Biology subjects

Hayashi, S.

Publications and source records attributed to Hayashi, S..

5 recordsLinked to original sources

bioRxiv2018

Nanopore formation in the cuticle of the insect olfactory sensillum

Insects sense odorants through small (50-200-nm diameter) pores in the cuticle covering the olfactory sensilla. These nanopores serve as a filter, preventing the entry of larger airborne particles and limiting water loss. Here we show that the nanopores in Drosophila originate from a curved ultrathin film formed in the outermost layer of the cuticle, secreted from specialized plasma membrane protrusions. The gore-tex/Osiris23 gene, encoding an endosomal protein, is required for nanopore formation and odor receptivity, and is expressed specifically in developing olfactory shaft cells. The 24-member Osiris gene family is expressed in various cuticle-secreting cells, and is found only in insect genomes. Some Osiris mutants show defective cuticle-associated functions, suggesting that Osiris genes may provide a platform for investigating functional surface nano-fabrication in insects.\n\nOne Sentence SummaryAn insect-specific endosomal protein promotes the formation of nano-scale pore structures of the apical extracellular matrix.

developmental biology↗

bioRxiv2018

ALPHLARD: a Bayesian method for analyzing HLA genes from whole genome sequence data

Although human leukocyte antigen (HLA) genotyping based on amplicon, whole exome sequence (WES), and RNA sequence data has been achieved in recent years, accurate genotyping from whole genome sequence (WGS) data remains a challenge due to the low depth. Furthermore, there is no method to identify the sequences of unknown HLA types not registered in HLA databases. We developed a Bayesian model, called ALPHLARD, that collects reads potentially generated from HLA genes and accurately determines a pair of HLA types for each of HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, and -DRB1 genes at 6-digit resolution. Furthermore, ALPHLARD can detect rare germline variants not stored in HLA databases and call somatic mutations from paired normal and tumor sequence data. We illustrate the capability of ALPHLARD using 253 WES data and 25 WGS data from Illumina platforms. By comparing the results of HLA genotyping from SBT and amplicon sequencing methods, ALPHLARD achieved 98.8% for WES data and 98.5% for WGS data at 4-digit resolution. We also detected three somatic point mutations and one case of loss of heterozygosity in the HLA genes from the WGS data. ALPHLARD showed good performance for HLA genotyping even from low-coverage data. It also has a potential to detect rare germline variants and somatic mutations in HLA genes. It would help to fill in the current gaps in HLA reference databases and unveil the immunological significance of somatic mutations identified in HLA genes.

bioinformatics↗

bioRxiv2018

Immuno-genomic PanCancer Landscape Reveals Diverse Immune Escape Mechanisms and Immuno-Editing Histories

Immune reactions in the tumor micro-environment are one of the cancer hallmarks and emerging immune therapies have been proven effective in many types of cancer. To investigate cancer genome-immune interactions and the role of immuno-editing or immune escape mechanisms in cancer development, we analyzed 2,834 whole genomes and RNA-seq datasets across 31 distinct tumor types from the PanCancer Analysis of Whole Genomes (PCAWG) project with respect to key immuno-genomic aspects. We show that selective copy number changes in immune-related genes could contribute to immune escape. Furthermore, we developed an index of the immuno-editing history of each tumor sample based on the information of mutations in exonic regions and pseudogenes. Our immuno-genomic analyses of pan-cancer analyses have the potential to identify a subset of tumors with immunogenicity and diverse background or intrinsic pathways associated with their immune status and immuno-editing history.

genomics↗

bioRxiv2017

Quantifying Immune-Based Counterselection of Somatic Mutations

It is now well established that somatic mutations in protein-coding regions can generate neoantigens, and that these can be recognized by the immune system and contribute to clearance of developing cancers. However, there is currently no model that can quantitatively predict the neoantigenic effect of any given somatic mutation. Here, we examined signatures of immune selection pressure on the distribution of somatic mutations. We quantified the extent to which somatic mutations are significantly depleted in peptides that are predicted to be displayed by major histocompatibility complex (MHC) class I proteins. We characterized the dependence of this depletion on expression level. We then examined whether immune selection pressure on somatic mutations changes depending on whether the patient had either one or two MHC-encoding alleles that can display the peptide. Our results indicate that MHC-encoding alleles are, in general, incompletely dominant, i.e., that having two copies of the display-enabling allele is more effective in displaying that peptide than having just one copy. More generally, a quantitative understanding of counter-selection of identifiable subclasses of neoantigenic somatic variation could guide immunotherapy or aid in developing personalized cancer vaccines.

genetics↗

bioRxiv2017

Germline determinants of the somatic mutation landscape in 2,642 cancer genomes

Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million germline single nucleotide variants, short insertions/deletions, and large structural variants in whole genomes from 2,642 cancer patients, and employed this genomic resource to study genetic determinants of somatic mutagenesis across 39 cancer types. Our analyses implicate damaging germline variants in a variety of cancer predisposition and DNA damage response genes with specific somatic mutation patterns. Mutations in the MBD4 DNA glycosylase gene showed association with elevated C>T mutagenesis at CpG dinucleotides, a ubiquitous mutational process acting across tissues. Analysis of somatic structural variation exposed complex rearrangement patterns, involving cycles of templated insertions and tandem duplications, in BRCA1-deficient tumours. Genome-wide association analysis implicated common genetic variation at the APOBEC3 gene cluster with reduced basal levels of somatic mutagenesis attributable to APOBEC cytidine deaminases across cancer types. We further inferred over a hundred polymorphic L1/LINE elements with somatic retrotransposition activity in cancer. Our study highlights the major impact of rare and common germline variants on mutational landscapes in cancer.

genomics↗