Periodicity of SNP distribution around transcription start sites

BACKGROUND: Several millions single nucleotide polymorphisms (SNPs) have already been collected and deposited in public databases and these are important resources not only for use as markers to identify disease-associated genes, but also to understand the mechanisms that underlie the genome diversification. RESULTS: A spectrum analysis of SNP density distribution in the genomic regions around transcription start sites (TSSs) revealed a remarkable periodicity of 146 nucleotides. This periodicity was observed in the regions that were associated with CpG islands (CGIs), but not in the regions without CpG islands (nonCGIs). An analysis of the sequence divergence of the same genomic regions between humans and chimpanzees also revealed a similar periodical pattern in CGI. The occurrences of any mono- or di-nucleotide sequences in these regions did not reveal such a periodicity, thus indicating that an interpretation of this periodicity solely based on the sequence-dependent susceptibility to mutation is highly unlikely. CONCLUSION: The periodical patterns of nucleotide variability suggest the location of nucleosomes that are phased at TSS, and can be viewed as the genetic footprint of the chromatin state that has been maintained throughout mammalian evolutionary history. The results suggest the possible involvement of the nucleosome structure in the promoter function, and also a fundamental functional/structural difference between the two promoter classes, i.e., those with and without CGIs

HERG遺伝子変異に伴う遺伝性QT延長症候群の分子遺伝学的研究

取得学位：博士(医学), 学位授与番号：医博甲第1466号, 学位授与年月日：平成13年3月31日, 学位授与年：200

Evaluation of Haplotype Inference Using Definitive Haplotype Data Obtained from Complete Hydatidiform Moles, and Its Significance for the Analyses of Positively Selected Regions

The haplotype map constructed by the HapMap Project is a valuable resource in the genetic studies of disease genes, population structure, and evolution. In the Project, Caucasian and African haplotypes are fairly accurately inferred, based mainly on the rules of Mendelian inheritance using the genotypes of trios. However, the Asian haplotypes are inferred from the genotypes of unrelated individuals based on population genetics, and are less accurate. Thus, the effects of this inaccuracy on downstream analyses needs to be assessed. We determined true Japanese haplotypes by genotyping 100 complete hydatidiform moles (CHM), each carrying a genome derived from a single sperm, using Affymetrix 500 K Arrays. We then assessed how inferred haplotypes can differ from true haplotypes, by phasing pseudo-individualized true haplotypes using the programs PHASE, fastPHASE, and Beagle. We found that, at various genomic regions, especially the MHC locus, the expansion of extended haplotype homozygosity (EHH), which is a measure of positive selection, is obscured when inferred Asian haplotype data is used to detect the expansion. We then mapped the genome using a new statistic, XDiHH, which directly detects the difference between the true and inferred haplotypes, in the determination of EHH expansion. We also show that the true haplotype data presented here is useful to assess and improve the accuracy of phasing of Asian genotypes

Polymorphic ventricular tachycardia in a patient with hypertrophic cardiomyopathy and digitalis intoxication

SummaryWe report the case of a 74-year-old woman who presented with recurrent episodes of polymorphic ventricular tachycardia (PVT) with a normal QT interval due to digitalis intoxication (serum digoxin concentration, 5.0 ng/mL) and severe hyperkalemia (serum potassium level, 8.3 mEq/L). In addition, laboratory data showed elevated levels of blood urea nitrogen (54 mg/dL) and serum creatinine (1.57 mg/dL), suggesting dehydration. She had been treated with a combination of digoxin and eplerenone for atrial fibrillation and heart failure. The PVT resolved after treatment for hyperkalemia. Cardiac magnetic resonance imaging and left ventriculography showed left ventricular hypertrophy predominantly in the apex, suggesting apical hypertrophic cardiomyopathy (HCM). We presume that the presence of HCM was related to the occurrence of PVT in this patient with digitalis intoxication and hyperkalemia.<Learning objective: PVT with a normal QT interval caused by digitalis intoxication with hyperkalemia was observed in a patient with HCM treated with digoxin and eplerenone for atrial fibrillation and heart failure. The presence of HCM may be related to the occurrence of PVT. Combination therapy with digoxin and aldosterone receptor antagonist may predispose severe hyperkalemia, and monitoring of serum digitalis concentration and potassium level should be done strictly.

Non-synonymous single-nucleotide variations of the human oxytocin receptor gene and autism spectrum disorders: a case-control study in a Japanese population and functional analysis.

Background: The human oxytocin receptor (hOXTR) is implicated in the etiology of autism spectrum disorders (ASDs) and is a potential target for therapeutic intervention. Several studies have reported single-nucleotide polymorphisms (SNPs) of the OXTR gene associated with ASDs. These SNPs, however, reside outside the protein-coding region. Not much is known about genetic variations that cause amino acid substitutions that alter receptor functions. Methods. Variations in the OXTR gene were analyzed in 132 ASD patients at Kanazawa University Hospital in Japan and 248 unrelated healthy Japanese volunteers by re-sequencing and real-time polymerase chain reaction-based genotyping. Functional changes in variant OXTRs were assessed by radioligand binding assay and measurements of intracellular free calcium concentrations ([Ca§ssup§2+§esup§]§ssub§i§esub§) and inositol 1,4,5-trisphosphate (IP§ssub§3§esub§) levels. Results: Six subjects (4.5%) in the ASD group and two in the control group (0.8%) were identified as heterozygotes carrying the R376G variation (rs35062132; c.1126C>G); one individual from the ASD group (0.8%) and three members of the control group (1.2%) were found to be carrying R376C (c.1126C>T). The C/G genotype significantly correlated with an increased risk of ASDs (odds ratio (OR) = 5.83; 95% confidence interval (CI) = 1.16 to 29.33; P = 0.024, Fisher\u27s exact test). Consistently, the G allele showed a correlation with an increased likelihood of ASDs (OR = 5.73; 95% CI = 1.15 to 28.61; P = 0.024, Fisher\u27s exact test). The frequencies of the C/T genotype and the T allele in the ASD and control groups did not differ significantly. We also examined changes in agonist-induced cellular responses mediated by the variant receptors hOXTR-376G and hOXTR-376C. OXT-induced receptor internalization and recycling were faster in hOXTR-376G-expressing HEK-293 cells than in cells expressing hOXTR-376R or hOXTR-376C. In addition, the elevation in [Ca§ssup§2+§esup§]§ssub§i§esub§ and IP§ssub§3§esub§ formation decreased in the cells expressing hOXTR-376G and hOXTR-376C tagged with enhanced green fluorescent protein (EGFP), in comparison with the cells expressing the common-type hOXTR-376R tagged with EGFP. Conclusions: These results suggest that the rare genetic variation rs35062132 might contribute to the pathogenesis of ASDs, and could provide a molecular basis of individual differences in OXTR-mediated modulation of social behavior. © 2013 Ma et al.; licensee BioMed Central Ltd