The 83rd In Silico Megabank Research Seminar will be held on Tuesday, September 19. This Time, we will be welcoming Dr. Daron Standley, Osaka University as our lecturer, and he will be speaking on “Quantifying structural and functional convergence in immune cell repertoires”. 

・Date/Time: September 19(Tuesday) 5:00‐6:30 pm 
・Venue: Small Conference Room 2(3rd Floor), Tohoku Medical Megabank Building  
・Title: Quantifying structural and functional convergence in immune cell repertoires 
・Lecturer: Daron Standley（Research Institute for Microbial Diseases, Osaka University）

＊This lecture is transferable as a class in the medical research-related lecture course. 

・Abstract: It is well established that protein structure is more conserved than sequence on an evolutionary timescale.  This fact allows functional inferences to be drawn from proteins that share the same fold, even when their sequence similarity is quite low. In the case of B cell receptors, the relationships between sequence and structure and function are more complex. Most BCRs look similar globally but differ in the details of their antigen-binding regions. These differences are due to the fact that each BCR is assembled from a patchwork of genes, which are combined randomly and can be further diverged by random mutations upon antigen encounter. Traditionally, bioinformatics analysis of BCR sequences involves clustering those that arise from the same genes into “lineages”, in order to identify BCRs in a given donor that target a common antigen.  The diversity of BCRs has been estimated to exceed 10¹³ in humans, which means that it is very unlikely that any two donors will display the same repertoire of BCRs, even after exposure to the same antigen. Nevertheless, x-ray crystallographic studies have demonstrated that structurally and sequentially similar BCRs targeting common antigens can arise in different donors using different genes. Our hypothesis is that clusters of BCRs targeting the same antigen are more likely to have sequence and structural features in common than BCRs targeting different antigens. High-throughput sequencing methodologies can now deliver paired (heavy-light chain) sequence datasets on the order of 10⁴  sequences per experiment, and are expected to improve rapidly in the near future. Clearly, x-ray crystallography will not be able to cope with so many emerging BCR sequences in a high-throughput manner. Thus, there is a strong motivation to leverage structural bioinformatics in order to infer structure and functional similarities. In this presentation, I will show results from our high-throughput BCR and TCR structural modeling platform (Si Repertoire Builder). Using multiple alignment and 3D rendering methods developed in our lab, we could reduce the time required to build an atomic-resolution BCR model to just seconds, corresponding to over 17,000 atomic resolution models per day on a single CPU. We then show that human BCRs acquired post flu vaccination display strong structural convergence, and even exhibit structural similarities to BCRs acquired from vaccinated mice. These findings suggest that BCR modeling, in combination with high-throughput sequencing may be able to identify diverse sequences targeting common antigens across donors and across species.  

・Organizer: Shunsuke Teraguchi, Masao Nagasaki

Professor Nagasaki will invited lecture at the IEICE Technical Committee Submission System on July 7

・Date: 13:15, July 7 (Fri), 2017
・Venue: Hitotsubashi Hall

IEICE Technical Committee Submission SystemAdvance Program

Professor Nagasaki will give a lecture at the 12th International Workshop on Advanced Genomics on June 27.

・Date: 11:00, June 27 (Tue), 2017
・Venue: Hitotsubashi Hall
・Session & Theme: Session 1 Population Genomics
・Title: The TMM150K Genome Cohort Project: Progress of Genome Information Analysis and Future

http://gt164.jpn.org/12agw/program.html

The 82nd In Silico Megabank Research Seminar will be held on Friday, February 10.

This Time, we will be welcoming Dr. Alexis Vandenbon, Osaka University Immunology Frontier Research Center as our lecturer, and he will be speaking on “Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system ”. 

・Date/Time: February 10(Friday) 5:00‐6:30 pm
・Venue: Small Conference Room 2(3rd Floor), Tohoku Medical Megabank Building 
 ・Title: Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system
・Lecturer: Alexis Vandenbon（Osaka University Immunology Frontier Research Center ）

 ＊This lecture is transferable as a class in the medical research-related lecture course.

・Abstract: Large amounts of experimental data available in public databases contain an enormous potential for elucidating gene regulatory interactions. However, in practice it is difficult to extract new knowledge or hypotheses from such data. One obstacle is the study-specific biases or batch effects that are present in the original data. Although gene coexpression is often used for inferring biological networks, how batch effects influence such networks is not well studied. Here, we prepared a large collection of gene expression data for 24 cell types of the mouse immune system. We found widespread batch effects in this data, and showed that they strongly affect gene coexpression estimates. Removal of batch effects considerably improved the consistency between inferred correlations and prior knowledge. Using the processed data, we constructed Immuno-Navigator, a batch-corrected gene coexpression database. Using our database, we generated hypotheses about candidate regulators in specific immune cells. In one application we successfully predicted known regulators of importance in naturally occurring Treg cells from their expression correlation with a set of Treg-specific genes. For one high-scoring gene, integrin β8 (Itgb8), we experimentally confirmed an association between Itgb8 expression and Treg-specific epigenetic remodelling. We believe that Immuno-Navigator (sysimm.ifrec.osaka-u.ac.jp/immuno-navigator/) will be of great use for generating hypotheses for specific cell types in studies of the immune system.  

・Organizer: Shunsuke Teraguchi, Masao Nagasaki

The 81st In Silico Megabank Research Seminar will be held on Thursday, February 2, 2017. This Time, we will be welcoming Professor Fumio Tajima, Graduate School of Science, The University of Tokyo as our lecturer, and he will be speaking on “A mathematical theory related to genetic variations at DNA-level ”.

・Date/Time: February 2 (Thursday) 3:30 pm‐5:00 pm
・Venue: Small Conference Room 2(3rd Floor), Tohoku Medical Megabank Building    http://www.megabank.tohoku.ac.jp/english/access/ 
・Title: A mathematical theory related to genetic variations at DNA-level
・Lecturer: Fumio Tajima（Department of Biological Sciences, Graduate School of Science, The University of Tokyo） 

＊This lecture is transferable as a class in the medical research-related lecture course.  

・Abstract: Genetic variation within a population is maintained over time. Several decades ago, genetic variations were detected by the genetic polymorphism of blood group and proteins, but nowadays they are detected as DNA polymorphism by DNA sequencing. Natural selection and neutral theory have been proposed as the maintenance mechanism for genetic variations. The amount and patterns of genetic variations are determined by various factors such as the size of the population, mutation rate, natural selection, and group structure. Can we deduce the factors from the amount and the patterns of the genetic variations observed? This is a very important question.  In order to do so, the establishment of a statistical approach and mathematical theory for the analysis of the observation results is essential.  In this seminar, based on the research I have conducted until today, I will introduce the amount and patterns of genetic variations (DNA polymorphism) at DNA level which is expected to be detected in a simple model. 

・Organizer: Kazuharu Misawa, Masao Nagasaki

The 80th In Silico Megabank Research Seminar will be held on Friday, January 13, 2017. This Time, we will be welcoming Dr. Shigehiro Kuraku, RIKEN Center for Life Science Technologies as our lecturer, and he will be speaking on “Examination on the origin of human genome using developmental control gene phylome of vertebrate as a clue”.

・Date/Time: January 13 (Friday) 5:00 pm‐6:30 pm
・Venue: Small Conference Room 2(3rd Floor), Tohoku Medical Megabank Building 
・Title: Examination on the origin of human genome using developmental control gene phylome of vertebrate as a clue
・Lecturer: Shigehiro Kuraku（RIKEN Center for Life Science Technologies）  

＊This lecture is transferable as a class in the medical research-related lecture course.  

・Abstract: Combined with the fact that the possibility of omics analysis for non-model organisms has largely expanded, genome-wide perspectives and data-driven approach have enabled discussion on the relationship between molecular evolution and phenotypic evolution in a big picture. I have conducted interspecific comparison of the developmental control gene patterns among vertebrates from the aspects of molecular phylogenetics and genome informatics. In the process, I have found some cases that have spread after becoming too simplified in basic knowledge on EvoDevo such as storability of so-called “tool kit genes.” For example, Pax6 gene which is the vertebrate ortholog of eyeless gene in drosophila has sister genes of Pax4 and Pax10 doubled through 2R genome duplication. Not much attention has pained to these genes. 
In addition to the above genes that have been “forgotten,” I have found Bmp16, Hox14, FoxG2, and FoxG3. The main reason that these genes have been “forgotten” is that these disappeared independently from multiple strains, and they possess other common characteristics such that the speed of the evolution of sequences is fast and their expression appears to be more restricted to some areas. What enabled the finding of these “forgotten” genes was the genomic information of organisms belonging to certain strains of vertebrates such as cartilaginous fishes that diverged at relatively early stage of evolution. I am currently organizing genomic information of various species at my laboratory. In this seminar, technological aspects of genomic sequencing as well as evaluation of completeness of genomic sequences of non-human vertebrates are introduced. Additionally, a new hypothesis on the evolution of human genome based on the analysis of the above “forgotten” genes is discussed.  

・Organizer: Tomoko Shibata, Kazuharu Misawa, Masao Nagasaki

The 78th In Silico Megabank Research Seminar will be held on Thursday, November 16, 2016.

This Time, we will be welcoming Dr. Masashi Mizokami, Research Institute, National Center for Global Health and Medicine as our lecturer, and he will be speaking on “Examination of host factors for Hepatitis B virus infectious disease”.

・Date/Time: November 16 (Thursday) 6:30 pm‐7:30 pm
・Venue: Conference Room(3rd Floor), Tohoku Medical Megabank Building
・Title: Examination of host factors for Hepatitis B virus infectious disease
・Lecturer: Masashi Mizokami（Research Institute, National Center for Global Health and Medicine） 

・Abstract: Liver cancer is the fourth leading cause of death from cancer in Japan, and 70% of the incidence of liver cancer is attributable to Hepatitis B virus (HBV) and Hepatitis C virus (HCV). Moreover, according of WHO, it is globally the seventh leading cause of death from cancer, meaning that it is a significant worldwide public health issue. For HCV, recent advancement of treatment has steadily decreased the number of liver cancer caused by HCV; it is expected that it will be rare disease by 2030. However, the situation with HBV-related cancers is different. Current treatment can only inhibit the growth of HBV, and the prospects for the clearance of HBV, which is the basic remedy, are still far from certain. In general, the pathology of infectious diseases is determined by the interaction of causative pathogens and infected individuals. However, only the viral factor has been examined for HBV-infected patients because there is technological difficulty to examine the interaction although it has been revealed that about 90% of HBV-infected individuals have no symptoms in their lifetime whereas about 10% of HBV-infected individuals develop liver cancer. Despite research effort, no difference has been found between the HBV-infected individuals without subjective symptoms in their lifetime and with cancer progression.
Thus, we collected genome and serum of 3500 samples whose clinical data were entered by nationwide specialized medical clinics for liver. These clinics had already completed various procedures such as IRB in the past 10 years. From the aspect of viral factors, we are currently conducting GWAS for HBVDNA sequencing and host factors. As research grant was provided to us by AMED, we would like to further reveal detailed host factors from joint research with ToMMo. Therefore, in this seminar, I would like to introduce the current situation and issues associated with HBV study and discuss the possibility for joint research with ToMMo. 

・Organizer: Masao Nagasaki

The 77th In Silico Megabank Research Seminar will be held on Thursday, November 10. This Time, we will be welcoming Dr. Koji Yahara, National Institute of Infectious Diseases as our lecturer, and he will be speaking on “Method to infer the tracemarks of recombination and population structure and its application based on genome data”.

・Date/Time: November 10 (Thursday) 5:00 pm‐6:30 pm
・Venue: Conference Room 2 (1st Floor), Building #6, Tohoku University School of Medicine
・Title: Method to infer the tracemarks of recombination and population structure and its application based on genome data
・Lecturer: Koji Yahara (National Institute of Infectious Diseases)

＊This lecture is transferable as a class in the medical research-related lecture course.

・Abstract: Mutation and recombination are the source of adaptive revolution of creatures which cause genomic diversity. Mutation rate is known to be high in certain regions within genome, and its relation with diseases is drawing attention. On the contrary, recombination is more difficult to detect than mutation. Especially, it is difficult to estimate the number of its occurrence. In the first half of this seminar, we will calculate the index of recombination rate at single nucleotide level along genome using genome data in bacterial genome and introduce new approach to infer recombination “hot regions” and its application to 11 types of pathogenic bacteria. In the latter half, the estimate of population structure which should be done at the very first of the process of population-level genome data analysis is to be discussed. Also, it is introduced that the as the first step method to detect the tracemarks of genome-wide recombination reveals the detailed population structure and also the method is useful to quantitatively understand the flow of genome information between populations.

・Organizer: Yosuke Kawai, Masao Nagasaki

Professor Nagasaki will give a lecture at the 23rd Annual Meeting of the Japanese Society Gene Diagnosis and Therapy on October 7

・Date: October 7 (Friday)
・Venue: Iino Hall & Conference Center
・Session&Thema: Symposium3 “Basics of Genome Statistics and its Clinical Application”
・Title: 日本人2049人の全ゲノムリファレンスパネルの構築と今後

The 75th In Silico Megabank Research Seminar will be held on Friday, September 2.

This Time, we will be welcoming Dr. Makoto Shimada, Fujita Health University as our lecturer, and he will be speaking on “Explore the relationship between triplet repeat disease and human revolution through selective pressure for human STR sequence ”.

・Date/Time: September 2 (Friday) 5:00 pm‐6:30 pm
・Venue: Small Conference Room 2(3rd Floor), Tohoku Medical Megabank Building 
・Title: Explore the relationship between triplet repeat disease and human revolution through selective pressure for human STR sequence
・Lecturer: Makoto Shimada (Institute for Comprehensive Medical Science, Fujita Health University)

＊This lecture is transferable as a class in the medical research-related lecture course.

・Abstract: In STR (Short Tandem Repeat), repeating sequences of very short base segments, the number of tandem repeats changes very frequently. Thus, there has been a hypothesis that adaptive trait and evolutionary stable state were quickly established using the high variability of the number of tandem repeat. On the contrary, human STR sequence is known to have multiple repetitive sequences which are the cause of neurodegenerative diseases. However, why such dangerous repetitive sequences are maintained among human population is not yet known well. We have identified the number of the STR repetition and repeat polymorphism within human genome by integrating information of polymorphism into H-invDB, the genetic database that we developed and released to the public. Furthermore, we evaluated the selective pressure for each STR through intercomparison. The result showed that repetitive amino-acid sequences were formed in STR in amino acid coding regions due to 2 mechanisms each of which are represented by proline repeats and glutamine repeats while keeping the repeats short at the DNA sequencing level.. Moreover, it was revealed that glutamine repeats have a tendency to have longer repeats at amino-acid level and that especially the repeat polymorphism exists in the genes related to the regulation of the generation of nervous system and brain. These results suggest the possibility that polymorphism of these repeats facilitated the diversification of the functions related to the regulation of the generation of nervous system and brain. In our article, we have further argued the relationship between the evolution of sociality throughout human evolution and the switch function for the regulation of STR neural development.

・Organizer: Yosuke Kawai, Kazuharu Misawa, Masao Nagasaki