Polymorphism, Single Nucleotide
Latest Paper:
Allergy, Asthma and Immunology Clinic of Georgetown, Georgetown, Texas, USA. txmd02@hotmail.com
BACKGROUND: Recent reports have suggested that Common Variable Immunodeficieny (CVID) can present as an autosomal dominant trait dependent on the inheritance of a set of uncommon mutations/alleles of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) involving exons 3 or 4. Penetrance, however, appears to be incomplete. Among our clinic population, the greatest genetic linkage for CVID is to the major histocompatibility complex (MHC) on chromosome 6. The majority of our patients have inherited HLA *DQ2,*DR7,*DR3(17),*B8, and/or *B44. Of these, HLA*B44 was present in almost half of the patients and was thus the most common susceptibility allele. HLA *B44 was also found to be over-represented among patients who presented to our clinic with adult-onset recurrent sinopulmonary infections (RESPI) and normal serum immunoglobulin levels, a cohort that included first and second degree relatives of patients with CVID. One of the two original reports of the association between TACI and CVID also reported Human Leukocyte Antigen (HLA) haplotypes. Of 13 affected subjects, nine had inherited HLA *B8 and six had inherited HLA B44. This raised the possibility that TACI mutations might synergize with MHC class I alleles to enhance susceptibility to humoral immune deficiency. METHODS: We identified 63 CVID patients irrespective of HLA status and 13 RESPI patients who had inherited HLA*B44. To evaluate for mutations in the gene for TACI, we PCR amplified and sequenced TACI exons 3 and 4 from these patients. RESULTS: Of the 76 patients, eleven proved heterozygous for a previously reported, silent T->G polymorphism [rs35062843] at proline 97 in exon 3. However, none of the 13 RESPI patients and only one of the 63 CVID patients inherited a TACI allele previously associated with CVID. This patient was heterozygous for the TACI A181E allele (exon 4). She did not carry *DQ2,*DR7,*DR3(17),*B8, or *B44. CONCLUSION: These findings suggest that TACI mutations are unlikely to play a critical role in creating susceptibility to CVID among patients with previously recognized MHC class I and class II susceptibility alleles. Supported by NIH/USIDNET N01-AI30070, NIH R21 AI079741 and NIH M01-RR00032.
Mesh-terms: Adult; Alleles; Common Variable Immunodeficiency :: genetics; Common Variable Immunodeficiency :: immunology; Exons; Female; Genotype; HLA-B8 Antigen :: genetics; Haplotypes; Humans; Major Histocompatibility Complex :: genetics; Male; Middle Aged; Mutation; Polymorphism, Single Nucleotide; Respiratory Tract Infections :: genetics; Respiratory Tract Infections :: immunology; Transmembrane Activator and CAML Interactor Protein :: genetics; Young Adult;
Most cited papers:
Stacey B Gabriel,
Stephen F Schaffner,
Huy Nguyen,
Jamie M Moore,
Jessica Roy,
Brendan Blumenstiel,
John Higgins,
Matthew DeFelice,
Amy Lochner,
Maura Faggart,
Shau Neen Liu-Cordero,
Charles Rotimi,
Adebowale Adeyemo,
Richard Cooper,
Ryk Ward,
Eric S Lander,
Mark J Daly,
David Altshuler
Whitehead/MIT Center for Genome Research, Cambridge, MA 02139, USA.
Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease.
Mesh-terms: Africa; African Americans; African Continental Ancestry Group :: genetics; Alleles; Asian Continental Ancestry Group :: genetics; China; Chromosome Mapping; Computational Biology; Computer Simulation; Europe; European Continental Ancestry Group :: genetics; Genome, Human; Genotype; Haplotypes; Human; Japan; Linkage Disequilibrium; Models, Genetic; Polymorphism, Single Nucleotide; Recombination, Genetic; Support, Non-U.S. Gov't; Variation (Genetics) ;
J P Hugot,
M Chamaillard,
H Zouali,
S Lesage,
J P Cézard,
J Belaiche,
S Almer,
C Tysk,
C A O'Morain,
M Gassull,
V Binder,
Y Finkel,
A Cortot,
R Modigliani,
P Laurent-Puig,
C Gower-Rousseau,
J Macry,
J F Colombel,
M Sahbatou,
G Thomas
Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
Mesh-terms: Alleles; Carrier Proteins; Chromosomes, Human, Pair 16; Cloning, Molecular; Colitis, Ulcerative :: genetics; Crohn Disease :: etiology; Crohn Disease :: genetics; Gene Frequency; Genetic Predisposition to Disease; Genotype; Human; Leucine; Linkage (Genetics) ; NF-kappa B :: metabolism; Polymorphism, Single Nucleotide; Proteins :: genetics; Repetitive Sequences, Amino Acid; Signal Transduction; Support, Non-U.S. Gov't; Variation (Genetics) ;
G C Johnson,
L Esposito,
B J Barratt,
A N Smith,
J Heward,
G Di Genova,
H Ueda,
H J Cordell,
I A Eaves,
F Dudbridge,
R C Twells,
F Payne,
W Hughes,
S Nutland,
H Stevens,
P Carr,
E Tuomilehto-Wolf,
J Tuomilehto,
S C Gough,
D G Clayton,
J A Todd
JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge, UK.
Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated, even the most recent studies have not placed significant emphasis on the most informative and cost-effective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers,(ii) reduce genotyping significantly (in this case from 122 to 34 SNPs),(iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.
J C Venter,
M D Adams,
E W Myers,
P W Li,
R J Mural,
G G Sutton,
H O Smith,
M Yandell,
C A Evans,
R A Holt,
J D Gocayne,
P Amanatides,
R M Ballew,
D H Huson,
J R Wortman,
Q Zhang,
C D Kodira,
X H Zheng,
L Chen,
M Skupski,
G Subramanian,
P D Thomas,
J Zhang,
G L Gabor Miklos,
C Nelson,
S Broder,
A G Clark,
J Nadeau,
V A McKusick,
N Zinder,
A J Levine,
R J Roberts,
M Simon,
C Slayman,
M Hunkapiller,
R Bolanos,
A Delcher,
I Dew,
D Fasulo,
M Flanigan,
L Florea,
A Halpern,
S Hannenhalli,
S Kravitz,
S Levy,
C Mobarry,
K Reinert,
K Remington,
J Abu-Threideh,
E Beasley,
K Biddick,
V Bonazzi,
R Brandon,
M Cargill,
I Chandramouliswaran,
R Charlab,
K Chaturvedi,
Z Deng,
V Di Francesco,
P Dunn,
K Eilbeck,
C Evangelista,
A E Gabrielian,
W Gan,
W Ge,
F Gong,
Z Gu,
P Guan,
T J Heiman,
M E Higgins,
R R Ji,
Z Ke,
K A Ketchum,
Z Lai,
Y Lei,
Z Li,
J Li,
Y Liang,
X Lin,
F Lu,
G V Merkulov,
N Milshina,
H M Moore,
A K Naik,
V A Narayan,
B Neelam,
D Nusskern,
D B Rusch,
S Salzberg,
W Shao,
B Shue,
J Sun,
Z Wang,
A Wang,
X Wang,
J Wang,
M Wei,
R Wides,
C Xiao,
C Yan,
A Yao,
J Ye,
M Zhan,
W Zhang,
H Zhang,
Q Zhao,
L Zheng,
F Zhong,
W Zhong,
S Zhu,
S Zhao,
D Gilbert,
S Baumhueter,
G Spier,
C Carter,
A Cravchik,
T Woodage,
F Ali,
H An,
A Awe,
D Baldwin,
H Baden,
M Barnstead,
I Barrow,
K Beeson,
D Busam,
A Carver,
A Center,
M L Cheng,
L Curry,
S Danaher,
L Davenport,
R Desilets,
S Dietz,
K Dodson,
L Doup,
S Ferriera,
N Garg,
A Gluecksmann,
B Hart,
J Haynes,
C Haynes,
C Heiner,
S Hladun,
D Hostin,
J Houck,
T Howland,
C Ibegwam,
J Johnson,
F Kalush,
L Kline,
S Koduru,
A Love,
F Mann,
D May,
S McCawley,
T McIntosh,
I McMullen,
M Moy,
L Moy,
B Murphy,
K Nelson,
C Pfannkoch,
E Pratts,
V Puri,
H Qureshi,
M Reardon,
R Rodriguez,
Y H Rogers,
D Romblad,
B Ruhfel,
R Scott,
C Sitter,
M Smallwood,
E Stewart,
R Strong,
E Suh,
R Thomas,
N N Tint,
S Tse,
C Vech,
G Wang,
J Wetter,
S Williams,
M Williams,
S Windsor,
E Winn-Deen,
K Wolfe,
J Zaveri,
K Zaveri,
J F Abril,
R Guigó,
M J Campbell,
K V Sjolander,
B Karlak,
A Kejariwal,
H Mi,
B Lazareva,
T Hatton,
A Narechania,
K Diemer,
A Muruganujan,
N Guo,
S Sato,
V Bafna,
S Istrail,
R Lippert,
R Schwartz,
B Walenz,
S Yooseph,
D Allen,
A Basu,
J Baxendale,
L Blick,
M Caminha,
J Carnes-Stine,
P Caulk,
Y H Chiang,
M Coyne,
C Dahlke,
A Mays,
M Dombroski,
M Donnelly,
D Ely,
S Esparham,
C Fosler,
H Gire,
S Glanowski,
K Glasser,
A Glodek,
M Gorokhov,
K Graham,
B Gropman,
M Harris,
J Heil,
S Henderson,
J Hoover,
D Jennings,
C Jordan,
J Jordan,
J Kasha,
L Kagan,
C Kraft,
A Levitsky,
M Lewis,
X Liu,
J Lopez,
D Ma,
W Majoros,
J McDaniel,
S Murphy,
M Newman,
T Nguyen,
N Nguyen,
M Nodell,
S Pan,
J Peck,
M Peterson,
W Rowe,
R Sanders,
J Scott,
M Simpson,
T Smith,
A Sprague,
T Stockwell,
R Turner,
E Venter,
M Wang,
M Wen,
D Wu,
M Wu,
A Xia,
A Zandieh,
X Zhu
A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.
Mesh-terms: Algorithms; Animals; Chromosome Banding; Chromosome Mapping; Chromosomes, Artificial, Bacterial; Computational Biology; Consensus Sequence; CpG Islands; DNA, Intergenic; Databases, Factual; Evolution, Molecular; Exons; Female; Gene Duplication; Genes; Genome, Human; Human; Human Genome Project; Introns; Male; Phenotype; Physical Chromosome Mapping; Polymorphism, Single Nucleotide; Proteins :: genetics; Proteins :: physiology; Pseudogenes; Repetitive Sequences, Nucleic Acid; Retroelements; Sequence Analysis, DNA :: methods; Species Specificity; Support, Non-U.S. Gov't; Variation (Genetics) ;
P Kuehl,
J Zhang,
Y Lin,
J Lamba,
M Assem,
J Schuetz,
P B Watkins,
A Daly,
S A Wrighton,
S D Hall,
P Maurel,
M Relling,
C Brimer,
K Yasuda,
R Venkataramanan,
S Strom,
K Thummel,
M S Boguski,
E Schuetz
Department of Molecular and Cell Biology, University of Maryland at Baltimore, Baltimore, Maryland, USA.
Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.
Albert O Edwards,
Robert Ritter 3rd,
Kenneth J Abel,
Alisa Manning,
Carolien Panhuysen,
Lindsay A Farrer
Age-related macular degeneration (AMD) is a common, late-onset, and complex trait with multiple risk factors. Concentrating on a region harboring a locus for AMD on 1q25-31, the ARMD1 locus, we tested single-nucleotide polymorphisms for association with AMD in two independent case-control populations. Significant association (P = 4.95 x 10(-10)) was identified within the regulation of complement activation locus and was centered over a tyrosine-402 --> histidine-402 protein polymorphism in the gene encoding complement factor H. Possession of at least one histidine at amino acid position 402 increased the risk of AMD 2.7-fold and may account for 50% of the attributable risk of AMD.
Mesh-terms: Aged; Alleles; Amino Acid Substitution; Case-Control Studies; Chromosomes, Human, Pair 1 :: genetics; Complement Activation :: genetics; Complement Factor H :: genetics; Complement Factor H :: physiology; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Haplotypes; Histidine; Homozygote; Humans; Linkage Disequilibrium; Macular Degeneration :: etiology; Macular Degeneration :: genetics; Male; Middle Aged; Multigene Family; Polymorphism, Single Nucleotide; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. ; Risk Factors; Tyrosine; Variation (Genetics) ;
R B Kim,
B F Leake,
E F Choo,
G K Dresser,
S V Kubba,
U I Schwarz,
A Taylor,
H G Xie,
J McKinsey,
S Zhou,
L B Lan,
J D Schuetz,
E G Schuetz,
G R Wilkinson
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. richard.kim@mcmail.vanderbilt.edu
MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1 ) or a site-directed Ser893 mutation (MDR1*2 ) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.
Mesh-terms: Africa :: ethnology; African Continental Ancestry Group :: genetics; Alleles; Anti-Allergic Agents :: pharmacokinetics; Area Under Curve; Cloning, Molecular; DNA Primers; Digoxin :: pharmacokinetics; Enzyme Inhibitors :: pharmacokinetics; Europe :: ethnology; European Continental Ancestry Group :: genetics; Genes, MDR :: genetics; Genotype; Haplotypes; Human; P-Glycoprotein :: metabolism; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. ; Terfenadine :: analogs & derivatives; Terfenadine :: pharmacokinetics; Time Factors; Variation (Genetics) ;
J C Stephens,
J A Schneider,
D A Tanguay,
J Choi,
T Acharya,
S E Stanley,
R Jiang,
C J Messer,
A Chew,
J H Han,
J Duan,
J L Carr,
M S Lee,
B Koshy,
A M Kumar,
G Zhang,
W R Newell,
A Windemuth,
C Xu,
T S Kalbfleisch,
S L Shaner,
K Arnold,
V Schulz,
C M Drysdale,
K Nandabalan,
R S Judson,
G Ruano,
G F Vovis
Genaissance Pharmaceuticals, Inc., Five Science Park, New Haven, CT 06511, USA. c.stephens@genaissance.com
Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.
Mesh-terms: African Continental Ancestry Group :: genetics; Alleles; Animals; Asian Continental Ancestry Group :: genetics; Comparative Study; Dinucleoside Phosphates :: genetics; European Continental Ancestry Group :: genetics; Evolution, Molecular; Female; Haplotypes; Heterozygote; Hispanic Americans :: genetics; Human; Linkage Disequilibrium; Male; Mutation; Pan troglodytes :: genetics; Polymorphism, Single Nucleotide; Variation (Genetics) ; X Chromosome :: genetics;
European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
Single nucleotide polymorphisms (SNPs) constitute the bulk of human genetic variation, occurring with an average density of approximately 1/1000 nucleotides of a genotype. SNPs are either neutral allelic variants or are under selection of various strengths, and the impact of SNPs on fitness remains unknown. Identification of SNPs affecting human phenotype, especially leading to risks of complex disorders, is one of the key problems of medical genetics. SNPs in protein-coding regions that cause amino acid variants (non-synonymous cSNPs) are most likely to affect phenotypes. We have developed a straightforward and reliable method based on physical and comparative considerations that estimates the impact of an amino acid replacement on the three-dimensional structure and function of the protein. We estimate that approximately 20% of common human non-synonymous SNPs damage the protein. The average minor allele frequency of such SNPs in our data set was two times lower than that of benign non-synonymous SNPs. The average human genotype carries approximately 10(3) damaging non-synonymous SNPs that together cause a substantial reduction in fitness.
Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California 94305-5120, USA.
Association studies with candidate genes have been widely used for the study of complex diseases. However, this approach has been criticized because of non-replication of results and limits on its ability to include all possible causative genes and polymorphisms. These challenges have led to pessimism about the candidate-gene approach and about the genetic analysis of complex diseases in general. We believe that these criticisms can be usefully countered with an appeal to the principles of epidemiological investigation.

