Special Issue "DNA Variations in Evolution and Human Diseases"

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)

Special Issue Editors

Guest Editor
Dr. Walid Fakhouri

University of Texas Health Science Center at Houston, Department of Diagnostic and Biomedical Sciences, School of Dentistry,1941 East Road,Houston, TX 77054
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Guest Editor
Dr. Ariadne Letra

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, Texas 77054
Website | E-Mail

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

Manuscript Submission Information

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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 (10 papers)

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Research

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Open AccessArticle Genetic Association with Subgingival Bacterial Colonization in Chronic Periodontitis
Received: 26 February 2018 / Revised: 11 May 2018 / Accepted: 14 May 2018 / Published: 23 May 2018
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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
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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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Open AccessArticle BSG and MCT1 Genetic Variants Influence Survival in Multiple Myeloma Patients
Received: 27 February 2018 / Revised: 16 April 2018 / Accepted: 17 April 2018 / Published: 24 April 2018
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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
[...] Read more.
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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Open AccessArticle Transgenic Xenopus laevis Line for In Vivo Labeling of Nephrons within the Kidney
Received: 28 February 2018 / Revised: 29 March 2018 / Accepted: 4 April 2018 / Published: 6 April 2018
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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
[...] Read more.
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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Open AccessArticle Influence of NKG2D Genetic Variants on Response to Anti-TNF Agents in Patients with Rheumatoid Arthritis
Received: 22 November 2017 / Revised: 16 January 2018 / Accepted: 18 January 2018 / Published: 25 January 2018
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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
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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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Open AccessArticle The IFNG rs1861494 Single Nucleotide Polymorphism Is Associated with Protection against Tuberculosis Disease in Argentina
Received: 25 October 2017 / Revised: 9 January 2018 / Accepted: 9 January 2018 / Published: 22 January 2018
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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
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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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Open AccessReview Can Genetic Factors Compromise the Success of Dental Implants? A Systematic Review and Meta-Analysis
Received: 23 July 2018 / Revised: 28 August 2018 / Accepted: 31 August 2018 / Published: 6 September 2018
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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
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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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Open AccessFeature PaperReview The Changing Landscape in the Genetic Etiology of Human Tooth Agenesis
Received: 3 April 2018 / Revised: 1 May 2018 / Accepted: 9 May 2018 / Published: 16 May 2018
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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
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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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Open AccessReview Genetic Mechanisms of Asthma and the Implications for Drug Repositioning
Received: 12 March 2018 / Revised: 21 April 2018 / Accepted: 26 April 2018 / Published: 3 May 2018
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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,
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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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Open AccessBrief Report APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation
Received: 14 May 2018 / Revised: 21 June 2018 / Accepted: 22 June 2018 / Published: 27 June 2018
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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
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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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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
Received: 1 February 2018 / Revised: 5 February 2018 / Accepted: 5 February 2018 / Published: 14 February 2018
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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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