Biology subjects

Motegi, T.

Publications and source records attributed to Motegi, T..

4 recordsLinked to original sources

bioRxiv2026

Benchmarking of local ancestry inference with different assays and parameters

Local ancestry inference (LAI) enables high-resolution characterization of chromosomal segments inherited from distinct ancestral populations, offering unique insights into genetic architecture in admixed cohorts. While LAI is commonly performed with high-coverage whole-genome sequencing (WGS), the ability of other genotyping assays or varying sequencing depths has not been thoroughly benchmarked. In this study, we systematically evaluated the accuracy of LAI across SNP microarrays, whole-exome sequencing (WES), and ultra low-pass WGS (ULP-WGS) using diverse validation samples and state-of-the-art imputation pipelines. We show that ULP-WGS, when paired with GLIMPSE2, achieves robust accuracy at 0.25x coverage with a minimum genome window size of 0.5 centimorgans, with mean accuracy minus one standard deviation exceeding 95%. For WES, using "on-target" reads alone yields suboptimal performance, particularly for European and South Asian ancestries with accuracy less than 79.1% and 70.6%, respectively. However, incorporating "off-target" reads in WES and utilizing GLIMPSE2 substantially improved accuracy [≥]95% with a minimum window size of 0.2 centimorgans. We further evaluated formalin-fixed, paraffin-embedded (FFPE) samples and found that LAI could be performed successfully using WES data with accuracies of [≥]95% at a minimum window size of 0.5 centimorgans. In contrast, SNP microarrays did not achieve substantial accuracies at any window size ([≤]95%). Together, these results demonstrate that LAI is achievable without conventional high-coverage WGS and establish optimal parameters for LAI across platforms.

genomics↗

bioRxiv2025

The caninized anti-canine PD-1 monoclonal antibody in canine oral malignant melanoma: Efficacy and exploratory biomarker analysis

BackgroundCanine oral malignant melanoma (OMM) is a highly aggressive tumor with few treatment options. Because of its biological similarity to human mucosal melanoma, canine OMM represents a valuable spontaneous model for translational immunotherapy studies. Anti-PD-1 antibody therapy has shown promise in canine OMM; however, predictive biomarkers for treatment response and survival have not been identified. MethodsWe conducted a multicenter, prospective, investigator-initiated clinical trial to evaluate the safety and efficacy of a caninized anti-canine PD-1 monoclonal antibody (ca-4F12-E6) in 150 dogs with advanced OMM. The dogs were administered 3 mg/kg ca-4F12-E6 intravenously every two weeks. Treatment response was assessed using cRECIST v1.0. Biomarker analyses included peripheral blood parameters, cytokine/chemokines, peripheral lymphocyte subsets, microsatellite instability (MSI), immunohistochemistry for immune cell and mismatch repair protein markers, and RNA sequencing of the tumor tissue. Associations with clinical outcomes were determined by logistic regression and Cox proportional hazard models. ResultsThe best overall response rate was 16.7%. Treatment-related adverse events occurred in 40.0% of the dogs, which were primarily grade 1-3. Increased baseline white blood cell, neutrophil count, and C-reactive protein (CRP) levels were significantly associated with poor response, shorter progression-free survival (PFS), and reduced overall survival (OS). MSI-high tumors were associated with significantly prolonged OS compared with MSI-low/microsatellite stable tumors. Transcriptome analysis revealed differentially expressed genes and enriched immune-related pathways in responders, though limited by sample size. Conclusionca-4F12-E6 exhibited durable antitumor activity and an acceptable safety profile in dogs with OMM. Baseline systemic inflammatory markers and MSI status may serve as predictive biomarkers for clinical outcomes. The results support the use of canine OMM as a comparative model for human immuno-oncology and biomarker discovery.

cancer biology↗

bioRxiv2023

Large-scale epidemiological study on feline autosomal dominant polycystic kidney disease and identification of novel PKD1 gene variants

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease in cats. In most cases, the responsible abnormality is a nonsense single nucleotide polymorphism in exon 29 of the PKD1 gene (chrE3:g.42858112C>A, the conventional PKD1 variant). Epidemiological studies on feline ADPKD caused by the conventional PKD1 variant have been conducted in several countries, including Japan. However, they were limited to Persian cats or cats already suspected of ADPKD. There are no data on the prevalence of the conventional PKD1 variant among a wider cat population in Japan that is not limited to certain breeds or clinical backgrounds. This large-scale epidemiological study involving 1,281 cats aimed to establish a new genotyping assay to detect the conventional PKD1 variant rapidly. Among the cats examined in this study, 1.8% (23/1,281) harbored the conventional PKD1 variant. The odds of having the conventional PKD1 variant were significantly higher in Persian cats, Scottish Folds, and Exotic Shorthairs than in the other breeds. Furthermore, targeted resequencing of PKD1 was performed in cats with ADPKD and healthy cats to search for new variants that may be involved in ADPKD. We identified four variants unique to ADPKD cats that were not found in healthy cats, all of which were in exon 15. This indicates that variants in exon 15 of PKD1, in addition to the conventional variant in exon 29, are key factors in the pathogenesis of ADPKD in cats.

molecular biology↗

bioRxiv2021

CCR4 blockade leads to clinical activity and prolongs survival in a canine model of advanced prostate cancer

Targeting regulatory T cell (Treg) infiltration is an emerging strategy for cancer immunotherapy. However, the efficacy of this strategy in advanced prostate cancer remains unclear. Here, we describe the therapeutic efficacy of this strategy in a canine model of advanced prostate cancer. We used dogs with naturally occurring prostate cancer to study the molecular mechanism underlying Treg infiltration into tumor tissues and the effect of anti-Treg treatment. We found that tumor-infiltrating Tregs were associated with poor prognosis in dogs bearing spontaneous prostate cancer. RNA sequencing and protein analyses showed that Treg infiltration was mediated by interaction between the tumor-producing chemokine, CCL17, and the receptor CCR4 expressed on Tregs. Dogs with advanced prostate cancer responded to mogamulizumab, a monoclonal antibody targeting CCR4, with improved survival and low incidence of clinically relevant adverse events. Exploratory analyses showed urinary CCL17 concentration and BRAFV595E mutation to be independently predictive of the response to mogamulizumab. Analysis of a publicly available transcriptomic dataset of human prostate cancer showed that the CCL17/CCR4 axis correlated with the Treg marker, Foxp3. In silico survival analyses showed that high expression of CCL17 was associated with poor prognosis. Immunohistochemistry confirmed that tumor-infiltrating Tregs expressed CCR4 in human patients with prostate cancer. These findings suggest that anti-Treg treatment through the blocking of CCR4 is a promising therapeutic approach for advanced prostate cancer. One Sentence SummaryTargeting regulatory T cell infiltration by CCR4 blockade induces objective responses and improves survival in a canine model of prostate cancer.

cancer biology↗