Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 January 2021) | Viewed by 31420

Share This Special Issue

Special Issue Editor

Prof. Dr. John P. Quinn

E-Mail Website
Guest Editor

Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Liverpool, United Kingdom
Interests: Neuroscience; Mental Health; Genomics; Bioinformatics; Gene Expression; Neurodegeneration; Ageing; Retrotransposons
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Human genetic studies have identified numerous polymorphic domains in non-coding DNA, ranging from single nucleotide polymorphisms to structural variants, which are not only risk factors for a disease or phenotype but are also implicated in the mechanism underpinning that condition. The non-coding genome orchestrates the developmental, tissue specific, and stimulus inducible gene expression pattern at several levels including epigenetic, transcriptional, and post-transcriptional mechanisms. Therefore, it is not unexpected that polymorphism in key regulatory domains alters the transcriptome response to the environment with subsequent modulation of cell function. These regulatory polymorphisms are central to gene–environment interactions, which determine how lifestyle modifications either exacerbate or lessen the potential for developing a particular disease. These non-coding polymorphisms are well established in all areas of biology as key regulators of our physiology and underpin our individuality. Thus, it could be argued that personalised medicine or lifestyle modulation is key to disease management.

This Special Issue of IJMS, “the Role of Polymorphic Variation in the Non-Coding DNA in Disease Pathogenesis”, will include a selection of original research articles, short communications, and current review articles examining how gene expression and/or pathogenesis at all levels is modified by genome variation. Authors from all relevant disciplines, including cancer, immunology, neuroscience, and ageing, are invited to submit research.

Prof. Dr. John P. Quinn
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

gene expression
polymorphism
retrotransposon
pathogenesis
nature and nurture
epigenetics
development
genomics
bioinformatics

Published Papers (10 papers)

Download All Papers

Research

Jump to: Review, Other

14 pages, 11897 KiB

Open AccessArticle

Long-Read Sequencing Improves the Detection of Structural Variations Impacting Complex Non-Coding Elements of the Genome

by Ghausia Begum, Ammar Albanna, Asma Bankapur, Nasna Nassir, Richa Tambi, Bakhrom K. Berdiev, Hosneara Akter, Noushad Karuvantevida, Barbara Kellam, Deena Alhashmi, Wilson W. L. Sung, Bhooma Thiruvahindrapuram, Alawi Alsheikh-Ali, Stephen W. Scherer and Mohammed Uddin

Int. J. Mol. Sci. 2021, 22(4), 2060; https://doi.org/10.3390/ijms22042060 - 19 Feb 2021

Cited by 12 | Viewed by 5689

Abstract

The advent of long-read sequencing offers a new assessment method of detecting genomic structural variation (SV) in numerous rare genetic diseases. For autism spectrum disorders (ASD) cases where pathogenic variants fail to be found in the protein-coding genic regions along chromosomes, we proposed a scalable workflow to characterize the risk factor of SVs impacting non-coding elements of the genome. We applied whole-genome sequencing on an Emirati family having three children with ASD using long and short-read sequencing technology. A series of analytical pipelines were established to identify a set of SVs with high sensitivity and specificity. At 15-fold coverage, we observed that long-read sequencing technology (987 variants) detected a significantly higher number of SVs when compared to variants detected using short-read technology (509 variants) (p-value < 1.1020 × 10⁻⁵⁷). Further comparison showed 97.9% of long-read sequencing variants were spanning within the 1–100 kb size range (p-value < 9.080 × 10⁻⁶⁷) and impacting over 5000 genes. Moreover, long-read variants detected 604 non-coding RNAs (p-value < 9.02 × 10⁻⁹), comprising 58% microRNA, 31.9% lncRNA, and 9.1% snoRNA. Even at low coverage, long-read sequencing has shown to be a reliable technology in detecting SVs impacting complex elements of the genome. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

15 pages, 1816 KiB

Open AccessArticle

CRISPR Deletion of a SVA Retrotransposon Demonstrates Function as a cis-Regulatory Element at the TRPV1/TRPV3 Intergenic Region

by Emma Price, Olympia Gianfrancesco, Patrick T. Harrison, Bernhard Frank, Vivien J. Bubb and John P. Quinn

Int. J. Mol. Sci. 2021, 22(4), 1911; https://doi.org/10.3390/ijms22041911 - 15 Feb 2021

Cited by 4 | Viewed by 2378

Abstract

SINE-VNTR-Alu (SVA) retrotransposons are a subclass of transposable elements (TEs) that exist only in primate genomes. TE insertions can be co-opted as cis-regulatory elements (CREs); however, the regulatory potential of SVAs has predominantly been demonstrated using bioinformatic approaches and reporter gene assays. The objective of this study was to demonstrate SVA cis-regulatory activity by CRISPR (clustered regularly interspaced short palindromic repeats) deletion and subsequent measurement of direct effects on local gene expression. We identified a region on chromosome 17 that was enriched with human-specific SVAs. Comparative gene expression analysis at this region revealed co-expression of TRPV1 and TRPV3 in multiple human tissues, which was not observed in mouse, highlighting key regulatory differences between the two species. Furthermore, the intergenic region between TRPV1 and TRPV3 coding sequences contained a human specific SVA insertion located upstream of the TRPV3 promoter and downstream of the 3′ end of TRPV1, highlighting this SVA as a candidate to study its potential cis-regulatory activity on both genes. Firstly, we generated SVA reporter gene constructs and demonstrated their transcriptional regulatory activity in HEK293 cells. We then devised a dual-targeting CRISPR strategy to facilitate the deletion of this entire SVA sequence and generated edited HEK293 clonal cell lines containing homozygous and heterozygous SVA deletions. In edited homozygous ∆SVA clones, we observed a significant decrease in both TRPV1 and TRPV3 mRNA expression, compared to unedited HEK293. In addition, we also observed an increase in the variability of mRNA expression levels in heterozygous ∆SVA clones. Overall, in edited HEK293 with SVA deletions, we observed a disruption to the co-expression of TRPV1 and TRPV3. Here we provide an example of a human specific SVA with cis-regulatory activity in situ, supporting the role of SVA retrotransposons as contributors to species-specific gene expression. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

12 pages, 2518 KiB

Open AccessArticle

Impact of an MT-RNR1 Gene Polymorphism on Hepatocellular Carcinoma Progression and Clinical Characteristics

by Yang-Hsiang Lin, Yu-De Chu, Siew-Na Lim, Chun-Wei Chen, Chau-Ting Yeh and Wey-Ran Lin

Int. J. Mol. Sci. 2021, 22(3), 1119; https://doi.org/10.3390/ijms22031119 - 23 Jan 2021

Cited by 12 | Viewed by 2269

Abstract

Mitochondrial DNA (mtDNA) mutations are highly associated with cancer progression. The poor prognosis of hepatocellular carcinoma (HCC) is largely due to high rates of tumor metastasis. This emphasizes the urgency of identifying these patients in advance and developing new therapeutic targets for successful intervention. However, the issue of whether mtDNA influences tumor metastasis in hepatoma remains unclear. In the current study, multiple mutations in mtDNA were identified by sequencing HCC samples. Among these mutations, mitochondrially encoded 12S rRNA (MT-RNR1) G709A was identified as a novel potential candidate. The MT-RNR1 G709A polymorphism was an independent risk factor for overall survival and distant metastasis-free survival. Subgroup analysis showed that in patients with cirrhosis, HBV-related HCC, α-fetoprotein ≥ 400 ng/mL, aspartate transaminase ≥ 31 IU/L, tumor number > 1, tumor size ≥ 5 cm, and histology grade 3-4, MT-RNR1 G709A was associated with both shorter overall survival and distant metastasis-free survival. Mechanistically, MT-RNR1 G709A was clearly associated with hexokinase 2 (HK2) expression and unfavorable prognosis in HCC patients. Our data collectively highlight that novel associations among MT-RNR1 G709A and HK2 are an important risk factor in HCC patients. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

29 pages, 1858 KiB

Open AccessArticle

Length Polymorphism and Methylation Status of UPS29 Minisatellite of the ACAP3 Gene as Molecular Biomarker of Epilepsy. Sex Differences in Seizure Types and Symptoms

by Irina O. Suchkova, Elena V. Borisova and Eugene L. Patkin

Int. J. Mol. Sci. 2020, 21(23), 9206; https://doi.org/10.3390/ijms21239206 - 2 Dec 2020

Cited by 6 | Viewed by 2225

Abstract

Epilepsy is a neurological disease with different clinical forms and inter-individuals heterogeneity, which may be associated with genetic and/or epigenetic polymorphisms of tandem-repeated noncoding DNA. These polymorphisms may serve as predictive biomarkers of various forms of epilepsy. ACAP3 is the protein regulating morphogenesis of neurons and neuronal migration and is an integral component of important signaling pathways. This study aimed to carry out an association analysis of the length polymorphism and DNA methylation of the UPS29 minisatellite of the ACAP3 gene in patients with epilepsy. We revealed an association of short UPS29 alleles with increased risk of development of symptomatic and cryptogenic epilepsy in women, and also with cerebrovascular pathologies, structural changes in the brain, neurological status, and the clinical pattern of seizures in both women and men. The increase of frequency of hypomethylated UPS29 alleles in men with symptomatic epilepsy, and in women with both symptomatic and cryptogenic epilepsy was observed. For patients with hypomethylated UPS29 alleles, we also observed structural changes in the brain, neurological status, and the clinical pattern of seizures. These associations had sex-specific nature similar to a genetic association. In contrast with length polymorphism epigenetic changes affected predominantly the long UPS29 allele. We suppose that genetic and epigenetic alterations UPS29 can modify ACAP3 expression and thereby affect the development and clinical course of epilepsy. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

12 pages, 2979 KiB

Open AccessArticle

A SINE-VNTR-Alu in the LRIG2 Promoter Is Associated with Gene Expression at the Locus

by Ashley Hall, Anni K. Moore, Dena G. Hernandez, Kimberley J. Billingsley, Vivien J. Bubb, John P. Quinn and NABEC (North American Brain Expression Consortium)

Int. J. Mol. Sci. 2020, 21(22), 8486; https://doi.org/10.3390/ijms21228486 - 11 Nov 2020

Cited by 6 | Viewed by 2803

Abstract

The hominid SINE-VNTR-Alu (SVA) retrotransposons represent a repertoire of genomic variation which could have significant effects on genome function. A human-specific SVA in the promoter region of the gene leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2), which we termed SVA_LRIG2, is a common retrotransposon insertion polymorphism (RIP), defined as an element which is polymorphic for its presence or absence in the genome. We hypothesised that this RIP might be associated with differential levels of expression of LRIG2. The RIP genotype of SVA_LRIG2 was determined in a subset of frontal cortex DNA samples from the North American Brain Expression Consortium (NABEC) cohort and was imputed for a larger set of that cohort. Utilising available frontal cortex total RNA-seq and CpG methylation data for this cohort, we observed that increased allele dosage of SVA_LRIG2 was non-significantly associated with a decrease in transcription from the region and significantly associated with increased methylation of the CpG probe nearest to SVA_LRIG2, i.e., SVA_LRIG2 is a significant methylation quantitative trait loci (mQTL) at the LRIG2 locus. These data are consistent with SVA_LRIG2 being a transcriptional regulator, which in part may involve epigenetic modulation. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

13 pages, 1079 KiB

Open AccessArticle

An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson’s Disease Risk and Progression in the PPMI Cohort

by Abigail L. Pfaff, Vivien J. Bubb, John P. Quinn and Sulev Koks

Int. J. Mol. Sci. 2020, 21(18), 6562; https://doi.org/10.3390/ijms21186562 - 8 Sep 2020

Cited by 16 | Viewed by 3242

Abstract

Long interspersed element-1 (LINE-1/L1s) contributes 17% of the human genome with more than 1 million elements present; however, fewer than 100 of these have evidence for being retrotransposition competent (RC). In addition to those RC-L1s present in the reference genome, there are a small number of known non-reference L1 insertions that are also retrotransposition competent. L1 activity, whether through the potentially detrimental effects of their mRNA or protein expression or somatic retrotransposition events, has been linked to several neurological conditions. The polymorphic nature of both reference and non-reference RC-L1s in terms of their presence or absence will result in individuals harboring a different combination of these elements and it is currently unknown if this type of germline variation contributes to the risk of neurological disease. Here, we utilized whole-genome sequencing data from 178 healthy controls and 372 Parkinson’s disease (PD) subjects from the Parkinson’s Progression Markers Initiative (PPMI) to investigate the role of RC-L1s in PD. In the PPMI cohort, we identified 22 reference and 50 non-reference polymorphic RC-L1 loci. Focusing on 16 highly active RC-L1 loci, an increased burden of these elements (≥9) was associated with PD (OR 1.25, 95% CI 1.03–1.51, p = 0.02). In addition, we identified significant associations of progression markers of PD and the burden of highly active RC-L1s. This study has identified a novel type of genetic element associated with PD risk and disease progression. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

Review

Jump to: Research, Other

28 pages, 2015 KiB

Open AccessReview

The Relevance of Noncoding DNA Variations of Paraoxonase Gene Cluster in Atherosclerosis-Related Diseases

by Anna Wysocka and Agnieszka Zwolak

Int. J. Mol. Sci. 2021, 22(4), 2137; https://doi.org/10.3390/ijms22042137 - 21 Feb 2021

Cited by 5 | Viewed by 2570

Abstract

The human paraoxonase (PON) gene cluster is comprised of three contiguous genes (PON1, PON2 and PON3) of presumably common origin coding three lactonases of highly similar structure and substrate specificity. The catalytic activity of PON proteins is directed toward artificial organophosphates and in physiological conditions toward thiolactones and oxidized phospholipids. Consequently, PON enzymes are regarded as an effective defense against oxidative stress and, as a result, against atherosclerosis development. Additionally, both PON’s serum activity and its concentration are influenced by several polymorphic variations in coding and noncoding DNA regions of the PON gene cluster remaining in linkage disequilibrium. Hence, the genetic polymorphism of the PON gene cluster may contribute to atherosclerotic process progression or deceleration. In this review the authors analyzed the relevance of noncoding DNA polymorphic variations of PON genes in atherosclerosis-related diseases involving coronary and peripheral artery disease, stroke, diabetes mellitus, dementia and renal disease and concluded that the effect of PON gene cluster’ polymorphism has a considerable impact on the course and outcome in these conditions. The following PON genetic variations may serve as additional predictors of the risk of atherosclerosis in selected populations and individuals. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

19 pages, 2385 KiB

Open AccessReview

8q24.21 Locus: A Paradigm to Link Non-Coding RNAs, Genome Polymorphisms and Cancer

by Claire Wilson and Aditi Kanhere

Int. J. Mol. Sci. 2021, 22(3), 1094; https://doi.org/10.3390/ijms22031094 - 22 Jan 2021

Cited by 13 | Viewed by 2853

Abstract

The majority of the human genome is comprised of non-protein-coding genes, but the relevance of non-coding RNAs in complex diseases has yet to be fully elucidated. One class of non-coding RNAs is long non-coding RNAs or lncRNAs, many of which have been identified to play a range of roles in transcription and translation. While the clinical importance of the majority of lncRNAs have yet to be identified, it is puzzling that a large number of disease-associated genetic variations are seen in lncRNA genes. The 8q24.21 locus is rich in lncRNAs and very few protein-coding genes are located in this region. Interestingly, the 8q24.21 region is also a hot spot for genetic variants associated with an increased risk of cancer. Research focusing on the lncRNAs in this area of the genome has indicated clinical relevance of lncRNAs in different cancers. In this review, we summarise the lncRNAs in the 8q24.21 region with respect to their role in cancer and discuss the potential impact of cancer-associated genetic polymorphisms on the function of lncRNAs in initiation and progression of cancer. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

15 pages, 1070 KiB

Open AccessReview

Genetic Risk Profiling in Parkinson’s Disease and Utilizing Genetics to Gain Insight into Disease-Related Biological Pathways

by Ashley Hall, Sara Bandres-Ciga, Monica Diez-Fairen, John P. Quinn and Kimberley J. Billingsley

Int. J. Mol. Sci. 2020, 21(19), 7332; https://doi.org/10.3390/ijms21197332 - 4 Oct 2020

Cited by 17 | Viewed by 4535

Abstract

Parkinson’s disease (PD) is a complex disorder underpinned by both environmental and genetic factors. The latter only began to be understood around two decades ago, but since then great inroads have rapidly been made into deconvoluting the genetic component of PD. In particular, recent large-scale projects such as genome-wide association (GWA) studies have provided insight into the genetic risk factors associated with genetically ‘’complex’’ PD (PD that cannot readily be attributed to single deleterious mutations). Here, we discuss the plethora of genetic information provided by PD GWA studies and how this may be utilized to generate polygenic risk scores (PRS), which may be used in the prediction of risk and trajectory of PD. We also comment on how pathway-specific genetic profiling can be used to gain insight into PD-related biological pathways, and how this may be further utilized to nominate causal PD genes and potentially druggable therapeutic targets. Finally, we outline the current limits of our understanding of PD genetics and the potential contribution of variation currently uncaptured in genetic studies, focusing here on uncatalogued structural variants. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

Other

Jump to: Research, Review

12 pages, 395 KiB

Open AccessOpinion

Perspective: Quality Versus Quantity; Is It Important to Assess the Role of Enhancers in Complex Disease from an In Vivo Perspective?

by Andrew R. McEwan and Alasdair MacKenzie

Int. J. Mol. Sci. 2020, 21(21), 7856; https://doi.org/10.3390/ijms21217856 - 23 Oct 2020

Cited by 1 | Viewed by 1801

Abstract

Sequencing of the human genome has permitted the development of genome-wide association studies (GWAS) to analyze the genetics of a number of complex disorders such as depression, anxiety and substance abuse. Thanks to their ability to analyze huge cohort sizes, these studies have successfully identified thousands of loci associated with a broad spectrum of complex diseases. Disconcertingly, the majority of these GWAS hits occur in non-coding regions of the genome, much of which controls the cell-type-specific expression of genes essential to health. In contrast to gene coding sequences, it is a challenge to understand the function of this non-coding regulatory genome using conventional biochemical techniques in cell lines. The current commentary scrutinizes the field of complex genetics from the standpoint of the large-scale whole-genome functional analysis of the promoters and cis-regulatory elements using chromatin markers. We contrast these large scale quantitative techniques against comparative genomics and in vivo analyses including CRISPR/CAS9 genome editing to determine the functional characteristics of these elements and to understand how polymorphic variation and epigenetic changes within these elements might contribute to complex disease and drug response. Most importantly, we suggest that, although the role of chromatin markers will continue to be important in identifying and characterizing enhancers, more emphasis must be placed on their analysis in relevant in-vivo models that take account of the appropriate cell-type-specific roles of these elements. It is hoped that offering these insights might refocus progress in analyzing the data tsunami of non-coding GWAS and whole-genome sequencing “hits” that threatens to overwhelm progress in the field. Full article

(This article belongs to the Special Issue The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease)

► Show Figures

Figure 1

Journal Menu

Journal Browser

The Role of Polymorphic Variation in Non-coding DNA in Predicting Disease

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI