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SUMMARY: VarSome.com is a search engine, aggregator and impact analysis tool for human genetic variation and a community-driven project aiming at sharing global expertise on human variants. AVAILABILITY AND IMPLEMENTATION: VarSome is freely available at http://varsome.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Genoma Humano , Motor de Búsqueda , Programas Informáticos , Genómica , HumanosRESUMEN
Intoduction: Inherited cataract, opacification of the lens, is the most common worldwide cause of blindness in children. We aimed to identify the genetic cause of autosomal dominant (AD) posterior nuclear cataract in a four generation British family. METHODS: Whole genome sequence (WGS) was performed on two affected and one unaffected individual of the family and further validated by direct sequencing. Haplotype analysis was performed via genotying. RESULTS: A splice-site mutation c.2826-9G>A in the gene EPHA2, encoding EPH receptor A2 was identified and found to co-segregate with disease. CONCLUSIONS: We have identified a recurrent splice-site mutation c.2826-9G>A in EPHA2 causing isolated posterior nuclear cataract, providing evidence of further phenotypic heterogeneity associated with this variant.
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Catarata/congénito , Efrina-A2/genética , Mutación , Sitios de Empalme de ARN/genética , Catarata/genética , Niño , Cromosomas Humanos Par 1/genética , Cartilla de ADN/química , Femenino , Haplotipos , Humanos , Cristalino/patología , Masculino , Linaje , Reacción en Cadena de la Polimerasa , Receptor EphA2 , Recurrencia , Secuenciación Completa del GenomaRESUMEN
Understanding the relationship between genetic and phenotypic variation is one of the great outstanding challenges in biology. To meet this challenge, comprehensive genomic variation maps of human as well as of model organism populations are required. Here, we present a nucleotide resolution catalog of single-nucleotide, multi-nucleotide, and structural variants in 39 Drosophila melanogaster Genetic Reference Panel inbred lines. Using an integrative, local assembly-based approach for variant discovery, we identify more than 3.6 million distinct variants, among which were more than 800,000 unique insertions, deletions (indels), and complex variants (1 to 6,000 bp). While the SNP density is higher near other variants, we find that variants themselves are not mutagenic, nor are regions with high variant density particularly mutation-prone. Rather, our data suggest that the elevated SNP density around variants is mainly due to population-level processes. We also provide insights into the regulatory architecture of gene expression variation in adult flies by mapping cis-expression quantitative trait loci (cis-eQTLs) for more than 2,000 genes. Indels comprise around 10% of all cis-eQTLs and show larger effects than SNP cis-eQTLs. In addition, we identified two-fold more gene associations in males as compared to females and found that most cis-eQTLs are sex-specific, revealing a partial decoupling of the genomic architecture between the sexes as well as the importance of genetic factors in mediating sex-biased gene expression. Finally, we performed RNA-seq-based allelic expression imbalance analyses in the offspring of crosses between sequenced lines, which revealed that the majority of strong cis-eQTLs can be validated in heterozygous individuals.
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Drosophila melanogaster/genética , Expresión Génica , Variación Genética , Genoma , Desequilibrio Alélico/genética , Animales , Mapeo Cromosómico , Mutación INDEL , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo/genéticaRESUMEN
The Myc proto-oncoproteins are transcription factors that recognize numerous target genes through hexameric DNA sequences called E-boxes. The mechanism by which they then activate the expression of these targets is still under debate. Here, we use an RNAi screen in Drosophila S2 cells to identify Drosophila host cell factor (dHCF) as a novel co-factor for Myc that is functionally required for the activation of a Myc-dependent reporter construct. dHCF is also essential for the full activation of endogenous Myc target genes in S2 cells, and for the ability of Myc to promote growth in vivo. Myc and dHCF physically interact, and they colocalize on common target genes. Furthermore, down-regulation of dHCF-associated histone acetyltransferase and histone methyltransferase complexes in vivo interferes with the Myc biological activities. We therefore propose that dHCF recruits such chromatin-modifying complexes and thereby contributes to the expression of Myc targets and hence to the execution of Myc biological activities.
