12010098 - 14 Jan 2021

Cited by 19 | Viewed by 3902

Abstract

Environmental contamination by petroleum hydrocarbons is of concern due to the carcinogenicity and neurotoxicity of these compounds. Successful bioremediation of organic contaminants requires bacterial populations with degradative capacity for these contaminants. Through successive enrichment of microorganisms from a petroleum-contaminated soil using diesel fuel [...] Read more.

Environmental contamination by petroleum hydrocarbons is of concern due to the carcinogenicity and neurotoxicity of these compounds. Successful bioremediation of organic contaminants requires bacterial populations with degradative capacity for these contaminants. Through successive enrichment of microorganisms from a petroleum-contaminated soil using diesel fuel as the sole carbon and energy source, we successfully isolated a bacterial consortium that can degrade diesel fuel hydrocarbons. Metagenome analysis revealed the specific roles of different microbial populations involved in the degradation of benzene, toluene, ethylbenzene and xylene (BTEX), and the metabolic pathways involved in these reactions. One hundred and five putative coding DNA sequences were identified as responsible for both the activation of BTEX and central metabolism (ring-cleavage) of catechol and alkylcatechols during BTEX degradation. The majority of the Coding DNA sequences (CDSs) were affiliated to Acidocella, which was also the dominant bacterial genus in the consortium. The inoculation of diesel fuel contaminated soils with the consortium resulted in approximately 70% hydrocarbon biodegradation, indicating the potential of the consortium for environmental remediation of petroleum hydrocarbons. Full article

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13 pages, 6726 KiB

Open AccessEditor’s ChoiceArticle

Inhibition of the Lipid Droplet–Peroxisome Proliferator-Activated Receptor α Axis Suppresses Cancer Stem Cell Properties

by Kenta Kuramoto, Masahiro Yamamoto, Shuhei Suzuki, Keita Togashi, Tomomi Sanomachi, Chifumi Kitanaka and Masashi Okada

Genes 2021, 12(1), 99; https://doi.org/10.3390/genes12010099 - 14 Jan 2021

Cited by 26 | Viewed by 3066

Abstract

Cancer stem cells (CSCs), having both self-renewal and tumorigenic capacity, utilize an energy metabolism system different from that of non-CSCs. Lipid droplets (LDs) are organelles that store neutral lipids, including triacylglycerol. Previous studies demonstrated that LDs are formed and store lipids as an [...] Read more.

Cancer stem cells (CSCs), having both self-renewal and tumorigenic capacity, utilize an energy metabolism system different from that of non-CSCs. Lipid droplets (LDs) are organelles that store neutral lipids, including triacylglycerol. Previous studies demonstrated that LDs are formed and store lipids as an energy source in some CSCs. LDs play central roles not only in lipid storage, but also as a source of endogenous lipid ligands, which are involved in numerous signaling pathways, including the peroxisome proliferator-activated receptor (PPAR) signaling pathway. However, it remains unclear whether LD-derived signal transduction is involved in the maintenance of the properties of CSCs. We investigated the roles of LDs in cancer stemness using pancreatic and colorectal CSCs and isogenic non-CSCs. PPARα was activated in CSCs in which LDs accumulated, but not in non-CSCs, and pharmacological and genetic inhibition of PPARα suppressed cancer stemness. In addition, inhibition of both re-esterification and lipolysis pathways suppressed cancer stemness. Our study suggested that LD metabolic turnover accompanying PPARα activation is a promising anti-CSC therapeutic target. Full article

(This article belongs to the Special Issue Molecular Oncology–Unmask the True Nature of Cancer)

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10 pages, 1089 KiB

Open AccessEditor’s ChoiceArticle

Overcoming Supply Shortage for SARS-CoV-2 Detection by RT-qPCR

by Gustavo Barcelos Barra, Ticiane Henriques Santa Rita, Pedro Góes Mesquita, Rafael Henriques Jácomo and Lídia Freire Abdalla Nery

Genes 2021, 12(1), 90; https://doi.org/10.3390/genes12010090 - 13 Jan 2021

Cited by 15 | Viewed by 2385

Abstract

In February 2020, our laboratory started to offer a RT-qPCR assay for the qualitative detection of severe acute respiratory syndrome coronavirus 2. A few months after the assay was released to our patients, some materials, reagents, and equipment became in short supply. Alternative [...] Read more.

In February 2020, our laboratory started to offer a RT-qPCR assay for the qualitative detection of severe acute respiratory syndrome coronavirus 2. A few months after the assay was released to our patients, some materials, reagents, and equipment became in short supply. Alternative protocols were necessary in order to avoid stopping testing to the population. However, the suitability of these alternatives needs to be validated before their use. Here, we investigated if saliva is a reliable alternative specimen to nasopharyngeal swabs; if 0.45% saline is a reliable alternative to guanidine hydrochloride as a collection viral transport media; the stability of SARS-COV-2 in guanidine hydrochloride and in 0.45% saline for 10 and 50 days at room temperature; and if the primers/probe concentration and thermocycling times could be reduced so as to overcome the short supply of these reagents and equipment, without a significant loss of the assay performance. We found that saliva is not an appropriated specimen for our method—nasopharyngeal swabs perform better. Saline (0.45%) and guanidine hydrochloride have a similar SARS-CoV-2 diagnostic capability as tube additives. Reliable SARS-CoV-2 RNA detection can be performed after sample storage for 10 days at room temperature (18–23 °C) in both 0.45% saline and guanidine hydrochloride. Using synthetic RNA, and decreasing the concentration of primers by five-fold and probes by 2.5-fold, changed the assay limit of detection (LOD) from 7.2 copies/reaction to 23.7 copies/reaction and the subsequent reducing of thermocycling times changed the assay LOD from 23.7 copies/reaction to 44.2 copies/reaction. However, using real clinical samples with Cq values ranging from ~12.15 to ~36.46, the results of the three tested conditions were almost identical. These alterations will not affect the vast majority of diagnostics and increase the daily testing capability in 30% and increase primers and probe stocks in 500% and 250%, respectively. Taken together, the alternative protocols described here overcome the short supply of tubes, reagents and equipment during the SARS-CoV-2 pandemic, avoiding the collapse of test offering for the population: 105,757 samples were processed, and 25,156 SARS-CoV-2 diagnostics were performed from 9 May 2020 to 30 June 2020. Full article

(This article belongs to the Special Issue Sequencing Techniques and Genomics Technologies to Help with Diagnostics and Virus Characterization – Focus on COVID 19)

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14 pages, 1214 KiB

Open AccessEditor’s ChoiceReview

Conserved and Divergent Mechanisms That Control TORC1 in Yeasts and Mammals

by Yuichi Morozumi and Kazuhiro Shiozaki

Genes 2021, 12(1), 88; https://doi.org/10.3390/genes12010088 - 12 Jan 2021

Cited by 25 | Viewed by 4077

Abstract

Target of rapamycin complex 1 (TORC1), a serine/threonine-protein kinase complex highly conserved among eukaryotes, coordinates cellular growth and metabolism with environmental cues, including nutrients and growth factors. Aberrant TORC1 signaling is associated with cancers and various human diseases, and TORC1 also plays a [...] Read more.

Target of rapamycin complex 1 (TORC1), a serine/threonine-protein kinase complex highly conserved among eukaryotes, coordinates cellular growth and metabolism with environmental cues, including nutrients and growth factors. Aberrant TORC1 signaling is associated with cancers and various human diseases, and TORC1 also plays a key role in ageing and lifespan, urging current active research on the mechanisms of TORC1 regulation in a variety of model organisms. Identification and characterization of the RAG small GTPases as well as their regulators, many of which are highly conserved from yeast to humans, led to a series of breakthroughs in understanding the molecular bases of TORC1 regulation. Recruitment of mammalian TORC1 (mTORC1) by RAGs to lysosomal membranes is a key step for mTORC1 activation. Interestingly, the RAG GTPases in fission yeast are primarily responsible for attenuation of TORC1 activity on vacuoles, the yeast equivalent of lysosomes. In this review, we summarize our current knowledge about the functions of TORC1 regulators on yeast vacuoles, and illustrate the conserved and divergent mechanisms of TORC1 regulation between yeasts and mammals. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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27 pages, 659 KiB

Open AccessEditor’s ChoiceReview

The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia

by Celia González-Gil, Jordi Ribera, Josep Maria Ribera and Eulàlia Genescà

Genes 2021, 12(1), 79; https://doi.org/10.3390/genes12010079 - 09 Jan 2021

Cited by 15 | Viewed by 3878

Abstract

Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives [...] Read more.

Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients. Full article

(This article belongs to the Special Issue Pleiotropic Roles of Tumor Suppressors)

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