Biology subjects

Kasahara, T.

Publications and source records attributed to Kasahara, T..

3 recordsLinked to original sources

bioRxiv2024

The structural diversity of telomeres and centromeres across mouse subspecies revealed by complete assemblies

It is over twenty years since the publication of the C57BL/6J mouse reference genome, which has been a key catalyst for understanding mammalian disease biology. However, the mouse reference genome still lacks telomeres and centromeres, contains 281 chromosomal sequence gaps, and only partially represents many biomedically relevant loci. We present the first T2T mouse genomes for two key inbred strains, C57BL/6J and CAST/EiJ. These T2T genomes reveal significant variability in telomere and centromere sizes and structural organisation. We add an additional 213 Mbp of novel sequence to the reference genome containing 517 protein-coding genes. We examined two important but incomplete loci in the mouse genome - the pseudoautosomal region (PAR) on the sex chromosomes and KRAB zinc finger proteins (KZFPs) loci. We identified distant locations of the PAR boundary, different copy number and sizes of segmental duplications, and a multitude of amino acid substitution mutations in PAR genes.

genomics↗

bioRxiv2024

Transcriptomic Hallmarks of Mortality Reveal Universal and Specific Mechanisms of Aging, Chronic Disease, and Rejuvenation

Health is strongly affected by aging and lifespan-modulating interventions, but the molecular mechanisms of mortality regulation remain unclear. Here, we conducted an RNA-seq analysis of mice subjected to 20 compound treatments in the Interventions Testing Program (ITP). By integrating it with the data from over 4,000 rodent tissues representing aging and responses to genetic, pharmacological, and dietary interventions with established survival data, we developed robust multi-tissue transcriptomic biomarkers of mortality, capable of quantifying aging and change in lifespan in both short-lived and long-lived models. These tools were further extended to single-cell and human data, demonstrating common mechanisms of molecular aging across cell types and species. Via a network analysis, we identified and annotated 26 co-regulated modules of aging and longevity across tissues, and developed interpretable module-specific clocks that capture aging- and mortality-associated phenotypes of functional components, including, among others, inflammatory response, mitochondrial function, lipid metabolism, and extracellular matrix organization. These tools captured and characterized acceleration of biological age induced by progeria models and chronic diseases in rodents and humans. They also revealed rejuvenation induced by heterochronic parabiosis, early embryogenesis, and cellular reprogramming, highlighting universal signatures of mortality, shared across models of rejuvenation and age-related disease. They included Cdkn1a and Lgals3, whose human plasma levels further demonstrated a strong association with all-cause mortality, disease incidence and risk factors, such as obesity and hypertension. Overall, this study uncovers molecular hallmarks of mammalian mortality shared across organs, cell types, species and models of disease and rejuvenation, exposing fundamental mechanisms of aging and longevity.

systems biology↗

bioRxiv2022

Complete sequencing of the mouse pseudoautosomal region, the most rapidly evolving 'chromosome'

The pseudoautosomal region (PAR) of mammalian sex chromosomes is a small region of sequence identity that allows pairing, crossover, recombination, and proper chromosome segregation during male meiosis. The structure of the mouse PAR is largely unknown. Here, we developed a new assembly method to robustly resolve repetitive sequences and employed highly accurate long-read sequencing data to reveal the entire PAR sequence. The PAR of the widely-used inbred strain C57BL/6J is [~]700 kb, comprising 10 protein- coding genes in a mass of complex repetitive sequences. A large segmental duplication exhibiting copy-number polymorphisms even among C57BL/6J littermates is present. High GC-content exons and short introns are common properties of PAR genes and are the consequence of maintaining gene function, while PAR is rapidly evolving. Elucidating the mouse PAR sequence completes the mouse euchromatic genome sequencing and enables the exploration of the function and evolution of the PAR using modern molecular genetic approaches.

genomics↗