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DNA Variations in Evolution and Human Diseases

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (28 February 2018) | Viewed by 67660

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Dr. Walid Fakhouri

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Department of Diagnostic & Biomedical Sciences, School of Dentistry,1941 East Road, Houston, TX 77054, USA
Interests: craniofacial tissue development; genetics of craniofacial birth defects; salivary gland development and disorders; computational biology of gene regulation
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Dr. Ariadne Letra

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University of Texas Health Science Center at Houston, Departments of Diagnostic and Biomedical Sciences, Endodontics, and Craniofacial Research Center, 7500 Cambridge Street, Room 5359, Houston, TX 77054, USA

Special Issue Information

Dear Colleagues,

In 1973, the biologist Theodosius Dobzhansky wrote "nothing in biology makes sense except in the light of evolution". Advances in sequencing technologies have provided the scientific community with essential information to determine which part of the mammalian genome has been going through rapid turnover. Based on DNA conservation and alignment, evolutionary studies have shown that DNA changes are taking place at higher rates in non-coding regulatory regions than in coding sequences that encode for functional protein. Further, molecular and genetic studies in animal models have shown that some DNA variations were maintained through evolution due to the positive effect in increasing the fitness to environmental condition; in contrast, certain DNA variations increase risk for simple and complex diseases.

In humans, genome-wide association studies have demonstrated that ~10% of the disease-related single nucleotide polymorphisms (SNPs) are located in amino acid-coding sequences, whereas 90% of the disease-associated SNPs are outside the protein-coding regions in common complex diseases. Although prediction of functional SNPs in coding regions can be easily accomplished using bioinformatic approaches, prediction of pathological non-coding DNA variations and their effect on target gene expression remains challenging. Identification of pathogenic DNA variants is critical for improving prognosis of genetic diseases in high-risk individuals and for targeted therapies in patients with genetic disorders.

The aim of this Special Issue is to provide an updated view of the current research to understanding the underlying mechanisms by which coding and non-coding DNA variations alter gene function and expression, gene transcriptional start site and post-transcriptional and post-translational regulations.

Dr. Walid Fakhouri
Dr. Ariadne Letra
Guest Editors

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Keywords

Genomic evolution
Coding DNA variations
Non-coding DNA variations
Alternative transcriptional start site
Alternative splicing and mRNA stability
Post-transcriptional and -translational regulation

Published Papers (13 papers)

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Editorial

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3 pages, 161 KiB

Open AccessEditorial

Identification of Disease Risk DNA Variations is Shaping the Future of Precision Health

by Walid D. Fakhouri and Ariadne Letra

Genes 2019, 10(6), 450; https://doi.org/10.3390/genes10060450 - 13 Jun 2019

Cited by 1 | Viewed by 2152

Abstract

In recent years, the knowledge generated by decoding the human genome has allowed groundbreaking genetic research to better understand genomic architecture and heritability in healthy and disease states. The vast amount of data generated over time and yet to be generated provides the basis for translational research towards the development of preventive and therapeutic strategies for many conditions. In this special issue, we highlight the discoveries of disease-associated and protective DNA variations in common human diseases and developmental disorders. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

Research

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18 pages, 2186 KiB

Open AccessArticle

Genetic Association with Subgingival Bacterial Colonization in Chronic Periodontitis

by Franco Cavalla, Claudia Cristina Biguetti, Jessica Lima Melchiades, Andre Pantenuci Tabanez, Michelle De Campos Soriani Azevedo, Ana Paula Favaro Trombone, Marcelo Faveri, Magda Feres and Gustavo Pompermaier Garlet

Genes 2018, 9(6), 271; https://doi.org/10.3390/genes9060271 - 23 May 2018

Cited by 16 | Viewed by 4661

Abstract

Chronic periodontitis is the most prevalent form of inflammatory destructive bone disease and has been affecting humans since antiquity. Evidence suggest that genetic factors can highly influence periodontitis risk, modulating disease elements such as the susceptibility to microbial colonization and the nature of subsequent host-microbe interaction. Several single-nucleotide polymorphisms (SNPs) have been associated with the occurrence of periodontitis, but the full range of genetic influence in periodontitis outcomes remains to be determined. In this context, this study comprises an analysis of possible correlation between periodontitis-related genetic variants with changes in the subgingival microbiological pattern performed in a Brazilian population (n = 167, comprising 76 chronic periodontitis patients and 91 healthy subjects). For the genetic characterization, 19 candidate SNPs were selected based on the top hits of previous large genome wide association studies (GWAS), while the subgingival microbiota was characterized for the presence and relative quantity of 40 bacterial species by DNA-DNA checkerboard. The case/control association test did not demonstrate a significant effect of the target SNPs with the disease phenotype. The polymorphism rs2521634 proved significantly associated with Tannerella. forsythia, Actinomyces gerencseriae, Fusobacterium periodonticum, and Prevotella nigrescens; rs10010758 and rs6667202 were associated with increased counts of Porphyromonas gingivalis; and rs10043775 proved significantly associated with decreased counts of Prevotella intermedia. In conclusion, we present strong evidence supporting a direct connection between the host’s genetic profile, specifically rs2521634, rs10010758, rs6667202, and rs10043775 polymorphisms, and the occurrence of chronic periodontitis-associated bacteria. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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9 pages, 1224 KiB

Open AccessArticle

BSG and MCT1 Genetic Variants Influence Survival in Multiple Myeloma Patients

by Piotr Łacina, Aleksandra Butrym, Grzegorz Mazur and Katarzyna Bogunia-Kubik

Genes 2018, 9(5), 226; https://doi.org/10.3390/genes9050226 - 24 Apr 2018

Cited by 14 | Viewed by 3875

Abstract

Multiple myeloma (MM) is a haematologic malignancy characterized by the presence of atypical plasma cells. Basigin (BSG, CD147) controls lactate export through the monocarboxylic acid transporter 1 (MCT1, SLC16A1) and supports MM survival and proliferation. Additionally, BSG is implicated in response to treatment with immunomodulatory drugs (thalidomide and its derivatives). We investigated the role of single nucleotide polymorphisms (SNPs) in the gene coding for BSG and SLC16A1 in MM. Following an in silico analysis, eight SNPs (four in BSG and four in SLC16A1) predicted to have a functional effect were selected and analyzed in 135 MM patients and 135 healthy individuals. Alleles rs4919859 C, rs8637 G, and haplotype CG were associated with worse progression-free survival (p = 0.006, p = 0.017, p = 0.002, respectively), while rs7556664 A, rs7169 T and rs1049434 A (all in linkage disequilibrium (LD), r² > 0.98) were associated with better overall survival (p = 0.021). Similar relationships were observed in thalidomide-treated patients. Moreover, rs4919859 C, rs8637 G, rs8259 A and the CG haplotype were more common in patients in stages II–III of the International Staging System (p < 0.05), while rs8259 A correlated with higher levels of β-2-microglobulin and creatinine (p < 0.05). Taken together, our results show that BSG and SLC16A1 variants affect survival, and may play an important role in MM. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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14 pages, 27552 KiB

Open AccessArticle

Transgenic Xenopus laevis Line for In Vivo Labeling of Nephrons within the Kidney

by Mark E. Corkins, Hannah L. Hanania, Vanja Krneta-Stankic, Bridget D. DeLay, Esther J. Pearl, Moonsup Lee, Hong Ji, Alan J. Davidson, Marko E. Horb and Rachel K. Miller

Genes 2018, 9(4), 197; https://doi.org/10.3390/genes9040197 - 06 Apr 2018

Cited by 12 | Viewed by 8878

Abstract

Xenopus laevis embryos are an established model for studying kidney development. The nephron structure and genetic pathways that regulate nephrogenesis are conserved between Xenopus and humans, allowing for the study of human disease-causing genes. Xenopus embryos are also amenable to large-scale screening, but studies of kidney disease-related genes have been impeded because assessment of kidney development has largely been limited to examining fixed embryos. To overcome this problem, we have generated a transgenic line that labels the kidney. We characterize this cdh17:eGFP line, showing green fluorescent protein (GFP) expression in the pronephric and mesonephric kidneys and colocalization with known kidney markers. We also demonstrate the feasibility of live imaging of embryonic kidney development and the use of cdh17:eGFP as a kidney marker for secretion assays. Additionally, we develop a new methodology to isolate and identify kidney cells for primary culture. We also use morpholino knockdown of essential kidney development genes to establish that GFP expression enables observation of phenotypes, previously only described in fixed embryos. Taken together, this transgenic line will enable primary kidney cell culture and live imaging of pronephric and mesonephric kidney development. It will also provide a simple means for high-throughput screening of putative human kidney disease-causing genes. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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15 pages, 262 KiB

Open AccessArticle

Influence of NKG2D Genetic Variants on Response to Anti-TNF Agents in Patients with Rheumatoid Arthritis

by Milena Iwaszko, Jerzy Świerkot, Katarzyna Kolossa, Sławomir Jeka, Piotr Wiland and Katarzyna Bogunia-Kubik

Genes 2018, 9(2), 64; https://doi.org/10.3390/genes9020064 - 25 Jan 2018

Cited by 19 | Viewed by 4520

Abstract

A natural killer group 2 member D (NKG2D) acts as a powerful activating and co-stimulatory receptor on immune effector cells including NK and T cells. Disruptions within the NKG2D signalling pathway may trigger an exacerbated immune response and promote autoimmune reactions. The objective of the study was to evaluate a plausible role of polymorphisms within the NKG2D gene as a predictor of how effective anti-tumor necrosis factor (TNF) therapy is in rheumatoid arthritis (RA) patients. A total of 280 RA patients receiving anti-TNF therapy were genotyped for NKG2D rs2255336 (A > G), rs1049174 (C > G), and rs1154831 (C > A). Clinical response was evaluated according to the European League against Rheumatism (EULAR) criteria at the 12th and 24th week. Both the NKG2D rs225336 and rs1049174 polymorphisms were significantly associated with efficacy of TNF inhibitors. Inefficient therapy was more frequently observed in patients with rs2255336 GG or rs1049174 CC genotype as compared to other genotypes (p-value = 0.003 and p-value = 0.004, respectively). The presence of the rs2255336 G or the rs1049174 C allele correlated with a worse EULAR response (p-value = 0.002, p-value = 0.031, respectively). Moreover, patients carrying the rs2255336 or rs1049174 heterozygous genotype achieved better EULAR responses than patients with homozygous genotypes (p-value = 0.010 and p-value = 0.002, respectively). Data from the present study provides evidence that NKG2D polymorphisms may affect response to anti-TNF inhibitors in RA patients. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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12 pages, 476 KiB

Open AccessArticle

The IFNG rs1861494 Single Nucleotide Polymorphism Is Associated with Protection against Tuberculosis Disease in Argentina

by Agustín Rolandelli, Joaquín M. Pellegrini, Nicolás O. Amiano, María C. Santilli, María P. Morelli, Florencia A. Castello, Nancy L. Tateosian, Alberto Levi, Nicolás Casco, Domingo J. Palmero and Verónica E. García

Genes 2018, 9(1), 46; https://doi.org/10.3390/genes9010046 - 22 Jan 2018

Cited by 15 | Viewed by 5545

Abstract

Interferon gamma (IFNG) plays a key role during Mycobacterium tuberculosis (Mtb) infection, and several polymorphisms located in its gene are associated with risk of tuberculosis in diverse populations. Nevertheless, the genetic resistance/susceptibility to tuberculosis in Argentina is unknown. The IFNG rs1861494 polymorphism (G→A) was reported to alter the binding of transcription factors to this region, influencing IFNG production. Using a case-control study, we found an association between the AA and AG genotypes and tuberculosis resistance (AA vs. GG: odds ratio (OR) = 0.235, p-value = 0.012; AG vs. GG: OR = 0.303, p-value = 0.044; AA vs. AG: OR = 0.776, p-value = 0.427; AA + AG vs. GG: OR = 0.270, p-value = 0.022). Moreover, Mtb-antigen stimulated peripheral blood mononuclear cells (PBMCs) from healthy donors and AA carriers secreted the highest amounts of IFNG in culture supernatants (p-value = 0.034) and presented the greatest percentage of CD4⁺IFNG⁺ lymphocytes (p-value = 0.035), in comparison with GG carriers. No association between the polymorphism and clinical parameters of tuberculosis severity was detected. However, our findings indicate that the rs1861494 single nucleotide polymorphism (SNP) could be considered as a biomarker of tuberculosis resistance in the Argentinean population. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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Review

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22 pages, 2083 KiB

Open AccessReview

Transcriptional Regulation of INSR, the Insulin Receptor Gene

by Sandhya Payankaulam, Ana-Maria Raicu and David N. Arnosti

Genes 2019, 10(12), 984; https://doi.org/10.3390/genes10120984 - 29 Nov 2019

Cited by 38 | Viewed by 6874

Abstract

The insulin receptor gene encodes an evolutionarily conserved signaling protein with a wide spectrum of functions in metazoan development. The insulin signaling pathway plays key roles in processes such as metabolic regulation, growth control, and neuronal function. Misregulation of the pathway features in diabetes, cancer, and neurodegenerative diseases, making it an important target for clinical interventions. While much attention has been focused on differential pathway activation through ligand availability, sensitization of overall signaling may also be mediated by differential expression of the insulin receptor itself. Although first characterized as a “housekeeping” gene with stable expression, comparative studies have shown that expression levels of the human INSR mRNA differ by tissue and in response to environmental signals. Our recent analysis of the transcriptional controls affecting expression of the Drosophila insulin receptor gene indicates that a remarkable amount of DNA is dedicated to encoding sophisticated feedback and feed forward signals. The human INSR gene is likely to contain a similar level of transcriptional complexity; here, we summarize over three decades of molecular biology and genetic research that points to a still incompletely understood regulatory control system. Further elucidation of transcriptional controls of INSR will provide the basis for understanding human genetic variation that underlies population-level physiological differences and disease. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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14 pages, 1244 KiB

Open AccessReview

Modular Proteoglycan Perlecan/HSPG2: Mutations, Phenotypes, and Functions

by Jerahme R. Martinez, Akash Dhawan and Mary C. Farach-Carson

Genes 2018, 9(11), 556; https://doi.org/10.3390/genes9110556 - 16 Nov 2018

Cited by 46 | Viewed by 7254

Abstract

Heparan sulfate proteoglycan 2 (HSPG2) is an essential, highly conserved gene whose expression influences many developmental processes including the formation of the heart and brain. The gene is widely expressed throughout the musculoskeletal system including cartilage, bone marrow and skeletal muscle. The HSPG2 gene product, perlecan is a multifunctional proteoglycan that preserves the integrity of extracellular matrices, patrols tissue borders, and controls various signaling pathways affecting cellular phenotype. Given HSPG2’s expression pattern and its role in so many fundamental processes, it is not surprising that relatively few gene mutations have been identified in viable organisms. Mutations to the perlecan gene are rare, with effects ranging from a relatively mild condition to a more severe and perinatally lethal form. This review will summarize the important studies characterizing mutations and variants of HSPG2 and discuss how these genomic modifications affect expression, function and phenotype. Additionally, this review will describe the clinical findings of reported HSPG2 mutations and their observed phenotypes. Finally, the evolutionary aspects that link gene integrity to function are discussed, including key findings from both in vivo animal studies and in vitro systems. We also hope to facilitate discussion about perlecan/HSPG2 and its role in normal physiology, to explain how mutation can lead to pathology, and to point out how this information can suggest pathways for future mechanistic studies. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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15 pages, 1882 KiB

Open AccessReview

Can Genetic Factors Compromise the Success of Dental Implants? A Systematic Review and Meta-Analysis

by Joel Ferreira Santiago Junior, Claudia Cristina Biguetti, Mariza Akemi Matsumoto, Guilherme Abu Halawa Kudo, Raquel Barroso Parra da Silva, Patrícia Pinto Saraiva and Walid D. Fakhouri

Genes 2018, 9(9), 444; https://doi.org/10.3390/genes9090444 - 06 Sep 2018

Cited by 16 | Viewed by 5124

Abstract

Dental implants provide a predictable treatment option for partial and complete edentulism via the placement of a fixed permanent artificial root to support prosthetic dental crowns. Despite the high survival rates, long-term dental implant failures are still reported, leading to implant removals and additional financial and health burdens. While extrinsic factors that improve the success rate of implants have been well explored, the impact of genetic factors on this matter is poorly understood. A systematic review and meta-analysis study was conducted to determine whether genetic factors contribute to an increased risk of dental implant failures. A comprehensive search for peer-reviewed articles on dental implants and genetic factors was performed using various literature database libraries. The study design was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, and the obtained records were registered in the International Prospective Register of Systematic Reviews (PROSPERO) database. According to the exclusion/inclusion criteria, 13 studies were eligible for this study out of 809 articles. The meta-analysis of the combined association studies of DNA variations and dental implants did not indicate an increased risk for implant failure due to DNA variations in IL-1B, IL-10 and TNF-α. This study emphasizes the need for larger randomized controlled clinical trials to inform clinicians and patients about the role of genetic factors on dental implant survival and the success rate in healthy and compromised patients. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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24 pages, 7477 KiB

Open AccessFeature PaperReview

The Changing Landscape in the Genetic Etiology of Human Tooth Agenesis

by Meredith A. Williams and Ariadne Letra

Genes 2018, 9(5), 255; https://doi.org/10.3390/genes9050255 - 16 May 2018

Cited by 38 | Viewed by 5335

Abstract

Despite much progress in understanding the genetics of syndromic tooth agenesis (TA), the causes of the most common, isolated TA remain elusive. Recent studies have identified novel genes and variants contributing to the etiology of TA, and revealed new pathways in which tooth development genes belong. Further, the use of new research approaches including next-generation sequencing has provided increased evidence supporting an oligogenic inheritance model for TA, and may explain the phenotypic variability of the condition. In this review, we present current knowledge about the genetic mechanisms underlying syndromic and isolated TA in humans, and highlight the value of incorporating next-generation sequencing approaches to identify causative and/or modifier genes that contribute to the etiology of TA. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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21 pages, 360 KiB

Open AccessReview

Genetic Mechanisms of Asthma and the Implications for Drug Repositioning

by Yue Huo and Hong-Yu Zhang

Genes 2018, 9(5), 237; https://doi.org/10.3390/genes9050237 - 03 May 2018

Cited by 14 | Viewed by 5354

Abstract

Asthma is a chronic disease that is caused by airway inflammation. The main features of asthma are airway hyperresponsiveness (AHR) and reversible airway obstruction. The disease is mainly managed using drug therapy. The current asthma drug treatments are divided into two categories, namely, anti-inflammatory drugs and bronchodilators. However, disease control in asthma patients is not very efficient because the pathogenesis of asthma is complicated, inducing factors that are varied, such as the differences between individual patients. In this paper, we delineate the genetic mechanisms of asthma, and present asthma-susceptible genes and genetic pharmacology in an attempt to find a diagnosis, early prevention, and treatment methods for asthma. Finally, we reposition some clinical drugs for asthma therapy, based on asthma genetics. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

Other

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10 pages, 886 KiB

Open AccessBrief Report

APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation

by Giovanna D’Elia, Gemma Caliendo, Amelia Casamassimi, Michele Cioffi, Anna Maria Molinari and Maria Teresa Vietri

Genes 2018, 9(7), 322; https://doi.org/10.3390/genes9070322 - 27 Jun 2018

Cited by 16 | Viewed by 4784

Abstract

APC and MUTYH genes are mutated in 70–90% and 10–30% of familial adenomatous polyposis cases (FAP) respectively. An association between mutation localization and FAP clinical phenotype is reported. The aims of this study were to determine APC and MUTYH mutational status in a small cohort of FAP patients and to evaluate the genotype-phenotype correlation in mutated patients. Here, we report the identification of a novel APC germline mutation, c.510_511insA. Overall, mutational analysis showed pathogenic mutations in 6/10 patients: 5/10 in APC and 1/10 in MUTYH. Additionally, we found three variants of unknown significance in MUTYH gene that showed no evidence of possible splicing defects by in silico analysis. Molecular analysis was also extended to family members of mutated patients. A genotype-phenotype correlation was observed for colonic signs whereas a variation of disease onset age was revealed for the same mutation. Moreover, we found an intrafamilial variability of FAP onset age. Regarding extracolonic manifestations, the development of desmoid tumors was related to surgery and not to mutation position, while a genotype-phenotype correspondence was observed for the onset of thyroid or gastric cancer. These findings can be useful in association to clinical data for early surveillance and suitable treatment of FAP patients. Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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1 pages, 124 KiB

Open AccessAddendum

Addendum: Iwaszko et al., Influence of NKG2D Genetic Variants on Response to Anti-TNF Agents in Patients with Rheumatoid Arthritis. Genes 2018, 9, 64

by Milena Iwaszko, Jerzy Świerkot, Katarzyna Kolossa, Sławomir Jeka, Piotr Wiland and Katarzyna Bogunia-Kubik

Genes 2018, 9(2), 94; https://doi.org/10.3390/genes9020094 - 14 Feb 2018

Viewed by 2387

Abstract

It has been brought to our attention that the funding of the National Center of Science (Poland) was missing in the acknowledgements section of our published paper [1], and therefore we would like to add this and report the acknowledgements as follows:[...] Full article

(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)

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