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1.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34437092

RESUMO

Systematic and extensive investigation of enzymes is needed to understand their extraordinary efficiency and meet current challenges in medicine and engineering. We present HT-MEK (High-Throughput Microfluidic Enzyme Kinetics), a microfluidic platform for high-throughput expression, purification, and characterization of more than 1500 enzyme variants per experiment. For 1036 mutants of the alkaline phosphatase PafA (phosphate-irrepressible alkaline phosphatase of Flavobacterium), we performed more than 670,000 reactions and determined more than 5000 kinetic and physical constants for multiple substrates and inhibitors. We uncovered extensive kinetic partitioning to a misfolded state and isolated catalytic effects, revealing spatially contiguous regions of residues linked to particular aspects of function. Regions included active-site proximal residues but extended to the enzyme surface, providing a map of underlying architecture not possible to derive from existing approaches. HT-MEK has applications that range from understanding molecular mechanisms to medicine, engineering, and design.


Assuntos
Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Fosfatase Alcalina/antagonistas & inibidores , Fosfatase Alcalina/química , Biocatálise , Domínio Catalítico , Flavobacterium/enzimologia , Hidrólise , Cinética , Microfluídica , Modelos Moleculares , Mutação , Oxigênio/metabolismo , Fosfatos/metabolismo , Conformação Proteica , Dobramento de Proteína , Termodinâmica
2.
Biometrika ; 106(1): 1-18, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30799875

RESUMO

Modern scientific studies often require the identification of a subset of explanatory variables. Several statistical methods have been developed to automate this task, and the framework of knockoffs has been proposed as a general solution for variable selection under rigorous Type I error control, without relying on strong modelling assumptions. In this paper, we extend the methodology of knockoffs to problems where the distribution of the covariates can be described by a hidden Markov model. We develop an exact and efficient algorithm to sample knockoff variables in this setting and then argue that, combined with the existing selective framework, this provides a natural and powerful tool for inference in genome-wide association studies with guaranteed false discovery rate control. We apply our method to datasets on Crohn's disease and some continuous phenotypes.

3.
Bioinformatics ; 32(16): 2556-8, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27153635

RESUMO

UNLABELLED: : Commonly used multiplicity adjustments fail to control the error rate for reported findings in many expression quantitative trait loci (eQTL) studies. TreeQTL implements a hierarchical multiple testing procedure which allows control of appropriate error rates defined relative to a grouping of the eQTL hypotheses. AVAILABILITY AND IMPLEMENTATION: The R package TreeQTL is available for download at http://bioinformatics.org/treeqtl CONTACT: sabatti@stanford.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Locos de Características Quantitativas , Software , Humanos
4.
Transl Psychiatry ; 2: e116, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22832960

RESUMO

Temperament has a strongly heritable component, yet multiple independent genome-wide studies have failed to identify significant genetic associations. We have assembled the largest sample to date of persons with genome-wide genotype data, who have been assessed with Cloninger's Temperament and Character Inventory. Sum scores for novelty seeking, harm avoidance, reward dependence and persistence have been measured in over 11,000 persons collected in four different cohorts. Our study had >80% power to identify genome-wide significant loci (P<1.25 × 10(-8), with correction for testing four scales) accounting for ≥0.4% of the phenotypic variance in temperament scales. Using meta-analysis techniques, gene-based tests and pathway analysis we have tested over 1.2 million single-nucleotide polymorphisms (SNPs) for association to each of the four temperament dimensions. We did not discover any SNPs, genes, or pathways to be significantly related to the four temperament dimensions, after correcting for multiple testing. Less than 1% of the variability in any temperament dimension appears to be accounted for by a risk score derived from the SNPs showing strongest association to the temperament dimensions. Elucidation of genetic loci significantly influencing temperament and personality will require potentially very large samples, and/or a more refined phenotype. Item response theory methodology may be a way to incorporate data from cohorts assessed with multiple personality instruments, and might be a method by which a large sample of a more refined phenotype could be acquired.


Assuntos
Estudo de Associação Genômica Ampla , Inventário de Personalidade/estatística & dados numéricos , Personalidade/genética , Temperamento , Adulto , Austrália , Estudos de Coortes , Feminino , Finlândia , Heterogeneidade Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Psicometria/estatística & dados numéricos , Reprodutibilidade dos Testes , Gêmeos/genética , Gêmeos/psicologia
5.
Mol Psychiatry ; 15(2): 115, 204-15, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19546860

RESUMO

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis.


Assuntos
Proteínas de Transporte/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo , Neuritos/fisiologia , Proteínas SNARE/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Proteínas de Transporte/genética , Bovinos , Células Cultivadas , Disbindina , Proteínas Associadas à Distrofina , Embrião de Mamíferos , Hipocampo/embriologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Ligação Proteica , Transporte Proteico , Proteínas Qa-SNARE/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas SNARE/genética , Proteína 25 Associada a Sinaptossoma/metabolismo , Proteína 2 Associada à Membrana da Vesícula/metabolismo
6.
Am J Med Genet B Neuropsychiatr Genet ; 150B(7): 998-1006, 2009 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-19319892

RESUMO

We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees.


Assuntos
Grupo com Ancestrais Nativos do Continente Americano/genética , Transtorno Bipolar/genética , Cromossomos Humanos Par 5/genética , Ligação Genética , Linhagem , Colômbia , Costa Rica , Família , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , América Latina , Escore Lod , Masculino , Polimorfismo de Nucleotídeo Único/genética
7.
Acta Otolaryngol ; 127(12): 1241-5, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17851970

RESUMO

CONCLUSION: Coexistent migraine affects relevant clinical features of patients with Ménière's disease (MD). OBJECTIVE: Epidemiological studies have shown an association between migraine and MD. We sought to determine whether the coexistence of migraine affects any clinical features in patients with MD. PATIENTS AND METHODS: In this retrospective case-control study of University Neurotology Clinic patients, 50 patients meeting 1995 AAO-HNS criteria for definite MD were compared to 18 patients meeting the same criteria in addition to the 2004 IHS criteria for migraine (MMD). All had typical low frequency sensorineural hearing loss and episodes of rotational vertigo. Outcome measures included: sex, age of onset of episodic vertigo or fluctuating hearing loss, laterality of hearing loss, aural symptoms, caloric responses, severity of hearing loss, and family history of migraine, episodic vertigo or hearing loss. RESULTS: Age of onset of episodic vertigo or fluctuating hearing loss was significantly lower in patients with MMD (mean +/- 1.96*SE = 37.2 +/- 6.3 years) than in those with MD (mean +/- 1.96*SE = 49.3 +/- 4.4 years). Concurrent bilateral aural symptoms and hearing loss were seen in 56% of MMD and 4% of MD patients. A family history of episodic vertigo was seen in 39% of MMD and 2% of MD patients.


Assuntos
Doença de Meniere/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Doença de Meniere/complicações , Pessoa de Meia-Idade , Transtornos de Enxaqueca/complicações , Estudos Retrospectivos
8.
Neurology ; 63(12): 2376-9, 2004 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-15623703

RESUMO

BACKGROUND: Of the more than 40 genetically defined dominantly inherited hearing loss syndromes, only a few are associated with bilateral vestibulopathy. No genetic mutations have been identified in families with bilateral vestibulopathy and normal hearing. OBJECTIVE: To perform a genome-wide scan for linkage in four families with dominantly inherited bilateral vestibulopathy. METHODS: Patients in four families reported brief episodes of vertigo followed by imbalance and oscillopsia. Bilateral vestibulopathy was documented with quantitative rotational testing. Most patients with bilateral vestibulopathy also had migraine. A 10 cM genome-wide screen was conducted using 423 microsatellite markers to identify linkage with vestibulopathy. RESULTS: The authors identified a 24 cM region on chromosome 6q suggestive of linkage to vestibulopathy in these four families (maximum lod score of 2.9 at marker D6S1556). A small fifth family with a different phenotype was not linked to this region on chromosome 6q. CONCLUSIONS: This is the first report of linkage in families with dominantly inherited vestibulopathy and normal hearing. Genetic heterogeneity is likely with inherited vestibulopathy.


Assuntos
Cromossomos Humanos Par 6/genética , Doenças Vestibulares/genética , Feminino , Genes Dominantes , Heterogeneidade Genética , Haplótipos , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem , Fenótipo , Vertigem/genética
9.
Neurology ; 59(3): 432-5, 2002 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-12177379

RESUMO

Horizontal gaze palsy with progressive scoliosis (HGPS) is a rare, autosomal recessive disorder characterized by a congenital absence of conjugate horizontal eye movement, with progressive scoliosis developing in childhood or adolescence. The authors identified two unrelated consanguineous families with HGPS. Genomewide homozygosity mapping and linkage analysis mapped the disease locus to a 30-cM interval on chromosome 11q23-25 (combined maximum multipoint lod score Z = 5.46).


Assuntos
Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 11/genética , Transtornos da Motilidade Ocular/genética , Escoliose/genética , Adolescente , Criança , Pré-Escolar , Mapeamento Cromossômico/estatística & dados numéricos , Consanguinidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Nistagmo Patológico/genética , Doenças do Nervo Oculomotor/genética , Linhagem
10.
Hum Mol Genet ; 10(26): 2961-72, 2001 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-11751678

RESUMO

Compared to mixed populations, population isolates such as Finland show distinct differences in the prevalence of disease mutations. However, little information exists of the differences on the prevalence of different disease alleles in regional populations with different history of multiple bottlenecks. We constructed a DNA-array and monitored the prevalence of 31 rare and common disease mutations underlying 27 clinical phenotypes in a large population-based study sample. Over 64 000 genotypes were assigned in 2151 samples from four geographical areas representing early and late settlement regions of Finland. Each sample was analyzed in duplicate and a total of 142 000 array-derived genotyping calls were made. On average one in three individuals was found to be a carrier of one of the 31 monitored mutations. This should remove fears of the stigmatizing effect of a carrier-screening program monitoring multiple diseases. Regional differences were found in the prevalence of mutations, providing molecular evidence for the deviating population histories of regional subisolates. The mutations introduced early into the population revealed relatively even distribution in different subregions. More recently introduced rare mutations showed local clustering of disease alleles, indicating the persistence of population subisolates and the effect of multiple bottlenecks in molding the population gene pool. Regional differences were observed also for common disease alleles. Such precise information of the carrier frequencies could form the basis for targeted genetic screens in this population. Our approach describes a general paradigm for large-scale carrier-screening programs also in other populations.


Assuntos
Testes Genéticos , Mutação , Alelos , Grupo com Ancestrais do Continente Europeu/genética , Finlândia , Frequência do Gene , Triagem de Portadores Genéticos , Doenças Genéticas Inatas/genética , Humanos , Desequilíbrio de Ligação , Reação em Cadeia da Polimerase
11.
Genome Res ; 11(10): 1716-24, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11591648

RESUMO

Haplotype analysis of disease chromosomes can help identify probable historical recombination events and localize disease mutations. Most available analyses use only marginal and pairwise allele frequency information. We have developed a Bayesian framework that utilizes full haplotype information to overcome various complications such as multiple founders, unphased chromosomes, data contamination, and incomplete marker data. A stochastic model is used to describe the dependence structure among several variables characterizing the observed haplotypes, for example, the ancestral haplotypes and their ages, mutation rate, recombination events, and the location of the disease mutation. An efficient Markov chain Monte Carlo algorithm was developed for computing the estimates of the quantities of interest. The method is shown to perform well in both real data sets (cystic fibrosis data and Friedreich ataxia data) and simulated data sets. The program that implements the proposed method, BLADE, as well as the two real datasets, can be obtained from http://www.fas.harvard.edu/~junliu/TechRept/01folder/diseq_prog.tar.gz.


Assuntos
Mapeamento Cromossômico/estatística & dados numéricos , Fibrose Cística/genética , Ataxia de Friedreich/genética , Haplótipos/genética , Desequilíbrio de Ligação/genética , Teorema de Bayes , Simulação por Computador , Humanos , Modelos Estatísticos
12.
Neurology ; 54(9): 1746-52, 2000 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-10802779

RESUMO

OBJECTIVE: To develop diagnostic testing guidelines for the DYT1 GAG deletion in the Ashkenazi Jewish (AJ) and non-Jewish (NJ) primary torsion dystonia (PTD) populations and to determine the range of dystonic features in affected DYT1 deletion carriers. METHODS: The authors screened 267 individuals with PTD; 170 were clinically ascertained for diagnosis and treatment, 87 were affected family members ascertained for genetic studies, and 10 were clinically and genetically ascertained and included in both groups. We used published primers and PCR amplification across the critical DYT1 region to determine GAG deletion status. Features of dystonia in clinically ascertained (affected) DYT1 GAG deletion carriers and noncarriers were compared to determine a classification scheme that optimized prediction of carriers. The authors assessed the range of clinical features in the genetically ascertained (affected) DYT1 deletion carriers and tested for differences between AJ and NJ patients. RESULTS: The optimal algorithm for classification of clinically ascertained carriers was disease onset before age 24 years in a limb (misclassification, 16.5%; sensitivity, 95%; specificity, 80%). Although application of this classification scheme provided good separation in the AJ group (sensitivity, 96%; specificity, 88%), as well as in the group overall, it was less specific in discriminating NJ carriers from noncarriers (sensitivity, 94%; specificity, 69%). Using age 26 years as the cut-off and any site at onset gave a sensitivity of 100%, but specificity decreased to 54% (63% in AJ and 43% in NJ). Among genetically ascertained carriers, onset up to age 44 years occurred, although the great majority displayed early limb onset. There were no significant differences between AJ and NJ genetically ascertained carriers, except that a higher proportion of NJ carriers had onset in a leg, rather than an arm, and widespread disease. CONCLUSIONS: Diagnostic DYT1 testing in conjunction with genetic counseling is recommended for patients with PTD with onset before age 26 years, as this single criterion detected 100% of clinically ascertained carriers, with specificities of 43% to 63%. Testing patients with onset after age 26 years also may be warranted in those having an affected relative with early onset, as the only carriers we observed with onset at age 26 or later were genetically ascertained relatives of individuals whose symptoms started before age 26 years.


Assuntos
Proteínas de Transporte/genética , Distonia Muscular Deformante/genética , Testes Genéticos , Judeus/genética , Chaperonas Moleculares , Fenótipo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Deleção Cromossômica , Distonia Muscular Deformante/diagnóstico , Feminino , Triagem de Portadores Genéticos , Aconselhamento Genético , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes
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