Biology subjects

Yonezawa, T.

Publications and source records attributed to Yonezawa, T..

8 recordsLinked to original sources

bioRxiv2026

Mammalian returns to the sea reveal broad genomic slowing rather than a fixed adaptive toolkit

Marine mammals - cetaceans, pinnipeds, sirenians, sea otters and polar bears - returned to the sea independently, yet whether their genomes converged on a shared adaptive programme or shifted in a common direction without a fixed toolkit has remained unclear. Here we separate marine specialization from general aquatic dependence across 302 mammals and 17,432 protein-coding genes and show that the dominant genomic signature of marine life is widespread evolutionary slowing, not acceleration: of 1,559 marine-associated genes, nearly 88% evolved more slowly, and this slow-direction bias persisted (98%) after removing cetaceans. Compact gene fingerprints that distinguish marine identity combine fast-rate remodeling of body-surface and sensory genes with slow-rate constraint on blood, metabolic and DNA-repair genes, but these fingerprints are sharpened by cetaceans and do not preserve a fixed functional toolkit across lineages. Species-level and ancestral-branch decompositions reveal that different marine mammals assembled marine-like genomic states through distinct gene combinations. Mammalian marine convergence is therefore directional rather than modular: a broad constraint landscape resolved into clade-weighted genomic fingerprints.

evolutionary biology↗

bioRxiv2025

Genome-wide analysis reveals mutual gene flow between goats from Island Southeast Asia and from Southern Africa

This study aimed to reveal a comprehensive genetic diversity and genetic structure of Island Southeast Asian (ISEA) goats, and infer the details of gene introgressions and propagation routes in ISEA goats using genome-wide SNPs. Correlation analysis of the distance from the domestication center and the genetic diversity of each Asian population showed a significant negative correlation (r = - 0.796, p = 2.66E-05), while the Philippines showed a relatively high genetic diversity (He = 0.363) against the distance, suggesting the multiple propagation routes and admixture history in Philippine goats. Reduced Representation Admixture Analysis at K=6 showed that six clusters (Europe, Northwest Africa, Southern Africa, Eastern Africa, Asia and Southeast Asia) were formed based primarily on geographical location, and ISEA goats included African and Europe components. However, this introgression is much lower in Indochinese goats. In addition, the Southern African and European populations included Southeast Asia component. Treemix and f4 statistics analyses showed the genetic influence and gene flow between ISEA and the Southern Africa. The results of this study have revealed obvious mutual gene flow between ISEA and the Southern African regions through the European maritime activities across the Indian Ocean since the Middle Ages.

ecology↗

bioRxiv2025

DNMT3A Stability Is Maintained by Ubiquitin-Specific Peptidase 11 (USP11) and Sumoylation Countering Degradation

DNA methyltransferase 3A (DNMT3A) plays crucial roles in mammalian development and hematopoiesis. DNMT3A protein instability is associated with blood diseases such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), as well as Tatton-Brown-Rahman syndrome, an overgrowth disorder. We found that certain unstable DNMT3A mutations cause DNMT3A localization changes, resulting in loss of function. This mislocalization is partially rescued by E1 enzyme inhibition or stable USP11 expression, as DNMT3A stability is maintained by deubiquitinating enzyme USP11 countering degradation by CUL4-DCAF8 E3 ligase. We also found that USP11 enhances DNMT3A SUMOylation by promoting the interaction between DNMT3A and SUMO E3 ligases. DNMT3A SUMOylation also is essential to maintain DNMT3A protein stability. Furthermore, we found USP11 enhances the binding of DNMT3A to the polycomb complex and maintains DNMT3A DNA methyltransferase (MTase) activity. This study uncovers the mechanism for DNMT3A protein turnover through USP11, which is essential to DNMT3A function, and may be a therapeutic approach for diseases caused by DNMT3A protein instability.

biochemistry↗

bioRxiv2024

CH-related Mutant ASXL1 Promotes Atherosclerosis in Mice via Dysregulated Innate Immunity

Certain somatic mutations confer a fitness advantage in hematopoietic stem and progenitor cells (HSPCs) over normal HSPCs, resulting in the clonal expansion of mutant blood cells1, otherwise known as clonal haematopoiesis (CH). CH is frequently observed among healthy elderly people and is closely associated with the risk of cardiovascular diseases (CVDs). The most frequently mutated genes of CH include DNMT3A, TET2, and ASXL12. Among them, even though ASXL1 mutations are clinically associated with the highest risk for developing CVDs, little is known whether and how the mutations contribute to CVDs. Here we show accelerated development of atherosclerosis and increased inflammatory monocytes in mice transplanted with the bone marrow cells (BMCs) from the mice expressing mutant ASXL1 (ASXL1-MT) selectively in hematopoietic cells. RNA sequencing analysis of the plaque-macrophages derived from BMCs expressing ASXL1-MT showed more inflammatory signatures than those from control BMCs. Mechanistically, wild-type ASXL1 inhibited innate immune signalling through direct interactions with IRAK1/TRAF6/TAK1 in the cytoplasm, while ASXL1-MT, which only interacted with TAK1, lost this regulatory function, leading to NF-{kappa}B activation. This mechanism is unique and distinct from those of CH with Tet2 or Dnmt3a mutations, where overactivation of the IL-1{beta}/NLRP3 inflammasome plays critical roles3-5. Intriguingly, IRAK1/4 inhibition decreased the number of inflammatory monocytes and attenuated the development of atherosclerosis driven by ASXL1-MT. The present work connects the mutations of an epigenetic factor, ASXL1, with inflammation and CVDs and gives an indication for the prevention of CVDs in CH.

cell 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↗

bioRxiv2023

Protective role of protease-activated receptor-2 in anaphylaxis model mice

Anaphylaxis is a severe life-threatening hypersensitivity reaction induced by mast cell degranulation. Among the various mediators of mast cells, little is known about the role of tryptase. Therefore, we aimed to elucidate the role of protease-activating receptor-2 (PAR-2), a receptor activated by tryptase, in murine anaphylactic models using PAR-2-deficient mice and newly generated tryptase-deficient mice. Anaphylaxis was induced by IgE-dependent and IgE-independent mast cell degranulation in mice. PAR-2 deficiency exacerbated the decrease in body temperature and hypotension during anaphylaxis; however, the number of skin mast cells, degree of mast cell degranulation, and systemic and local vascular hyperpermeability were comparable in PAR-2 knockout and wild-type mice. Nitric oxide, which is produced by endothelial nitric oxide synthase (eNOS), is an indispensable vasodilator in anaphylaxis. In the lungs of anaphylactic mice, PAR-2 deficiency promoted eNOS expression and phosphorylation, suggesting a protective effect of PAR-2 against anaphylaxis by downregulating eNOS activation and expression. Based on the hypothesis that the ligand for PAR-2 in anaphylaxis is mast cell tryptase, tryptase-deficient mice were generated using CRISPR-Cas9. In wild-type mice, the PAR-2 antagonist exacerbated the body temperature drop due to anaphylaxis; however, the effect of the PAR-2 antagonist was abolished in tryptase-deficient mice. These results suggest that tryptase is a possible ligand of PAR-2 in anaphylaxis and that the tryptase/PAR-2 pathway attenuates the anaphylactic response in mice.

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↗

bioRxiv2019

Rates of molecular evolution predict intraspecies genetic diversity

What determines genetic diversity and how it connects to the various biological traits is unknown. In this work, we offer answers to these questions. By comparing genetic variation of 14,671 mammalian gene trees with thousands of individual genomes of human, chimpanzee, gorilla, mouse and dog/wolf, we found that intraspecific genetic diversity is determined by long-term molecular evolutionary rates, rather than de novo mutation rates. This relationship was established during the early stage of mammalian evolution. Expanding this new finding, we developed a method to detect fluctuations of species-specific selection on genes as the deviations of intra-species genetic diversity predicted from long-term rates. We show that the evolution of epithelial cells, rather than of connective tissue, mainly contributes to morphological evolution of different species. For humans, evolution of the immune system and selective sweeps subjected by infectious diseases are most representative of adaptive evolution.

evolutionary biology↗