RESUMO
Adenosine-to-inosine (A-to-I) RNA editing is a neurodevelopmentally regulated epigenetic modification shown to modulate complex behavior in animals. Little is known about human A-to-I editing, but it is thought to constitute one of many molecular mechanisms connecting environmental stimuli and behavioral outputs. Thus, comprehensive exploration of A-to-I RNA editing in human brains may shed light on gene-environment interactions underlying complex behavior in health and disease. Synaptic function is a main target of A-to-I editing, which can selectively recode key amino acids in synaptic genes, directly altering synaptic strength and duration in response to environmental signals. Here, we performed a high-resolution survey of synaptic A-to-I RNA editing in a human population, and examined how it varies in autism, a neurodevelopmental disorder in which synaptic abnormalities are a common finding. Using ultra-deep (>1000 × ) sequencing, we quantified the levels of A-to-I editing of 10 synaptic genes in postmortem cerebella from 14 neurotypical and 11 autistic individuals. A high dynamic range of editing levels was detected across individuals and editing sites, from 99.6% to below detection limits. In most sites, the extreme ends of the population editing distributions were individuals with autism. Editing was correlated with isoform usage, clusters of correlated sites were identified, and differential editing patterns examined. Finally, a dysfunctional form of the editing enzyme adenosine deaminase acting on RNA B1 was found more commonly in postmortem cerebella from individuals with autism. These results provide a population-level, high-resolution view of A-to-I RNA editing in human cerebella and suggest that A-to-I editing of synaptic genes may be informative for assessing the epigenetic risk for autism.
Assuntos
Transtorno Autístico/genética , Transtorno Autístico/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Edição de RNA/genética , Adenosina Desaminase/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Filaminas/genética , Biblioteca Gênica , Humanos , Canal de Potássio Kv1.1/genética , Masculino , Análise Numérica Assistida por Computador , Isoformas de Proteínas/genética , Proteínas de Ligação a RNA , Receptor 5-HT2C de Serotonina/genética , Receptores de AMPA/genética , Transcriptoma , Adulto JovemRESUMO
We report results from a study of Lambda(0) polarization in the exclusive reaction pp --> p(f)(Lambda0K+) at 800-GeV/c. We observe a dependence of the polarization on the Lambda0K+ invariant mass with large (+71%) positive polarization at small mass (1.63-GeV/c(2)) and large (-43%) negative polarization at large mass (2.75-GeV/c(2)). This observation confirms the result of the CERN ISR R608 experiment and extends the range over which the effect is observed. The strong dependence of the polarization on the Lambda0K+ invariant mass suggests that the origin of the polarization is closely related to the production dynamics of the diffractively produced Lambda0K+ system.
RESUMO
We report the first observation of diffractively produced open charm in 800-GeV/c pp collisions of the type pp-->pD*X. We measure cross sections of sigma(diff)(D*+) = (0.185+/-0.044+/-0.054) (mu)b and sigma(diff)(D(*-)) = (0.174+/-0.034+/-0.029) (mu)b. Our measurements are based on 4.3x10(9) events recorded by FNAL E690 in the fixed-target run of 1991. We compare our results with previous fixed-target charm experiments.
RESUMO
Computational constraints currently limit exact multipoint linkage analysis to pedigrees of moderate size. We introduce new algorithms that allow analysis of larger pedigrees by reducing the time and memory requirements of the computation. We use the observed pedigree genotypes to reduce the number of inheritance patterns that need to be considered. The algorithms are implemented in a new version (version 2.1) of the software package GENEHUNTER. Performance gains depend on marker heterozygosity and on the number of pedigree members available for genotyping, but typically are 10-1,000-fold, compared with the performance of the previous release (version 2.0). As a result, families with up to 30 bits of inheritance information have been analyzed, and further increases in family size are feasible. In addition to computation of linkage statistics and haplotype determination, GENEHUNTER can also perform single-locus and multilocus transmission/disequilibrium tests. We describe and implement a set of permutation tests that allow determination of empirical significance levels in the presence of linkage disequilibrium among marker loci.
Assuntos
Algoritmos , Mapeamento Cromossômico/métodos , Software , Alelos , Mapeamento Cromossômico/estatística & dados numéricos , Simulação por Computador , Computadores , Feminino , Marcadores Genéticos/genética , Haplótipos/genética , Heterozigoto , Humanos , Desequilíbrio de Ligação/genética , Masculino , Núcleo Familiar , Linhagem , Polimorfismo Genético/genética , Tamanho da Amostra , Fatores de TempoRESUMO
We present a joint linkage analysis of eight data sets collected for asthma. Three of the data sets are full genome scans, while the remaining five concentrate on a 40-cM region on chromosome 5. We perform the analysis using one qualitative and one quantitative phenotype: asthma status and IgE level. Considering all data sets simultaneously, we do not find evidence for linkage to asthma affection status beyond the level expected to occur by chance twice per genome scan. In contrast, we observe significant linkage to IgE level on chromosome 6.