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Hypospadias is a congenital birth defect in which the opening of the urethra is on the underside of the penis instead of the normal position in the head. Since the SRY TF located on the Y chromosome is a transcriptional regulator that controls a genetic switch in male development, this SNP might be expected to have an impact on male etiology as has been shown to be the case with its risk of hypospadias. The TF which is involved with embryonic development and tissue differentiation might also have an impact on hypospadias.

The TFs for these binding sites are involved the transcriptional machinery including transcriptional regulation and suppression [20] which may in part be involved with sexual differentiation and the hypospadias trait. The v-akt murine thymoma viral oncogene homolog 3 AKT 3 is one of three isoforms of the AKTs which are major downstream targets of growth factor receptor tyrosine kinases that signal through PI3K [35].

This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. This TF is a member of the homeodomain-containing superfamily of transcription factors and regulates development of the embryonic pancreas.

The ADRBK1 gene, which transcribes the G protein-coupled receptor kinase 2 GRK2 , is an important regulator of adrenergic signaling and plays a central role in heart failure pathology [].

Gene Regulatory Sequences and Human Disease

The GRK2 gene is an important regulator of beta-adrenergic signaling and plays a central role in heart failure HF pathology []. The type 2 deiodeinase gene DIO2 encodes a deiodinase that coverts the thyroid prohormone, thyroxine T4 , to the biologically active triiodothyronine T3 hormone where T3 is involved in the vital role of regulating energy balance and glucose metabolism [].

DIO2 is found in the thyroid gland, cardiac and skeletal muscle, brown adipose tissue, placenta, pituitary, central nervous system CNS and at low levels in kidney and pancreases [].

MPG Primer: Clinical interpretation of genes for disease causality, Part 1 (2018)

Several SNPs have been found in the gene which have been studied is association with mental retardation MR [53], osteoarthritis [54], early-onset type 2 diabetes mellitus T2DM [55] and insulin resistance IR [56,57]. This SNP has been found to be significantly associated with insulin resistance [56,57] suggesting that the elimination of the PDX1 binding site by the A-allele may result in this human condition.

Hypoxia is a major geographical condition associated with high-altitude environments [58]. EPAS1 is expressed in organs that are involved in oxygen transport and metabolism, such the lung, placenta and vascular endothelium [59], and is associated with many biological processes and diseases related to metabolism [60], angiogenesis [61,62], inflammation [63,64] and cancer []. These TFs are involved with inflammation, immunity, differentiation, cell growth, tumorigenesis, apoptosis, hematopoiesis, transcriptional activation and repression, respectively [23] and the elimination of these TFBS by the alternate C-allele should have a tremendous impact on gene regulation.

As an example, RUNX1 is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters and can either activate or suppress transcription. These TFs modulate immune responses through suppression of chemokine and cytokine production and protecting cells from oxidative stress and damage as well as mediates aldosterone actions on salt and water balance within target cells [23]. The lysosomal acid lipase A LIPA gene encodes lysosomal acid lipase LAL which hydrolyzes cholesteryl esters and triglycerides in the cell lysosome to generate free cholesterol and fatty acids [68].

Alterations in the LAL enzyme activity could produce an accumulation of triglycerides and cholesterol esters in the cell which would result in foam cell formation, complement activation, an inflammation process and atherosclerotic plaque formation [69]. Un-esterified cholesterol is a distinguishing characteristic of atherosclerotic lesions [70]. Cholesteryl ester hydrolysis has been shown to be a critical step in the enzymatic modification of low density lipoprotein LDL particles in the intima [71,72] where the particles create a risk for cardiovascular disease CD.

This TF is involved in the activation of cytochrome oxidase expression and nuclear control of mitochondrial function. Consequently, individuals carrying T allele maybe at risk for mitochondrial related diseases such skeletal muscles, kidney and the endocrine and respiratory systems. In fact, the T allele has been significantly associated with CAD [73,74,76,77] where the T allele frequency was found to change from 0. The peroxisome proliferator-activated receptors PPARs are ligand-activated transcriptional factors TFs that regulate many genes in cell differentiation and various metabolic processes including lipid and glucose homeostasis.

They are nuclear hormone receptors belonging to a steroid receptor superfamily that include estrogen, thyroid hormone, vitamin D3 and glucocorticoid receptors []. There has been much published concerning the PPARs significant involvement in the progression of human disease [78,80,]. The TBX4 transcription factor is associated with the disease heritable pulmonary arterial hypertension [97], which may in part be responsible for the variation in lipid serum levels and disease risks found to be significantly associated with the this SNP.

The occurrence of the G allele in the Han Chinese population is 0. One of its SNPs rs has been associated with obesity risk and intracerebral hemorrhages while a second SNP rs has been found to be associated with hypertriglyceridemia and obesity in Han Chinese [85,90,93]. These TFs could in part be associated with obesity risk and intracerebral hemorrhages. The deletion of these TFBS caused by the minor G allele for these two TFs could in part be associated with hypertriglyceridemia and obesity risk in Han Chinese [86,93].

One of its SNPs rs has been associated with obesity risk, systemic sclerosis and low-density lipoprotein-cholesterol in Han Chinese [85,89,92]. This TF is found in immunoglobulin gene promoters and the absence of this BS with the minor G-allele in part may be responsible for the association of this SNP with systemic sclerosis. In addition, the creation of the motor neuron and pancreas homeobox 1 MNX1 and regulatory factor X3 RXF3 TFBS by the common C-allele and not the minor G-allele as well as the creation of the NK6 homeobox 1 NKX TFBS with the minor G-allele and not the major C-allele may in part be responsible for association of this SNP with obesity risk and low-density lipoprotein-cholesterol since these TFs are involved with the pancreas development and function as well as insulin gene regulation, respectively [94].

The minor G-allele creates a unique punitive TFBS not found with the common C-allele for the myocyte enhancer factor 2C MEF2C TF which is a transcriptional activator that controls cardiac morphogenesis and myogenesis, and is also involved in vascular development [94]. The occurrence of these punitive unique TFBS for the opposite SNP alleles may in part be responsible for hypertriglyceridemia, dyslipidemia, low-density lipoprotein-cholesterol found in Han Chinese.

JAK-STAT is a principal signal transduction pathway in cytokine and growth factor signaling as well as regulating various cellular processes such as cell proliferation, differentiation migration and survival []. The STAT4 gene which is important for signaling by interleukins IL and IL and type 1 interferons [] has been found to have several simple nucleotide polymorphisms SNPs associated with human disease [].

The rs STAT4 SNP has been found to be significantly associated with diabetes [], hepatitis B virus HBV infection, HBV-related cirrgisus and hepatocellular carcinoma [], severe renal insufficiency in lupus nephritis [], and systemic lupus erythematosus []. The absence of this TFBS with the minor T-allele should have a major effect relating to the diseases or conditions mentioned above.

The occurrence of these TFBS with the minor allele and not the major allele could very well explain why the SNP is significantly associated with the above diseases. The thromboxane A2 receptor TBXA2R gene is a member of the seven-transmembrane G-protein-coupled receptor super family, which interacts with intracellular G proteins, regulates different downstream signaling cascades, and induces many cellular responses including the intracellular calcium influx, cell migration and proliferation, and apoptosis []. This gene is abundantly expressed in tissues at the mRNA and protein levels targeted by the TBXA2R ligand thromboxane A2 TXA2 that include erythroleukaemia cells, vascular and bronchial smooth muscle, uterus and placental tissue, endothelium, epithelium, trophoblasts, thymus, liver and small intestine [].

The activation of TBXA2R in bronchial smooth muscle cells by its ligand results in intercellular calcium mobilization with subsequent bronchoconstriction, which contributes to bronchial smooth muscle hyperplasia and airway remodeling, which occurs in response to chronic airway inflammation in asthma []. The rs TBXA2R SNP has been found to be associated with adult asthma in a Japanese population [] and childhood atopic asthma in a Chinese population [], while the rs SNP was found to be associated with atopic asthma in a Korean population [].

The minor C-allele of the SNP creates a unique punitive TFBS not found with the major T-allele for the nuclear receptor subfamily 3, group C, member 1 NR3C1 TF which is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues []. The vascular endothelial growth factor VEGF is a family of key regulators in critical physiological and pathological angiogenesis [] including tissue growth, wound healing, rheumatoid arthritis, proliferative retinopathies, cardiovascular disease, and cancer [], and is a growth factor activator for angiogenesis, vasculogenesis, and endothelial cell growth.

In most [] but not all [] studies, It has been shown that the VEGF is an important component of the pathogenesis of high altitude adaptation and sickness. Presently, seven VEGF family members and 14 alternative splicing variants have been identified in humans []. Of the 14 splicing variants, 12 are VEGFA isoforms [] with three VEGFA, and being differentially expressed in humans visiting or living in high altitude environments and also in chronic mountain sickness CMS patients [,].

VEGFA is a signaling protein involved in the regulation of angiogenesis, vasculogenesis and endothelial cell growth. It induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. VEGFA is also a key regulator of hypoxia. Those near a gene causing changes in gene expression levels are considered regulatory r SNPs [].

There have been many reports on the possible outcome of such alterations by identifying punitive TFBS based on the two alleles of the SNP associated with a disease or sickness []. In this review a number of examples from previously reports were discussed with an emphasis on the more important dynamics from the reports. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Read More. Special Issues Frequently Asked Questions. Links Advanced knowledge sharing through global community… Read More. Take a look at the Recent articles. SNPs, transcriptional factor binding sites and disease Norman E. Genomewide methodologies have revealed general chromatin signatures for enhancers and the human and mouse noncoding genomes have undergone an extensive functional annotation.

An increasing number of enhancer mutations are showing association with human disease, and disease mechanisms are being described that result from altered gene expression. Owing to the modular nature of enhancers, mutations can generate disease phenotypes that represent either a subset of the symptoms of coding mutations or due to a change in specificity of enhancer activity, a novel phenotype.

Topologically associated domains, also known as TADs, have emerged as a fundamental structural unit to limit enhancer regulatory activity and disruptions of these boundaries result in gene misexpression and disease. Enhancers function over large genomic distances to activate the target gene. Methodologies have been developed to annotate the functional elements in the noncoding genome. Mutations in enhancers that regulate developmental gene expression can cause congenital abnormalities.

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  8. Owing to the modular nature of enhancers the disease presentation may be different from mutations in the coding region of the target gene. Disruption of TAD boundaries can result in gene misexpression and disease. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account. If the address matches an existing account you will receive an email with instructions to retrieve your username.

    Tools Request permission Export citation Add to favorites Track citation. Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Genotypes for this subset of polyTEs from the genome samples analyzed here were regressed against gene expression levels characterized from lymphoblastoid cell lines for the same individuals.

    Quantile—quantile Q—Q plots comparing the observed vs. The results of the TE-eQTL analysis further underscore the regulatory potential of the disease-linked polyTEs characterized here and also allowed us to narrow down the list of candidate insertions. This allowed us to converge on a final set of seven high-confidence disease-associated TE insertion polymorphisms Figure 2 and Table 1. Bar-charts show tissue-specific expression levels as normalized RPKM values green. Six of the seven disease-associated polyTE insertions are considered to be population-specific, based on significant eQTL results in only one population, whereas a single case is shared between both the AFR and EUR population groups Figure 6C.

    However, two of the six cases considered to be population-specific using the eQTL criterion do show consistent trends across populations but failed to reach genome-wide significance when controls for multiple statistical tests were implemented Figures 6D , 7B. PolyTE insertions associated with immune- and blood-related conditions.

    Epigenetics and Human Disease

    The inset shows the genomic locations of co-located enhancers, characterized based on chromatin signatures from a variety of tissue-specific epigenomes locations, as yellow bars. The inset shows the genomic locations of co-located enhancers yellow bars.

    Here, we described two specific examples of the effects that polyTE insertions can exert on immune- and blood-related disease phenotypes. Figure 7A shows the SVA insertion that is co-located with a cell-type specific enhancer found in the second intron of the Beta-1,4-Galactosyltransferase 1 B4GALT1 encoding gene, which is normally expressed at high levels in immune-related tissues. B4GALT1 encodes a glycosyltransferase that functions in the glycosylation of the Immunoglobulin G IgG antibody in such a way as to convert its activity from pro- to anti-inflammatory Figure 7C Kaneko et al.

    Down-regulation of this gene in individuals with the enhancer SVA insertion should thereby serve to keep the IgG molecule in a pro-inflammatory state. The SVA insertion is associated with increased expression of TMEM , which would be expected to lead to increased blood glucose levels. This expectation is consistent with the fact that the SVA insertion is also linked to the risk allele T of the SNP rs, which is associated with a reduced metabolic clearance rate of insulin MCRI , an endophenotype that is associated with the risk of type 2 diabetes Palmer et al.

    In other words, up-regulation of TMEM by the SVA insertion may be mechanistically linked to insulin resistance by virtue of increasing blood sugar and decreasing insulin clearance. The results reported here underscore the influence that retrotransposon insertion polymorphisms can exert on human health- and disease-related phenotypes.

    The integrative data analysis approach that we took for this study also revealed how polyTE disease-associations are mediated by the gene regulatory properties of retrotransposon insertions. Retrotransposons that insert into enhancer sequences could entail loss-of-function mutants by virtue of disrupting enhancer sequences, or they could serve as gain-of-function mutants by altering enhancer activity. Our results can be considered to show instances of both loss- and gain-of-function enhancer mutations with respect to the decrease or increase, respectively, of gene expression levels that are associated with element insertion genotypes Figures 6 , 7.

    Nevertheless, it is worth noting that our conservative approach could be prone to false negatives as it would not uncover novel enhancer activity provided by element insertions at new locations in the genome. The TE regulatory findings that we report here are consistent with previous studies showing that TE-derived sequences have contributed a wide variety of gene regulatory elements to the human genome Feschotte, ; Rebollo et al.

    Human TEs can also influence gene regulation by modulating various aspects of chromatin structure throughout the genome Lander et al. It is important to note that the research efforts which have uncovered the regulatory properties of human TEs, including a number of our own studies, have dealt exclusively with sequences derived from relatively ancient insertion events.

    These ancient TE insertions are present at the same fixed locations in the genome sequences of all human individuals. In other words, previously described TE-derived regulatory sequences are uniformly present among individual human genomes and thereby do not represent a source of structural genetic variation. Such fixed TE-derived regulatory sequences may not be expected to provide for gene regulatory variation among individuals or for that matter to contribute to inter-individual differences related to health and disease. Nevertheless, we recently showed that TE insertion polymorphisms also exert regulatory effects on the human genome Wang L.

    Specifically, polyTE insertions were shown to contribute to both inter-individual and population-specific differences in gene expression and to facilitate the re-wiring of transcriptional networks. The results reported here extend those findings up the hierarchy of human biological organization by revealing potential mechanistic links between polyTE-induced gene regulatory changes and the endophenotypes that underlie human health and disease.

    LW performed all of the analyses described in the study. IJ conceived of, designed and supervised the study. All authors contributed to the drafting and revision of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

    The authors would like to thank Jianrong Wang for his advice on the analysis of tissue-specific enhancer elements. Ackermann, A. Altshuler, D. A global reference for human genetic variation. Nature , 68— Anthony, R. Batzer, M. A human-specific subfamily of Alu sequences. Genomics 9, — Amplification dynamics of human-specific HS Alu family members. Nucleic Acids Res.

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    Bejerano, G. A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature , 87— Brouha, B. Hot L1s account for the bulk of retrotransposition in the human population. Chuong, E. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science , — Regulatory activities of transposable elements: from conflicts to benefits. Endogenous retroviruses function as species-specific enhancer elements in the placenta. Clayton, E. Patterns of transposable element expression and insertion in cancer.

    Conley, A. Cell type-specific termination of transcription by transposable element sequences. DNA Retroviral promoters in the human genome. Bioinformatics 24, — Repetitive elements may comprise over two-thirds of the human genome.

    Original Research ARTICLE

    PLoS Genet. Ernst, J. ChromHMM: automating chromatin-state discovery and characterization. Methods 9, — Feschotte, C. Transposable elements and the evolution of regulatory networks. Flicek, P. Ensembl Hancks, D. Roles for retrotransposon insertions in human disease. Active human retrotransposons: variation and disease. Jacques, P. The majority of primate-specific regulatory sequences are derived from transposable elements.

    Jordan, I. Origin of a substantial fraction of human regulatory sequences from transposable elements. Trends Genet. Kaneko, Y. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation.