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Evidence of selection on splicing-associated loci in human populations and relevance to disease loci mapping.
Gamazon ER, Konkashbaev A, Derks EM, Cox NJ, Lee Y
(2017) Sci Rep 7: 5980
MeSH Terms: Chromosome Mapping, Disease, Genetic Loci, Genetics, Population, Genome-Wide Association Study, Humans, Introns, Nucleotide Motifs, Polymorphism, Single Nucleotide, RNA Splicing, Selection, Genetic
Show Abstract · Added October 27, 2017
We performed a whole-genome scan of genetic variants in splicing regulatory elements (SREs) and evaluated the extent to which natural selection has shaped extant patterns of variation in SREs. We investigated the degree of differentiation of single nucleotide polymorphisms (SNPs) in SREs among human populations and applied long-range haplotype- and multilocus allelic differentiation-based methods to detect selection signatures. We describe an approach, sampling a large number of loci across the genome from functional classes and using the consensus from multiple tests, for identifying candidates for selection signals. SRE SNPs in various SNP functional classes show different patterns of population differentiation compared with their non-SRE counterparts. Intronic regions display a greater enrichment for extreme population differentiation among the potentially tissue-dependent transcript ratio quantitative trait loci (trQTLs) than SRE SNPs in general and includ outlier trQTLs for cross-population composite likelihood ratio, suggesting that incorporation of context annotation for regulatory variation may lead to improved detection of signature of selection on these loci. The proportion of extremely rare SNPs disrupting SREs is significantly higher in European than in African samples. The approach developed here will be broadly useful for studies of function and disease-associated variation in the human genome.
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11 MeSH Terms
Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.
Liu CT, Raghavan S, Maruthur N, Kabagambe EK, Hong J, Ng MC, Hivert MF, Lu Y, An P, Bentley AR, Drolet AM, Gaulton KJ, Guo X, Armstrong LL, Irvin MR, Li M, Lipovich L, Rybin DV, Taylor KD, Agyemang C, Palmer ND, Cade BE, Chen WM, Dauriz M, Delaney JA, Edwards TL, Evans DS, Evans MK, Lange LA, Leong A, Liu J, Liu Y, Nayak U, Patel SR, Porneala BC, Rasmussen-Torvik LJ, Snijder MB, Stallings SC, Tanaka T, Yanek LR, Zhao W, Becker DM, Bielak LF, Biggs ML, Bottinger EP, Bowden DW, Chen G, Correa A, Couper DJ, Crawford DC, Cushman M, Eicher JD, Fornage M, Franceschini N, Fu YP, Goodarzi MO, Gottesman O, Hara K, Harris TB, Jensen RA, Johnson AD, Jhun MA, Karter AJ, Keller MF, Kho AN, Kizer JR, Krauss RM, Langefeld CD, Li X, Liang J, Liu S, Lowe WL, Mosley TH, North KE, Pacheco JA, Peyser PA, Patrick AL, Rice KM, Selvin E, Sims M, Smith JA, Tajuddin SM, Vaidya D, Wren MP, Yao J, Zhu X, Ziegler JT, Zmuda JM, Zonderman AB, Zwinderman AH, AAAG Consortium, CARe Consortium, COGENT-BP Consortium, eMERGE Consortium, MEDIA Consortium, Adeyemo A, Boerwinkle E, Ferrucci L, Hayes MG, Kardia SL, Miljkovic I, Pankow JS, Rotimi CN, Sale MM, Wagenknecht LE, Arnett DK, Chen YD, Nalls MA, MAGIC Consortium, Province MA, Kao WH, Siscovick DS, Psaty BM, Wilson JG, Loos RJ, Dupuis J, Rich SS, Florez JC, Rotter JI, Morris AP, Meigs JB
(2016) Am J Hum Genet 99: 56-75
MeSH Terms: African Continental Ancestry Group, Asian Continental Ancestry Group, Blood Glucose, Continental Population Groups, Diabetes Mellitus, Type 2, Enhancer Elements, Genetic, Ethnic Groups, European Continental Ancestry Group, Fasting, Female, Gene Frequency, Genome-Wide Association Study, Humans, Insulin, Insulin Resistance, Introns, Islets of Langerhans, Male, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcription Factors
Show Abstract · Added July 10, 2016
Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
Copyright © 2016 American Society of Human Genetics. All rights reserved.
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22 MeSH Terms
EGFR Fusions as Novel Therapeutic Targets in Lung Cancer.
Konduri K, Gallant JN, Chae YK, Giles FJ, Gitlitz BJ, Gowen K, Ichihara E, Owonikoko TK, Peddareddigari V, Ramalingam SS, Reddy SK, Eaby-Sandy B, Vavalà T, Whiteley A, Chen H, Yan Y, Sheehan JH, Meiler J, Morosini D, Ross JS, Stephens PJ, Miller VA, Ali SM, Lovly CM
(2016) Cancer Discov 6: 601-11
MeSH Terms: Adult, Antineoplastic Agents, Biomarkers, Cell Line, Tumor, Combined Modality Therapy, ErbB Receptors, Exons, Female, Genetic Loci, High-Throughput Nucleotide Sequencing, Humans, Introns, Lung Neoplasms, Magnetic Resonance Imaging, Male, Middle Aged, Models, Molecular, Molecular Targeted Therapy, Neoplasm Metastasis, Oncogene Proteins, Fusion, Protein Conformation, Protein Kinase Inhibitors, Rad51 Recombinase, Young Adult
Show Abstract · Added April 8, 2017
UNLABELLED - Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration.
SIGNIFICANCE - We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601-11. ©2016 AACR.See related commentary by Paik, p. 574This article is highlighted in the In This Issue feature, p. 561.
©2016 American Association for Cancer Research.
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24 MeSH Terms
A novel splice site mutation in SMARCAL1 results in aberrant exon definition in a child with Schimke immunoosseous dysplasia.
Carroll C, Hunley TE, Guo Y, Cortez D
(2015) Am J Med Genet A 167A: 2260-4
MeSH Terms: Arteriosclerosis, Child, DNA Helicases, DNA Replication, Exons, Female, Gene Expression, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Introns, Lymphocytes, Mutation, Nephrotic Syndrome, Osteochondrodysplasias, Pedigree, Primary Immunodeficiency Diseases, Pulmonary Embolism, RNA Splice Sites
Show Abstract · Added February 4, 2016
Schimke Immunoosseous Dysplasia (SIOD) is a rare, autosomal recessive disorder of childhood characterized by spondyloepiphyseal dysplasia, focal segmental glomerulosclerosis and renal failure, T-cell immunodeficiency, and cancer in certain instances. Approximately half of patients with SIOD are reported to have biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA translocase that localizes to sites of DNA replication and repairs damaged replication forks. We present a novel mutation (NM_014140.3:c.2070+2insT) that results in defective SMARCAL1 mRNA splicing in a child with SIOD. This mutation, within the donor site of intron 12, results in the skipping of exon 12, which encodes part of a critical hinge region connecting the two lobes of the ATPase domain. This mutation was not recognized as deleterious by diagnostic SMARCAL1 sequencing, but discovered through next generation sequencing and found to result in absent SMARCAL1 expression in patient-derived lymphoblasts. The splicing defect caused by this mutation supports the concept of exon definition. Furthermore, it illustrates the need to broaden the search for SMARCAL1 mutations in patients with SIOD lacking coding sequence variants.
© 2015 Wiley Periodicals, Inc.
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19 MeSH Terms
Obesity-associated variants within FTO form long-range functional connections with IRX3.
Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF, Lee JH, Puviindran V, Tam D, Shen M, Son JE, Vakili NA, Sung HK, Naranjo S, Acemel RD, Manzanares M, Nagy A, Cox NJ, Hui CC, Gomez-Skarmeta JL, Nóbrega MA
(2014) Nature 507: 371-5
MeSH Terms: Adipose Tissue, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Animals, Basal Metabolism, Body Mass Index, Body Weight, Brain, Diabetes Mellitus, Type 2, Diet, Genes, Dominant, Homeodomain Proteins, Humans, Hypothalamus, Introns, Male, Mice, Mixed Function Oxygenases, Obesity, Oxo-Acid-Lyases, Phenotype, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Proteins, Thinness, Transcription Factors, Zebrafish
Show Abstract · Added February 22, 2016
Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.
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26 MeSH Terms
CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with reduced CYP3A4 protein level and function in human liver microsomes.
Okubo M, Murayama N, Shimizu M, Shimada T, Guengerich FP, Yamazaki H
(2013) J Toxicol Sci 38: 349-54
MeSH Terms: Alleles, Asian Continental Ancestry Group, Cytochrome P-450 CYP3A, Genotype, Humans, Introns, Microsomes, Liver, Oxidation-Reduction, Pharmaceutical Preparations, Polymorphism, Genetic
Show Abstract · Added March 10, 2014
Effects of the CYP3A4 intron 6 C>T (CYP3A4*22) polymorphism, which has recently been reported to have a critical role in vivo, were investigated by measuring CYP3A4 protein expression levels and CYP3A4-dependent drug oxidation activities in individual human liver microsomes in vitro. Prior to protein analysis, analysis of DNA samples indicated that 36 Caucasian subjects were genotyped as CYP3A4*1/*1 and five subjects were CYP3A4*1/*22, with a CYP3A4*22 allelic frequency of 6.1%. No CYP3A4*22 alleles were found in the Japanese samples (106 alleles). Individual differences in CYP2D6-dependent dextromethorphan O-demethylation activities in liver microsomes from Caucasians were not affected by either the CYP3A4*1/*22 or CYP3A5*1/*3 genotype. Liver microsomes genotyped as CYP3A4*1/*22 (n = 4) showed significantly lower CYP3A-dependent dextromethorphan N-demethylation, midazolam 1'-hydroxylation, and testosterone 6β-hydroxylation activities, as well as lower expression levels of CYP3A protein (28% of control), compared with those of the CYP3A4*1/*1 group (n = 19). The other polymorphism, CYP3A5*1/*3, did not show these differences (n = 4). The CYP3A4*22 polymorphism was associated with reduced CYP3A4 protein expression levels and resulted in decreased CYP3A4-dependent activities in human livers. The present results suggest an important role of low expression of CYP3A4 protein associated with the CYP3A4*22 allele in the individual differences in drug clearance.
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10 MeSH Terms
Putting pleiotropy and selection into context defines a new paradigm for interpreting genetic data.
Predazzi IM, Rokas A, Deinard A, Schnetz-Boutaud N, Williams ND, Bush WS, Tacconelli A, Friedrich K, Fazio S, Novelli G, Haines JL, Sirugo G, Williams SM
(2013) Circ Cardiovasc Genet 6: 299-307
MeSH Terms: Alleles, Animals, Data Mining, Evolution, Molecular, Genetic Pleiotropy, Genetics, Population, Humans, Introns, Phylogeny, Polymorphism, Single Nucleotide, Primates, Scavenger Receptors, Class E, Selection, Genetic
Show Abstract · Added May 30, 2014
BACKGROUND - Natural selection shapes many human genes, including some related to complex diseases. Understanding how selection affects genes, especially pleiotropic ones, may be important in evaluating disease associations and the role played by environmental variation. This may be of particular interest for genes with antagonistic roles that cause divergent patterns of selection. The lectin-like low-density lipoprotein 1 receptor, encoded by OLR1, is exemplary. It has antagonistic functions in the cardiovascular and immune systems because the same protein domain binds oxidized low-density lipoprotein and bacterial cell wall proteins, the former contributing to atherosclerosis and the latter presumably protecting from infection. We studied patterns of selection in this gene, in humans and nonhuman primates, to determine whether variable selection can lead to conflicting results in cardiovascular disease association studies.
METHODS AND RESULTS - We analyzed sequences from 11 nonhuman primate species, as well as single-nucleotide polymorphisms and sequence data from multiple human populations. Results indicate that the derived allele is favored across primate lineages (probably because of recent positive selection). However, both the derived and ancestral alleles were maintained in human populations, especially European ones (possibly because of balancing selection derived from dual roles of LOX-1). Balancing selection likely reflects response to diverse environmental pressures among humans.
CONCLUSIONS - These data indicate that differential selection patterns, within and between species, in OLR1 render association studies difficult to replicate even if the gene is etiologically connected to cardiovascular disease. Selection analyses can identify genes exhibiting gene-environment interactions critical for unraveling disease association.
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13 MeSH Terms
Polymorphisms in the Selenoprotein S gene and subclinical cardiovascular disease in the Diabetes Heart Study.
Cox AJ, Lehtinen AB, Xu J, Langefeld CD, Freedman BI, Carr JJ, Bowden DW
(2013) Acta Diabetol 50: 391-9
MeSH Terms: Aged, Cardiovascular Diseases, Carotid Artery Diseases, Carotid Intima-Media Thickness, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Female, Genotype, Humans, Introns, Linkage Disequilibrium, Male, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Selenoproteins, Vascular Calcification
Show Abstract · Added February 15, 2014
Selenoprotein S (SelS) has previously been associated with a range of inflammatory markers, particularly in the context of cardiovascular disease (CVD). The aim of this study was to examine the role of SELS genetic variants in risk for subclinical CVD and mortality in individuals with type 2 diabetes mellitus (T2DM). The association between 10 polymorphisms tagging SELS and coronary (CAC), carotid (CarCP) and abdominal aortic calcified plaque, carotid intima media thickness and other known CVD risk factors was examined in 1220 European Americans from the family-based Diabetes Heart Study. The strongest evidence of association for SELS SNPs was observed for CarCP; rs28665122 (5' region; β = 0.329, p = 0.044), rs4965814 (intron 5; β = 0.329, p = 0.036), rs28628459 (3' region; β = 0.331, p = 0.039) and rs7178239 (downstream; β = 0.375, p = 0.016) were all associated. In addition, rs12917258 (intron 5) was associated with CAC (β = -0.230, p = 0.032), and rs4965814, rs28628459 and rs9806366 were all associated with self-reported history of prior CVD (p = 0.020-0.043). These results suggest a potential role for the SELS region in the development subclinical CVD in this sample enriched for T2DM. Further understanding the mechanisms underpinning these relationships may prove important in predicting and managing CVD complications in T2DM.
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18 MeSH Terms
Variants affecting exon skipping contribute to complex traits.
Lee Y, Gamazon ER, Rebman E, Lee Y, Lee S, Dolan ME, Cox NJ, Lussier YA
(2012) PLoS Genet 8: e1002998
MeSH Terms: Alternative Splicing, Computational Biology, Cyclin-Dependent Kinases, Exons, Genetic Predisposition to Disease, Humans, Introns, Models, Molecular, Phenotype, Polymorphism, Single Nucleotide, Protein Conformation, Proteins, Quantitative Trait Loci, Quantitative Trait, Heritable, RNA Isoforms
Show Abstract · Added February 22, 2016
DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs) in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1) experimentally validate our in silico predictions of skipped exons and 2) characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits.
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15 MeSH Terms
Tailoring of membrane proteins by alternative splicing of pre-mRNA.
Mittendorf KF, Deatherage CL, Ohi MD, Sanders CR
(2012) Biochemistry 51: 5541-56
MeSH Terms: Alternative Splicing, Alzheimer Disease, Animals, Humans, Introns, Membrane Proteins, Organ Specificity, Protein Folding, Protein Sorting Signals, Protein Transport, RNA Precursors, RNA, Messenger
Show Abstract · Added March 7, 2014
Alternative splicing (AS) of RNA is a key mechanism for diversification of the eukaryotic proteome. In this process, different mRNA transcripts can be produced through altered excision and/or inclusion of exons during processing of the pre-mRNA molecule. Since its discovery, AS has been shown to play roles in protein structure, function, and localization. Dysregulation of this process can result in disease phenotypes. Moreover, AS pathways are promising therapeutic targets for a number of diseases. Integral membrane proteins (MPs) represent a class of proteins that may be particularly amenable to regulation by alternative splicing because of the distinctive topological restraints associated with their folding, structure, trafficking, and function. Here, we review the impact of AS on MP form and function and the roles of AS in MP-related disorders such as Alzheimer's disease.
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12 MeSH Terms