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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 22756

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Dr. Chulso Moon

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1. Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Baltimore, MD 21205, USA
2. Principal Investigator HJM Cancer Research Foundation, Timonium, MD 21093, USA
Interests: genetics of human disease; cell models; animal models; novel therapeutics; disease screening; cancer; neuropsychiatric disease; autoimmune disease
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Special Issue Information

Dear Colleagues,

Family history is often one of the strongest risk factors for common disease complexes such as cancer, cardiovascular disease (CVD), diabetes, autoimmune disorders, and psychiatric illnesses. Inherited genetic variation within families clearly contributes both directly and indirectly to the pathogenesis of disease. For more than 100 years, human geneticists have been studying how variations in genes contribute to variations in disease risk. These studies take two approaches. The first approach focuses on identifying the individual genes with variations that give rise to simple Mendelian patterns of disease inheritance. The second approach seeks to understand the genetic susceptibility to disease as the consequence of the joint effects of many genes. We are currently preparing a Special Issue entitled: ‘The Genetics of Health and Disease’.

We are interested in reviews that describe general genetic studies uncovering various human diseases and underlying mechanistic studies using cell models and mice/other animal studies. We are also keen to discover the clinical applications of research endeavors, such as disease screening or the development of novel therapeutics. The subjects we are interested in covering are as follows:

First group: GENETICS AND NEUROBIOLOGY BEHIND ADDICTION AND SCHIZOPHRENIA. AUTISM SPECTRUM DISORDERS, POST TRAUMATIC STRESS DISORDER AND MULTIPLE SCLEROSIS;
Second group: GENETICS AND CANCER BIOLOGY BEHIND THE SUSCECPTIBILITY TO THE DEVELOPMENT OF LUNG CANCER, APNCREATIC CANCER AND PROSTATE CANCER;
Third group: GENOMIC INSTABILITY, CANCER STEM CELLS AND MICROSTAELLITE INSTABILITY.

However, any subjects that extend beyond the topics of these groups, such as studies of autoimmune disease or metabolic disease, will be welcome provided that such reviews are rigorous and indicate future research directions.

Dr. Chulso Moon
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

genetics of human disease
cell models
animal models
novel therapeutics
disease screening
cancer
neuropsychiatric disease
autoimmune disease

Related Special Issue

The Role of Genes Variation in Cancer and Other Pathologies in International Journal of Molecular Sciences (3 articles)

Published Papers (10 papers)

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Research

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23 pages, 2734 KiB

Open AccessArticle

Results Obtained from a Pivotal Validation Trial of a Microsatellite Analysis (MSA) Assay for Bladder Cancer Detection through a Statistical Approach Using a Four-Stage Pipeline of Modern Machine Learning Techniques

by Thomas Reynolds, Gregory Riddick, Gregory Meyers, Maxie Gordon, Gabriela Vanessa Flores Monar, David Moon and Chulso Moon

Int. J. Mol. Sci. 2024, 25(1), 472; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25010472 - 29 Dec 2023

Viewed by 804

Abstract

Several studies have shown that microsatellite changes can be profiled in urine for the detection of bladder cancer. The use of microsatellite analysis (MSA) for bladder cancer detection requires a comprehensive analysis of as many as 15 to 20 markers, based on the amplification and interpretations of many individual MSA markers, and it can be technically challenging. Here, to develop fast, more efficient, standardized, and less costly MSA for the detection of bladder cancer, we developed three multiplex-polymerase-chain-reaction-(PCR)-based MSA assays, all of which were analyzed via a genetic analyzer. First, we selected 16 MSA markers based on 9 selected publications. Based on samples from Johns Hopkins University (the JHU sample, the first set sample), we developed an MSA based on triplet, three-tube-based multiplex PCR (a Triplet MSA assay). The discovery, validation, and translation of biomarkers for the early detection of cancer are the primary focuses of the Early Detection Research Network (EDRN), an initiative of the National Cancer Institute (NCI). A prospective study sponsored by the EDRN was undertaken to determine the efficacy of a novel set of MSA markers for the early detection of bladder cancer. This work and data analysis were performed through a collaboration between academics and industry partners. In the current study, we undertook a re-analysis of the primary data from the Compass study to enhance the predictive power of the dataset in bladder cancer diagnosis. Using a four-stage pipeline of modern machine learning techniques, including outlier removal with a nonlinear model, correcting for majority/minority class imbalance, feature engineering, and the use of a model-derived variable importance measure to select predictors, we were able to increase the utility of the original dataset to predict the occurrence of bladder cancer. The results of this analysis showed an increase in accuracy (85%), sensitivity (82%), and specificity (83%) compared to the original analysis. The re-analysis of the EDRN study results using machine learning statistical analysis proved to achieve an appropriate level of accuracy, sensitivity, and specificity to support the use of the MSA for bladder cancer detection and monitoring. This assay can be a significant addition to the tools urologists use to both detect primary bladder cancers and monitor recurrent bladder cancer. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

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17 pages, 301 KiB

Open AccessArticle

Qualification of the Microsatellite Instability Analysis (MSA) for Bladder Cancer Detection: The Technical Challenges of Concordance Analysis

by Thomas Reynolds, Katie Bertsche, David Moon and Chulso Moon

Int. J. Mol. Sci. 2024, 25(1), 209; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25010209 - 22 Dec 2023

Cited by 1 | Viewed by 629

Abstract

Bladder cancer (here we refer to transitional carcinoma of bladder) is a major cause of morbidity and mortality in the Western world, and recent understanding of its etiology, the molecular characteristics associated with its progression, renders bladder cancer an ideal candidate for screening. Cystoscopy is invasive and sometimes carries unwanted complications, but it is the gold standard for the detection of bladder cancer. Urine cytology, while the most commonly used test as an initial screening tool, is of limited value due to its low sensitivity, particularly for low-grade tumors. Several new “molecular assays” for the diagnosis of urothelial cancer have been developed over the last two decades. Here, we have established our new bladder cancer test based on an assay established for the Early Detection Research Network (EDRN) study. As a part of the study, a quality control CLIA/College of American Pathology (CAP) accredited laboratory, (QA Lab), University of Maryland Baltimore Biomarker Reference Laboratory (UMB-BRL), performed quality assurance analysis. Quality assurance measures included a concordance study between the testing laboratory (AIBioTech), also CLIA/CAP accredited, and the QA lab to ensure that the assay was performed and the results were analyzed in a consistent manner. Therefore, following the technical transfer and training of the microsatellite analysis assay to the UMB-BRL and prior to the initiation of analysis of the clinical samples by the testing lab, a series of qualification studies were performed. This report details the steps taken to ensure qualification of the assay and illustrates the technical challenges facing biomarker validation of this kind. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

14 pages, 1179 KiB

Open AccessArticle

Cannabis Use and Endocannabinoid Receptor Genes: A Pilot Study on Their Interaction on Brain Activity in First-Episode Psychosis

by Maitane Oscoz-Irurozqui, Carmen Almodóvar-Payá, Maria Guardiola-Ripoll, Amalia Guerrero-Pedraza, Noemí Hostalet, Raymond Salvador, Maria Isabel Carrión, Teresa Maristany, Edith Pomarol-Clotet and Mar Fatjó-Vilas

Int. J. Mol. Sci. 2023, 24(8), 7501; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087501 - 19 Apr 2023

Viewed by 1291

Abstract

The role of both cannabis use and genetic background has been shown in the risk for psychosis. However, the effect of the interplay between cannabis and variability at the endocannabinoid receptor genes on the neurobiological underpinnings of psychosis remains inconclusive. Through a case-only design, including patients with a first-episode of psychosis (n = 40) classified as cannabis users (50%) and non-users (50%), we aimed to evaluate the interaction between cannabis use and common genetic variants at the endocannabinoid receptor genes on brain activity. Genetic variability was assessed by genotyping two Single Nucleotide Polymorphisms (SNP) at the cannabinoid receptor type 1 gene (CNR1; rs1049353) and cannabinoid receptor type 2 gene (CNR2; rs2501431). Functional Magnetic Resonance Imaging (fMRI) data were obtained while performing the n-back task. Gene × cannabis interaction models evidenced a combined effect of CNR1 and CNR2 genotypes and cannabis use on brain activity in different brain areas, such as the caudate nucleus, the cingulate cortex and the orbitofrontal cortex. These findings suggest a joint role of cannabis use and cannabinoid receptor genetic background on brain function in first-episode psychosis, possibly through the impact on brain areas relevant to the reward circuit. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

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14 pages, 585 KiB

Open AccessArticle

Genetic Determinants of Leisure-Time Physical Activity in the Hungarian General and Roma Populations

by Péter Pikó, Éva Bácsné Bába, Zsigmond Kósa, János Sándor, Nóra Kovács, Zoltán Bács and Róza Ádány

Int. J. Mol. Sci. 2023, 24(5), 4566; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054566 - 26 Feb 2023

Viewed by 1490

Abstract

Leisure-time physical activity (LTPA) is one of the modifiable lifestyle factors that play an important role in the prevention of non-communicable (especially cardiovascular) diseases. Certain genetic factors predisposing to LTPA have been previously described, but their effects and applicability on different ethnicities are unknown. Our present study aims to investigate the genetic background of LTPA using seven single nucleotide polymorphisms (SNPs) in a sample of 330 individuals from the Hungarian general (HG) and 314 from the Roma population. The LTPA in general and three intensity categories of it (vigorous, moderate, and walking) were examined as binary outcome variables. Allele frequencies were determined, individual correlations of SNPs to LTPA, in general, were determined, and an optimized polygenetic score (oPGS) was created. Our results showed that the allele frequencies of four SNPs differed significantly between the two study groups. The C allele of rs10887741 showed a significant positive correlation with LTPA in general (OR = 1.48, 95% CI: 1.12–1.97; p = 0.006). Three SNPs (rs10887741, rs6022999, and rs7023003) were identified by the process of PGS optimization, whose cumulative effect shows a strong significant positive association with LTPA in general (OR = 1.40, 95% CI: 1.16–1.70; p < 0.001). The oPGS showed a significantly lower value in the Roma population compared with the HG population (oPGS_Roma: 2.19 ± SD: 0.99 vs. oPGS_HG: 2.70 ± SD: 1.06; p < 0.001). In conclusion, the coexistence of genetic factors that encourage leisure-time physical activity shows a more unfavorable picture among Roma, which may indirectly contribute to their poor health status. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

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16 pages, 5097 KiB

Open AccessArticle

miRNA-124 Prevents Rat Diabetic Retinopathy by Inhibiting the Microglial Inflammatory Response

by Ying Chen, Andrea Schlotterer, Luke Kurowski, Lin Li, Marcus Dannehl, Hans-Peter Hammes and Jihong Lin

Int. J. Mol. Sci. 2023, 24(3), 2291; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032291 - 24 Jan 2023

Cited by 9 | Viewed by 2198

Abstract

Diabetic retinopathy (DR) is characterized by vasoregression and glial activation. miRNA-124 (miR-124) reduces retinal microglial activation and alleviates vasoregression in a neurodegenerative rat model. Our aim was to determine whether miR-124 affects vascular and neural damage in the early diabetic retina. Diabetes was induced in 8-week-old Wistar rats by streptozotocin (STZ) injection. At 16 and 20 weeks, the diabetic rats were intravitreally injected with miR-124 mimic, and retinae were analyzed at 24 weeks. Microvascular damage was identified by evaluating pericyte loss and acellular capillary (AC) formation. Müller glial activation was assessed by glial fibrillary acidic protein (GFAP) immunofluorescence staining. Microglial activation was determined by immunofluorescent staining of ionized calcium-binding adaptor molecule 1 (Iba1) in whole mount retinae. The neuroretinal function was assessed by electroretinography. The expression of inflammation-associated genes was evaluated by qRT-PCR. A wound healing assay was performed to quantitate the mobility of microglial cells. The results showed that miR-124 treatment alleviated diabetic vasoregression by reducing AC formation and pericyte loss. miR-124 blunted Müller glial- and microglial activation in diabetic retinae and ameliorated neuroretinal function. The retinal expression of inflammatory factors including Tnf-α, Il-1β, Cd74, Ccl2, Ccl3, Vcam1, Tgf-β1, Arg1, and Il-10 was reduced by miR-124 administration. The elevated mobility of microglia upon high glucose exposure was normalized by miR-124. The expression of the transcription factor PU.1 and lipid raft protein Flot1 was downregulated by miR-124. In rat DR, miR-124 prevents vasoregression and glial activation, improves neuroretinal function, and modulates microglial activation and inflammatory responses. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

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13 pages, 881 KiB

Open AccessArticle

A 5′ UTR Mutation Contributes to Down-Regulation of Bbs7 in the Berlin Fat Mouse

by Kourosh Mohebian, Deike Hesse, Danny Arends and Gudrun A. Brockmann

Int. J. Mol. Sci. 2022, 23(21), 13018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113018 - 27 Oct 2022

Cited by 3 | Viewed by 1352

Abstract

The Bardet–Biedl Syndrome 7 (Bbs7) gene was identified as the most likely candidate gene causing juvenile obesity in the Berlin Fat Mouse Inbred (BFMI) line. Bbs7 expression is significantly lower in the brain, adipose tissue, and liver of BFMI mice compared to lean C57BL/6NCrl (B6N) mice. A DNA sequence comparison between BFMI and B6N revealed 16 sequence variants in the Bbs7 promoter region. Here, we tested if these mutations contribute to the observed differential expression of Bbs7. In a cell-based dual-luciferase assay, we compared the effects of the BFMI and the B6N haplotypes of different regions of the Bbs7 promotor on the reporter gene expression. A single-nucleotide polymorphism (SNP) was identified causing a significant reduction in the reporter gene expression. This SNP (rs29947545) is located in the 5′ UTR of Bbs7 at Chr3:36.613.350. The SNP is not unique to BFMI mice but also occurs in several other mouse strains, where the BFMI allele is not associated with lower Bbs7 transcript amounts. Thus, we suggest a compensatory mutation in the other mouse strains that keeps Bbs7 expression at the normal level. This compensatory mechanism is missing in BFMI mice and the cell lines tested. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

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14 pages, 4319 KiB

Open AccessArticle

A Bioengineered In Vitro Model to Assess AAV-Based Gene Therapies for Cyclic GMP-Related Disorders

by Marina Pavlou, Sabrina Babutzka and Stylianos Michalakis

Int. J. Mol. Sci. 2022, 23(9), 4538; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094538 - 20 Apr 2022

Cited by 1 | Viewed by 2749

Abstract

The emergence of efficient viral vectors derived from adeno-associated viruses (AAV) has led many groups to develop gene therapies for inherited monogenic diseases, such as retinal dystrophies. To evaluate the potency of new gene therapy vectors in a preclinical context, it is common to use animal models, such as gene-deficient or mutant animal models of a given human disease, and then assess vision restoration with functional or behavioral assays. While such animal models are invaluable to the preclinical testing process, they cannot be readily used as batch release tests during manufacturing or to validate biological activity at later stages of development. There is therefore a need for rapid and reliable in vitro models that can determine whether therapeutic vectors have delivered their cargo gene, and more importantly, whether this has resulted in the intended biological activity. Given our previous experience, we chose CNGA3-linked achromatopsia to develop a cell-based system to verify biological activity of AAV vectors designed to deliver a healthy CNGA3 gene copy into human cone photoreceptors. Our system is based on an immortalized cell line with high susceptibility to AAV transduction, i.e., HeLa cells, which we engineered to express a fungal rhodopsin guanylyl cyclase (RhGC) from Blastocladiella emersonii and a sensitive genetically encoded calcium indicator (GECI) under the control of a tetracycline operator. Using this system, we were able to confirm and quantify the function of the ion channel encoded by AAV/CNGA3 and differentiate between AAV vector potencies with a simple fluorometric assay. Finally, we show that this approach can be readily adapted for the assessment of phosphodiesterase function. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

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Review

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28 pages, 808 KiB

Open AccessReview

Selected Genetic Factors Associated with Primary Ovarian Insufficiency

by Mengchi Chen, Haotian Jiang and Chunping Zhang

Int. J. Mol. Sci. 2023, 24(5), 4423; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054423 - 23 Feb 2023

Cited by 13 | Viewed by 4328

Abstract

Primary ovarian insufficiency (POI) is a heterogeneous disease resulting from non-functional ovaries in women before the age of 40. It is characterized by primary amenorrhea or secondary amenorrhea. As regards its etiology, although many POI cases are idiopathic, menopausal age is a heritable trait and genetic factors play an important role in all POI cases with known causes, accounting for approximately 20% to 25% of cases. This paper reviews the selected genetic causes implicated in POI and examines their pathogenic mechanisms to show the crucial role of genetic effects on POI. The genetic factors that can be found in POI cases include chromosomal abnormalities (e.g., X chromosomal aneuploidies, structural X chromosomal abnormalities, X-autosome translocations, and autosomal variations), single gene mutations (e.g., newborn ovary homeobox gene (NOBOX), folliculogenesis specific bHLH transcription factor (FIGLA), follicle-stimulating hormone receptor (FSHR), forkhead box L2 (FOXL2), bone morphogenetic protein 15 (BMP15), etc., as well as defects in mitochondrial functions and non-coding RNAs (small ncRNAs and long ncRNAs). These findings are beneficial for doctors to diagnose idiopathic POI cases and predict the risk of POI in women. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

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23 pages, 1100 KiB

Open AccessReview

A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge

by Maria Guardiola-Ripoll and Mar Fatjó-Vilas

Int. J. Mol. Sci. 2023, 24(4), 3597; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043597 - 10 Feb 2023

Cited by 6 | Viewed by 3782

Abstract

Schizophrenia is a psychiatric disorder that results from genetic and environmental factors interacting and disrupting neurodevelopmental trajectories. Human Accelerated Regions (HARs) are evolutionarily conserved genomic regions that have accumulated human-specific sequence changes. Thus, studies on the impact of HARs in the context of neurodevelopment, as well as with respect to adult brain phenotypes, have increased considerably in the last few years. Through a systematic approach, we aim to offer a comprehensive review of HARs’ role in terms of human brain development, configuration, and cognitive abilities, as well as whether HARs modulate the susceptibility to neurodevelopmental psychiatric disorders such as schizophrenia. First, the evidence in this review highlights HARs’ molecular functions in the context of the neurodevelopmental regulatory genetic machinery. Second, brain phenotypic analyses indicate that HAR genes’ expression spatially correlates with the regions that suffered human-specific cortical expansion, as well as with the regional interactions for synergistic information processing. Lastly, studies based on candidate HAR genes and the global “HARome” variability describe the involvement of these regions in the genetic background of schizophrenia, but also in other neurodevelopmental psychiatric disorders. Overall, the data considered in this review emphasise the crucial role of HARs in human-specific neurodevelopment processes and encourage future research on this evolutionary marker for a better understanding of the genetic basis of schizophrenia and other neurodevelopmental-related psychiatric disorders. Accordingly, HARs emerge as interesting genomic regions that require further study in order to bridge the neurodevelopmental and evolutionary hypotheses in schizophrenia and other related disorders and phenotypes. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

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22 pages, 766 KiB

Open AccessReview

Oncogenic Pathways in Neurodegenerative Diseases

by Luis Varela and Maria E. R. Garcia-Rendueles

Int. J. Mol. Sci. 2022, 23(6), 3223; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063223 - 17 Mar 2022

Cited by 9 | Viewed by 3327

Abstract

Cancer and neurodegenerative diseases are two of the leading causes of premature death in modern societies. Their incidence continues to increase, and in the near future, it is believed that cancer will kill more than 20 million people per year, and neurodegenerative diseases, due to the aging of the world population, will double their prevalence. The onset and the progression of both diseases are defined by dysregulation of the same molecular signaling pathways. However, whereas in cancer, these alterations lead to cell survival and proliferation, neurodegenerative diseases trigger cell death and apoptosis. The study of the mechanisms underlying these opposite final responses to the same molecular trigger is key to providing a better understanding of the diseases and finding more accurate treatments. Here, we review the ten most common signaling pathways altered in cancer and analyze them in the context of different neurodegenerative diseases such as Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s (HD) diseases. Full article

(This article belongs to the Special Issue Genetics of Health and Disease)

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