イデン シンリョウ ノ キホン チシキ ゲンジョウ ト コレカラ ノ テンボウ

In the personal genome sequencing era, genetic medicine using next-generation sequencing will be spread rapidly in the clinical setting. In such a situation, everyone in the society should understand the genetic knowledge of an individual through two aspect, heredity and variation. In addition, health care provider should establish the system to provide the appropriate genetic medicine

ゲノム エピゲノム イジョウ オ シヒョウ トスル ガン ト イデン シッカン カンレン イデンシ タンサク ケンキュウ

Genetic abnormalities/variations contribute to the most of human diseases including cancer and congenital disorders. Advances in tools for human genome analysis, such as genomic arrays and next-generation sequences, based on the information of human genome sequences provided a great opportunity to identify novel causative genes and disease-associated genes through whole exploration of disease-specific abnormalities in the sequence and copy-number levels. Novel target genes for cancer diagnosis and therapy could be identified through combined structural and functional approach for cancer genome using whole genome and epigenome scanning by array and sequencer as well as functional and expression analyses of candidate genes, resulting in the development of novel diagnostic and therapeutic methods useful for the ‘ personalized medicine’

Ancestral Y-linked genes were maintained by translocation to the X and Y chromosomes fused to an autosomal pair in the Okinawa spiny rat Tokudaia muenninki

Two species of the genus Tokudaia lack the Y chromosome and SRY, but several Y-linked genes have been rescued by translocation or transposition to other chromosomes. Tokudaia muenninki is the only species in the genus that maintains the Y owing to sex chromosome-autosome fusions. According to previous studies, many SRY pseudocopies and other Y-linked genes have evolved by excess duplication in this species. Using RNA-seq and RT-PCR, we found that ZFY, EIF2S3Y, TSPY, UTY, DDX3Y, USP9Y, and RBMY, but not UBA1Y, had high deduced amino acid sequence similarity and similar expression patterns with other rodents, suggesting that these genes were functional. Based on FISH and quantitative real-time PCR, all of the genes except for UTY and DDX3Y were amplified on the X and Y chromosomes with approximately 10-66 copies in the male genome. In a comparative analysis of the 372.4-kb BAC sequence and Y-linked gene transcripts from T. muenninki with the mouse Y genomic sequence, we observed that multiple-copy genes in the ancestral Y genome were nonfunctional, indicating that the gene functions were assumed by amplified copies. We also found a LTR sequence at the distal end of a SRY duplication unit, suggesting that unequal sister chromatid exchange mediated by retrotransposable elements could have been involved in SRY amplification. Our results revealed that the Y-linked genes were rescued from degeneration via translocations to other sex chromosomal regions and amplification events in T. muenninki

Novel PTCH1 mutation in Gorlin syndrome

Gorlin syndrome is an autosomal dominant disorder characterized by a wide range of developmental abnormalities and a predisposition to various tumors, and it is linked to the alteration of several causative genes, including PTCH1. We performed targeted resequencing using a next-generation sequencer to analyze genes associated with known clinical phenotypes in an 11-year-old male with sporadic jaw keratocysts. A novel duplication mutation (c.426dup) in PTCH1, resulting in a truncated protein, was identified

Elastin Variants in Two Angiographic PCV Subtypes

Objective To compare the association of elastin (ELN) gene variants between two different angiographic phenotypes of polypoidal choroidal vasculopathy (PCV). Methods We included 411 treatment-naïve PCV patients and 350 controls in the present study. PCV was classified into two phenotypes (152 Type 1 and 259 Type 2) according to the presence or absence of feeding vessels found in indocyanine-green angiography. Single nucleotide polymorphisms (SNPs) in the ELN region including rs868005, rs884843, rs2301995, rs13239907 and rs2856728 were genotyped using TaqMan Genotyping Assays. Results In the allelic association analyses, rs868005 showed the strongest association with Type 2 PCV (allelic odds ratio 1.56; p = 7.4x10-6), while no SNP was significantly associated with Type 1 PCV. Genotype association analyses revealed the significant association of rs868005 with Type 2 PCV in log additive model and predominant model (odds ratio 1.75; p = 1.5x10-6 and odds ratio 1.60; p = 0.0044, respectively), but not with Type 1 PCV. These findings were further corroborated by another control group in the literature. Conclusions There may be significantly different associations in genetic variants of elastin between two angiographic phenotypes of PCV

Novel CLCN7 mutations in IARO

Osteopetrosis is a heritable disorder of the skeleton that is characterized by increased bone density on radiographs caused by defects in osteoclast formation and function. Mutations in >10 genes are identified as causative for this clinically and genetically heterogeneous disease in humans. We report two novel missense variations in a compound heterozygous state in the CLCN7 gene, detected through targeted exome sequencing, in a 15-year-old Japanese female with intermediate autosomal recessive osteopetrosis

Initiation of recombination suppression and PAR formation during the early stages of neo-sex chromosome differentiation in the Okinawa spiny rat, Tokudaia muenninki

Background: Sex chromosomes of extant eutherian species are too ancient to reveal the process that initiated sex-chromosome differentiation. By contrast, the neo-sex chromosomes generated by sex-autosome fusions of recent origin in Tokudaia muenninki are expected to be evolutionarily ‘young’, and therefore provide a good model in which to elucidate the early phases of eutherian sex chromosome evolution. Here we describe the genomic evolution of T. muenninki in neo-sex chromosome differentiation. Results: FISH mapping of a T. muenninki male, using 50 BAC clones as probes, revealed no chromosomal rearrangements between the neo-sex chromosomes. Substitution-direction analysis disclosed that sequence evolution toward GC-richness, which positively correlates with recombination activity, occurred in the peritelomeric regions, but not middle regions of the neo-sex chromosomes. In contrast, the sequence evolution toward AT-richness was observed in those pericentromeric regions. Furthermore, we showed genetic differentiation between the pericentromeric regions as well as an accelerated rate of evolution in the neo-Y region through the detection of male-specific substitutions by gene sequencing in multiple males and females, and each neo-sex–derived BAC sequencing. Conclusions: Our results suggest that recombination has been suppressed in the pericentromeric region of neo-sex chromosomes without chromosome rearrangement, whereas high levels of recombination activity is limited in the peritelomeric region of almost undifferentiated neo-sex chromosomes. We conclude that PAR might have been formed on the peritelomeric region of sex chromosomes as an independent event from spread of recombination suppression during the early stages of sex chromosome differentiation

Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis

Background: The results of meta-analyses conducted by previous association studies between total homocysteine and schizophrenia suggest that an elevated total homocysteine level is a risk factor for schizophrenia. However, observational studies have potential limitations, such as confounding and reverse causation. In the present study, we evaluated a causal relationship between plasma total homocysteine and schizophrenia by conducting a Mendelian randomization analysis. Methods: We used the MTHFR C677T polymorphism as an instrumental variable, which affects the plasma total homocysteine levels. To calculate the risk estimate for the association of this single nucleotide polymorphism (SNP) with schizophrenia, we conducted a meta-analysis of case–control studies that comprise a total of 11,042 patients with schizophrenia and 14,557 control subjects. We obtained an estimate for the association of this SNP with the plasma total homocysteine levels from a meta-analysis of genome-wide association studies comprising 44,147 individuals. Results: By combining these two estimates, we demonstrated a significant effect of the plasma total homocysteine on schizophrenia risk, representing an OR of 2.15 (95 % CI = 1.39–3.32; p = 5.3 x 10−4) for schizophrenia per 1-SD increase in the natural log-transformed plasma total homocysteine levels. Conclusions: We provided evidence of a causal relationship between the plasma total homocysteine and schizophrenia, and this result will add insight into the pathology and treatment of schizophrenia

Current status of collaborative relationships between dialysis facilities and dental facilities in Japan : results of a nationwide survey

Background: Recent studies have reported an association between periodontal disease and mortality among dialysis patients. Therefore, preventive dental care should be considered very important for this population. In Japan, no systematic education has been undertaken regarding the importance of preventive dental care for hemodialysis patients—even though these individuals tend to have oral and dental problems. The aim of this study was to investigate the current state of collaborative relationships between hemodialysis facilities and dental services in Japan and also to identify strategies to encourage preventive dental visits among hemodialysis outpatients. Methods: A nationwide questionnaire on the collaborative relationship between dialysis facilities and dental facilities was sent by mail to all medical facilities in Japan offering outpatient hemodialysis treatment. Results: Responses were obtained from 1414 of 4014 facilities (35.2%). Among the 1414 facilities, 272 (19.2%) had a dental service department. Approximately 100,000 dialysis outpatients were receiving treatment at these participating facilities, which amounts to one-third of all dialysis patients in Japan. Of those patients, 82.9% received hemodialysis at medical facilities without dental departments. Only 87 of 454 small clinics without in-house dental departments (19.2%) had collaborative registered dental clinics. Medical facilities with registered dental clinics demonstrated a significantly more proactive attitude to routine collaboration on dental matters than facilities lacking such clinics. Conclusions: Our nationwide survey revealed that most dialysis facilities in Japan have neither an in-house dental department nor a collaborative relationship with a registered dental clinic. Registration of dental clinics appears to promote collaboration with dental facilities on a routine basis, which would be beneficial for oral health management in hemodialysis patients