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Background: The University of California, Santa Cruz (UCSC) genome database is among the most used sources of genomic annotation in human and other organisms. The database offers an excellent web-based graphical user interface (the UCSC genome browser) and several means for programmatic queries. A simple application programming interface (API) in a scripting language aimed at the biologist was however not yet available. Here, we present the Ruby UCSC API, a library to access the UCSC genome database using Ruby. Results: The API is designed as a BioRuby plug-in and built on the ActiveRecord 3 framework for the object-relational mapping, making writing SQL statements unnecessary. The current version of the API supports databases of all organisms in the UCSC genome database including human, mammals, vertebrates, deuterostomes, insects, nematodes, and yeast. The API uses the bin index—if available—when querying for genomic intervals. The API also supports genomic sequence queries using locally downloaded *.2bit files that are not stored in the official MySQL database. The API is implemented in pure Ruby and is therefore available in different environments and with different Ruby interpreters (including JRuby). Conclusions: Assisted by the straightforward object-oriented design of Ruby and ActiveRecord, the Ruby UCSC API will facilitate biologists to query the UCSC genome database programmatically. The API is available through the RubyGem system. Source code and documentation are available at https://github.com/misshie/bioruby-ucsc-api/ under the Ruby license. Feedback and help is provided via the website at http://rubyucscapi.userecho.com/., BMC Bioinformatics, 13, 240; 2012

Background: Since multiple lung cancer treatment strategies differ, it is essential for clinicians to be able to distinguish between separate primary lesions and metastasis. In the present study, we used array comparative genomic hybridization (aCGH) and somatic mutation (epidermal growth factor receptor: EGFR) to analyze genomic alteration profiles in lung cancer patients. To validate the consistency among the pathological assessments and clarify the clinical differences between double primary lesions and metastasis, we also examined synchronous double lung cancer clinical data. Methods: Between January 1970 and March 2010, 2215 patients with lung cancer underwent surgical resection at Nagasaki University Hospital. We performed molecular analysis of 12 synchronous double lung cancer patients without lymph node metastasis (intrapulmonary metastasis in the same lobe (pm1): n = 6, primary: n = 6). We then evaluated the clinical outcomes of patients with pathologically diagnosed synchronous double lung cancers (intrapulmonary metastasis (pm): n = 80, primary: n = 39) and other T3 tumors (n = 230). Results: Examination of the concordance rate (CR) of the copy number changes (CNCs) for paired tumors showed that the metastasis group was larger than the primary group (55.5% vs. 19.6%, p = 0.04). Pathological diagnosis and molecular classification were the same in 10 out of 12 cases (83%). As compared to the primary group, there tended to be an inferior 5-year survival curve for the pm group. However, in N0 patients, the survival curve for the pm group overlapped the primary group, while the survival rate of the pm1 group was much higher than that of other T3 group (p < 0.01). Conclusions: Both pathological and molecular assessment using aCGH adapted in the current study appeared to have a consistency. Pathological pm1(T3)N0 patients may have a better prognosis than other T3N0 patients., Lung Cancer, 77(2), pp.281-287; 2012

The aim of the present study was to investigate chromosomal aberrations in sporadic Japanese papillary thyroid carcinomas (PTCs), concomitant with the analysis of oncogene mutational status. Twenty-five PTCs (11 with BRAF V600E, 4 with RET/PTC1, and 10 without mutation in HRAS, KRAS, NRAS, BRAF, RET/PTC1, or RET/PTC3) were analyzed using Genome-Wide Human SNP Array 6.0 which allows us to detect copy number alteration (CNA) and uniparental disomy (UPD), also referred to as copy neutral loss of heterozygosity, in a single experiment. The Japanese PTCs showed relatively stable karyotypes. Seven cases (28%) showed CNA(s), and 6 (24%) showed UPD(s). Interestingly, CNA and UPD were rarely overlapped in the same tumor; the only one advanced case showed both CNA and UPD with a highly complex karyotype. Thirteen (52%) showed neither CNA nor UPD. Regarding CNA, deletions tended to be more frequent than amplifications. The most frequent and recurrent region was the deletion in chromosome 22; however, it was found in only 4 cases (16%). The degree of genomic instability did not depend on the oncogene status. However, in oncogene-positive cases (BRAF V600E and RET/PTC1), tumors with CNA/UPD were less frequent (5/15, 33%), whereas tumors with CNA/UPD were more frequent in oncogene-negative cases (7/10, 70%), suggesting that chromosomal aberrations may play a role in the development of PTC, especially in oncogene-negative tumors. These data suggest that Japanese PTCs may be classified into three distinct groups: CNA +, UPD +, and no chromosomal aberrations. BRAF V600E mutational status did not correlate with any parameters of chromosomal defects., PLoS ONE, 7(4), e36063; 2012

The recent development of high-resolution DNA microarrays, in which hundreds of thousands of single nucleotide polymorphisms (SNPs) are genotyped, enables the rapid identification of susceptibility genes for complex diseases. Clusters of these SNPs may show runs of homozygosity (ROHs) that can be analyzed for association with disease. An analysis of patients whose parents were first cousins enables the search for autozygous segments in their offspring. Here, using the Affymetrix® Genome-Wide Human SNP Array 5.0 to determine ROHs, we genotyped 9 individuals with schizophrenia (SCZ) whose parents were first cousins. We identified overlapping ROHs on chromosomes 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 19, 20, and 21 in at least 3 individuals. Only the locus on chromosome 5 has been reported previously. The ROHs on chromosome 5q23.3-q31.1 include the candidate genes histidine triad nucleotide binding protein 1 (HINT1) and acyl-CoA synthetase long-chain family member 6 (ACSL6). Other overlapping ROHs may contain novel rare recessive variants that affect SCZ specifically in our samples, given the highly heterozygous nature of SCZ. Analysis of patients whose parents are first cousins may provide new insights for the genetic analysis of psychiatric diseases., PLoS One, 6(5), e20589; 2011

BACKGROUND: In bioinformatics projects, scientific workflow systems are widely used to manage computational procedures. Full-featured workflow systems have been proposed to fulfil the demand for workflow management. However, such systems tend to be over-weighted for actual bioinformatics practices. We realize that quick deployment of cutting-edge software implementing advanced algorithms and data formats, and continuous adaptation to changes in computational resources and the environment are often prioritized in scientific workflow management. These features have a greater affinity with the agile software development method through iterative development phases after trial and error.Here, we show the application of a scientific workflow system Pwrake to bioinformatics workflows. Pwrake is a parallel workflow extension of Ruby's standard build tool Rake, the flexibility of which has been demonstrated in the astronomy domain. Therefore, we hypothesize that Pwrake also has advantages in actual bioinformatics workflows. FINDINGS: We implemented the Pwrake workflows to process next generation sequencing data using the Genomic Analysis Toolkit (GATK) and Dindel. GATK and Dindel workflows are typical examples of sequential and parallel workflows, respectively. We found that in practice, actual scientific workflow development iterates over two phases, the workflow definition phase and the parameter adjustment phase. We introduced separate workflow definitions to help focus on each of the two developmental phases, as well as helper methods to simplify the descriptions. This approach increased iterative development efficiency. Moreover, we implemented combined workflows to demonstrate modularity of the GATK and Dindel workflows. CONCLUSIONS: Pwrake enables agile management of scientific workflows in the bioinformatics domain. The internal domain specific language design built on Ruby gives the flexibility of rakefiles for writing scientific workflows. Furthermore, re, BMC Research Notes, 4, 331; 2011

Cleft of the soft palate (CSP) and the hard palate (CHP) are subtypes of cleft palate. Patients with either condition often have difficulty with speech and swallowing. Nonsyndromic, cleft palate isolated has been reported to be associated with several genes, but to our knowledge there have been no detailed genetic investigations of CSP. We performed a genome-wide linkage analysis using an SNP-based microarray platform and successively using microsatellite markers in a family where six members, across three successive generations, had CSP. A maximum LOD score of 2.408 was obtained at 2p24.2-24.1 and 2p21-p12, assuming autosomal dominant inheritance. Our results suggest that either of these regions is responsible for this type of CSP.

BACKGROUND: Two types of cerumen occur in humans: the wet type with brownish, sticky earwax, and the dry type with a lack of or reduced ceruminous secretion. The wet type is common in populations of European and African origin, while the dry type is frequently seen in Eastern Asian populations. An association between axillary odor and the wet-type earwax was first identified approximately 70 years ago. The data were based on a phenotypical analysis of the two phenotypes among the Japanese by a researcher or by self-declaration of the subjects examined, and were not obtained using definite diagnostic methods. Recently, we identified a single-nucleotide polymorphism (SNP; rs17822931) of the ABCC11 gene as the determinant of the earwax types. In the present study, to determine whether the SNP can serve as a diagnostic marker for axillary osmidrosis (AO), we examined genotypes at rs17822931 in 79 Japanese AO individuals. AO was defined here as a clinical condition of individuals with a deep anxiety regarding axillary odor and had undergone the removal of bilateral axillary apocrine glands. RESULTS: A comparison of the frequencies of genotypes at rs17822931 in the 79 AO individuals and in 161 Japanese from the general population showed that AO was strongly associated with the wet earwax genotype. A total of 78 (98.7%) of 79 AO patients had either the GG or GA genotype, while these genotypes were observed in 35.4% (57/161) of the subjects from the general population (p < 1.1 x 10(-24), by Fisher's exact test). CONCLUSION: The strong association between the wet-earwax associated ABCC11-genotypes (GG and GA) and AO identified in this study indicates that the genotypes are good markers for the diagnosis of AO. In addition, these results suggest that having the allele G is a prerequisite for the axillary odor expression. In other words, the ABCC11 protein may play a role in the excretory function of the axillary apocrine gland. Together, these results suggest that when an AO, BMC Genetics, 10, 42; 2009

The Kabuki syndrome (KS, OMIM 147920), also known as the Niikawa-Kuroki syndrome, is a multiple congenital anomaly/mental retardation syndrome characterized by a distinct facial appearance. The cause of KS has been unidentified, even by whole-genome scan with array comparative genomic hybridization (CGH). In recent years, high-resolution oligonucleotide array technologies have enabled us to detect fine copy number alterations. In 17 patients with KS, molecular karyotyping was carried out with GeneChip 250K NspI array (Affymetrix) and Copy Number Analyser for GeneChip (CNAG). It showed seven copy number alterations, three deleted regions and four duplicated regions among the patients, with the exception of registered copy number variants (CNVs). Among the seven loci, only the region of 9q21.11-q21.12 ( approximately 1.27 Mb) involved coding genes, namely, transient receptor potential cation channel, subfamily M, member 3 (TRPM3), Kruppel-like factor 9 (KLF9), structural maintenance of chromosomes protein 5 (SMC5) and MAM domain containing 2 (MAMDC2). Mutation screening for the genes detected 10 base substitutions consisting of seven single-nucleotide polymorphisms (SNPs) and three silent mutations in 41 patients with KS. Our study could not show the causative genes for KS, but the locus of 9q21.11-q21.12, in association with a cleft palate, may contribute to the manifestation of KS in the patient. As various platforms on oligonucleotide arrays have been developed, higher resolution platforms will need to be applied to search tiny genomic rearrangements in patients with KS.Journal of Human Genetics (2009) 54, 304-309; doi:10.1038/jhg.2009.30; published online 03 April 2009., Journal of Human Genetics (2009) 54, 304?309

Journal of Medical Genetics, 45(7), pp.479-480; 2008

Kabuki (Niikawa-Kuroki) syndrome (KS) is a multiple congenital anomaly/mental retardation (MCA/MR) syndrome characterized by long palpebral fissures with eversion of the lower eyelids, skeletal anomalies, persistence of fingerpads, short stature, joint laxity, and occasional immune abnormalities. Previous molecular cytogenetic approaches including fluorescence in situ hybridization and whole-genome CGH microarray analysis failed to find copy-number changes in the genome of KS patients. Recently, germline mutations in PTPN11/KRAS/SOS1/RAF1, HRAS, and KRAS/BRAF/MEK1/MEK2 were shown to be causes of Noonan syndrome, Costello syndrome and cardio-facio-cutaneous syndrome, respectively. Since KS patients share some phenotypical manifestations with the syndromes above, we hypothesized that KS may be associated with mutations in genes involving the RAS-MAPK pathway. Sixteen genes (PTPN11, GRB2, SOS1, HRAS, ERAS, NRAS, KRAS, ARAF, BRAF, RAF1, MEK1, MEK2, RASA1, RASA2, RASA3, and RASA4) in the pathway were screened for mutations. DNA from 30 KS patients (14 females and 16 males) was sequenced for entire coding regions and splice junctions of the 16 genes. We identified 29 base substitutions in the genes, including 9 nonsynonymous changes, 18 synonymous changes, one in 5’ untranslated region and one at position “-4” in splice acceptor site. But they were almost all confirmed as SNPs listed in the NCBI database or found in 82-89 normal Japanese individuals, while two of them were rare variants with nonsynonymous changes., American journal of medical genetics. Part A, 146A(14), pp.1893-1896; 2009