PosMed (Positional Medline): prioritizing genes with an artificial neural network comprising medical documents to accelerate positional cloning

Yoshida, Yuko; Makita, Yuko; Heida, Naohiko; Asano, Satomi; Matsushima, Akihiro; Ishii, Manabu; Mochizuki, Yoshiki; Masuya, Hiroshi; Wakana, Shigeharu; Kobayashi, Norio; Toyoda, Tetsuro

doi:10.1093/nar/gkp384

Cited by 43 publications

(26 citation statements)

References 24 publications

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“…ENU was administered to male C57BL/6J mice, and their sperm was mated to wild-type eggs and preserved as founder embryos (8,21) for use in our screening.…”

Section: Methodsmentioning

confidence: 99%

A Novel Gene Essential for the Development of Single Positive Thymocytes

Kakugawa

Yasuda

Miura

et al. 2009

Molecular and Cellular Biology

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A critical step during intrathymic T-cell development is the transition of CD4؉ CD8 ؉ double-positive (DP) cells to the major histocompatibility complex class I (MHC-I)-restricted CD4؊ CD8 ؉ and MHC-II-restricted CD4 ؉ CD8 ؊ single-positive (SP) cell stage. Here, we identify a novel gene that is essential for this process. Through the T-cell phenotype-based screening of N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we established a mouse line in which numbers of CD4 and CD8 SP thymocytes as well as peripheral CD4 and CD8 T cells were dramatically reduced. Using linkage analysis and DNA sequencing, we identified a missense point mutation in a gene, E430004N04Rik (also known as themis), that does not belong to any known gene family. This orphan gene is expressed specifically in DP and SP thymocytes and peripheral T cells, whereas in mutant thymocytes the levels of protein encoded by this gene were drastically reduced. We generated E430004N04Rik-deficient mice, and their phenotype was virtually identical to that of the ENU mutant mice, thereby confirming that this gene is essential for the development of SP thymocytes.The differentiation step from the double-positive (DP) to single-positive (SP) thymocyte stage is critically regulated by signals originating from the T-cell receptor ␣/␤ (TCR␣/␤) expressed on their surface (3,5,16,17). By using reverse genetic approaches by knocking out or overexpressing various genes that are expected to be involved in TCR signaling, including its ligand major histocompatibility complex molecules and coreceptors CD4 and CD8, the roles of these genes in T-cell development have been investigated intensively (11,12). However, to identify totally unknown mechanisms in T-cell development, the forward genetic approach is required. Nethyl-N-nitrosourea (ENU) is a potent mutagen that randomly induces point mutations throughout the genome in a dosedependent manner, and ENU mutagenesis has been a representative forward genetic strategy (4, 15). We have been screening phenotypes of ENU-mutagenized mice, focusing on defects in T-cell development. MATERIALS AND METHODSMice. C57BL/6 (B6) and B6Ly5.1 congenic mice were purchased from CLEA Japan, Inc. All mice were maintained in the animal facility at the RIKEN Research Center for Allergy and Immunology, and all experiments were done in accordance with institutional guidelines for animal care. ENU mutagenesis. ENU was administered to male C57BL/6J mice, and their sperm was mated to wild-type eggs and preserved as founder embryos (8, 21) for use in our screening.Mapping and sequencing. Phenodeviants that showed CD3 ϩ cell reduction were crossed to wild-type C3H/HeJ mice to test for phenotype transmission and for the genetic mapping of the causative genes. Single-nucleotide polymorphism (SNP) mapping was performed as described elsewhere (13). For sequencing, we focused on the ptprk and E430004N04Rik genes, which were among candidate genes listed by PosMed (21) (http://omicspace.riken.jp). cDNA and genomic DNA were amplified by PCR and sequenced us...

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“…ENU was administered to male C57BL/6J mice, and their sperm was mated to wild-type eggs and preserved as founder embryos (8,21) for use in our screening.…”

Section: Methodsmentioning

confidence: 99%

A Novel Gene Essential for the Development of Single Positive Thymocytes

Kakugawa

Yasuda

Miura

et al. 2009

Molecular and Cellular Biology

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“…Phenodeviants that showed skin anomalies were crossed with C3H/HeJ mice to test for phenotype transmission and for genetic mapping using SNPs (9). For sequencing, we focused on Jak1 among the candidate genes identified by the PosMed bioinformatics-based search engine (47). Genomic DNA was amplified by PCR and sequenced using Jak1-specific primers (Supplemental Table 2).…”

Section: R879hmentioning

confidence: 99%

Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

Yasuda¹,

Fukada²,

Nishida³

et al. 2016

Journal of Clinical Investigation

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“…Five freely accessible gene prioritization web tools were selected: Endeavour (Aerts et al 2006), GeneWanderer (Kohler et al 2008), PosMed (Yoshida et al 2009), Suspect (Adie et al 2006) and ToppGene (Chen et al 2009) (Table 1). These Wve web tools use diVerent data sources and require diVerent inputs.…”

Section: Web Tools For Gene Prioritizationmentioning

confidence: 99%

Outcome of array CGH analysis for 255 subjects with intellectual disability and search for candidate genes using bioinformatics

et al. 2010

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Array CGH enables the detection of pathogenic copy number variants (CNVs) in 5-15% of individuals with intellectual disability (ID), making it a promising tool for uncovering ID candidate genes. However, most CNVs encompass multiple genes, making it difficult to identify key disease gene(s) underlying ID etiology. Using array CGH we identified 47 previously unreported unique CNVs in 45/255 probands. We prioritized ID candidate genes using five bioinformatic gene prioritization web tools. Gene priority lists were created by comparing integral genes from each CNV from our ID cohort with sets of training genes specific either to ID or randomly selected. Our findings suggest that different training sets alter gene prioritization only moderately; however, only the ID gene training set resulted in significant enrichment of genes with nervous system function (19%) in prioritized versus non-prioritized genes from the same de novo CNVs (7%, p < 0.05). This enrichment further increased to 31% when the five web tools were used in concert and included genes within mitogen-activated protein kinase (MAPK) and neuroactive ligand-receptor interaction pathways. Gene prioritization web tools enrich for genes with relevant function in ID and more readily facilitate the selection of ID candidate genes for functional studies, particularly for large CNVs.

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PosMed (Positional Medline): prioritizing genes with an artificial neural network comprising medical documents to accelerate positional cloning

Cited by 43 publications

References 24 publications

A Novel Gene Essential for the Development of Single Positive Thymocytes

A Novel Gene Essential for the Development of Single Positive Thymocytes

Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

Outcome of array CGH analysis for 255 subjects with intellectual disability and search for candidate genes using bioinformatics

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