Negatively skewed locomotor activity is related to autistic traits and behavioral problems in typically developing children and those with autism spectrum disorders.

University of Yamanashi (山梨大学)博士(医学)医工博4甲第252号thesi

Chromosome-scale assembly with improved annotation provides insights into breed-wide genomic structure and diversity in domestic cats

Introduction Comprehensive genomic resources offer insights into biological features, including traits/disease-related genetic loci. The current reference genome assembly for the domestic cat (Felis catus), Felis_Catus_9.0 (felCat9), derived from sequences of the Abyssinian cat, may inadequately represent the general cat population, limiting the extent of deducible genetic variations. Objectives The goal was to develop Anicom American Shorthair 1.0 (AnAms1.0), a reference-grade chromosome-scale cat genome assembly. Methods In contrast to prior assemblies relying on Abyssinian cat sequences, AnAms1.0 was constructed from the sequences of more popular American Shorthair breed, which is related to more breeds than the Abyssinian cat. By combining advanced genomics technologies, including PacBio long-read sequencing and Hi-C- and optical mapping data-based sequence scaffolding, we compared AnAms1.0 to existing Felidae genome assemblies (20 scaffolds, scaffolds N50 > 150 Mbp). Homology-based and ab initio gene annotation through Iso-Seq and RNA-Seq was used to identify new coding genes and splice variants. Results AnAms1.0 demonstrated superior contiguity and accuracy than existing Felidae genome assemblies. Using AnAms1.0, we identified over 1.5 thousand structural variants and 29 million repetitions compared to felCat9. Additionally, we identified > 1,600 novel protein-coding genes. Notably, olfactory receptor structural variants and cardiomyopathy-related variants were identified. Conclusion AnAms1.0 facilitates the discovery of novel genes related to normal and disease phenotypes in domestic cats. The analyzed data are publicly accessible on Cats-I (https://cat.annotation.jp/), which we established as a platform for accumulating and sharing genomic resources to discover novel genetic traits and advance veterinary medicine.journal articl

Observation of b→dγ and Determination of |Vtd/Vts|

journal articl

The Design on Yamagano Gold Mine（山ヶ野金山計画）

東京帝国大学工科大学種別:卒業論文thesi

初期マルクスの階級把握と唯物論のプロブレマティーク―集団形成の論理をめぐって―

2002-03departmental bulletin pape

Example of the discrete time branching process in Chiron.

<p>Aneuploidy is generated at a specific rate (<i>p</i>) of mitotic mis-segregation, where trisomic (red circles) and monosomic cells (green circles) have certain probabilites (<i>s</i>_t and <i>s</i>_m respectively) of permanent proliferative arrest/death (black horizontal bars) at each mitotic cycle. Two or more aneusomies will result in increased probabilities of arrest/death as exemplified by cells labelled++and +−.</p

Clonal expansion in a context of normal chromosome mis-segregation.

<p>(A) Evaluation of clonal expansion of cells with trisomy for a single chromosome (+C), set up under similar conditions as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070445#pone-0070445-g008" target="_blank">Figure 8</a> but with a mis-segregation rate similar to normal fibroblasts (<i>p</i> = 4×10⁻⁴), a constant rate of positive selection (<i>S_p</i>) of 50%, and a variable degree of negative selection against aneuploidy (<i>S_n</i>). Parallel simulations were performed with a control population with equal conditions except for an absence of positive selection. (B, C) A clonal expansion resulting in dominance of cells with +C (prevalence >99%) after 1000 generations is observed when <i>S_p</i>> <i>S_n</i>, while <i>S_p</i> = <i>S_n</i> results in variable prevalence of cells with +C, including expansion up to a prevalence of 33% (<i>S_n</i> = 50%:1 in C), expansion followed by regression (<i>S_n</i> = 50%:2 in C), and a lack of clonal expansion (<i>S_n</i> = 50%:3 in C). Each circle in B corresponds to a single run of simulations, with 10 runs per level of <i>S_n</i>, while the red line corresponds to mean results. Red plots in C correspond to prevalence of +C cells under positive selection and blue plots reflect the results of parallel control simulations with <i>S_p</i> = 0; x axes denote mitotic generations.</p

Reverse engineering <i>in silico</i> of the LoVo stemline genome by introducing positive selection.

<p>(A) The LoVo stemline with trisomies of chromosomes 5, 7 and 12 was recreated by modelling clonal expansion from a normal diploid (N) state where aneuploid cells were subject to negative selection (<i>S</i>_n) at the magnitude measured in LoVo, with the exception of cells with one or more of the trisomies +5, +7, +12. Such cells were subjected to a variable degree of positive selection (<i>S</i>_p), <i>i.e.</i> a higher probability of undergoing mitotic proliferation than diploid cells. For simplicity, diploid cells were given an average probability of 50% for proliferative survival, resulting in one daughter cell on overage for each mother cell (left). Cells having acquired +5/+7/+12 were set to generate on average >1 daughter cell, with the maximum survival benefit for cells having all three trisomies (right). <i>S</i>_p was set in relation to the proliferation of normal cells with <i>S</i>_p = 100% equalling the generation of 2 daughter cells per mother cell with all three trisomies. Each of +5/+7/+12 were coupled to an identical degree of positive selection i.e. 1/3 <i>S</i>_p for each. Aneusomies were acquired through mis-segregation at the rate measured in LoVo. (B) The prevalence of aneuploid cells reaches a stable, high level in the population (1,000 cells) with 100% positive selection for +5/+7/+12 (red plot), while a parallel proliferation in absence of positive selection retains a diploid genome in the majority of cells (blue plot). (C) In the same simulation of positive selection, the prevalence of cells with each of +5/+7/+12 increase rapidly; chromosome 1, used as an internal control, remains disomic. (D) When the prevalence of aneuploidy has reached a stable state the modal number has shifted to 49 as expected with positive selection for +5/+7/+12, while it remains diploid (E) in the absence of positive selection for trisomies. (F) Using the same parameters as in B–D but introducing <i>S</i>_n = 30% for all aneusomies including +5/+7/+12 prevents expansion of aneuploid clones. Instead a state of mutation/selection balance is reached where trisomic cells never reach a higher prevalence than 4%.</p

Elevated Tolerance to Aneuploidy in Cancer Cells: Estimating the Fitness Effects of Chromosome Number Alterations by <i>In Silico</i> Modelling of Somatic Genome Evolution

<div><p>An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various magnitudes. We then assessed experimentally the frequency of chromosomal mis-segregation as well as the prevalence of aneuploid cells in human non-neoplastic cells and in cancer cells. Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells. In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance. Simulations based on the combined presence of chromosomal mis-segregation and aneuploidy tolerance reproduced distributions of chromosome aberrations in >400 cancer cases with higher fidelity than models based on chromosomal mis-segregation alone. Reverse engineering of aneuploid cancer cell development <i>in silico</i> predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate. In conclusion, our findings indicate that not only an elevated chromosomal mis-segregation rate, but also a generalised tolerance to novel chromosomal imbalances contribute to the genomic landscape of human tumours.</p></div

Modelling the distribution of aneuploidy burden in human cancers.

<p>(A) Reported cytogenetic data from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer show a log-linear relationship between the relative prevalence and the number of numerical aberrations per tumour (Nnapt), with highly similar distributions for Wilms tumour (WT) and colorectal cancer (CRC). (B) Modelling of a certain number of cancer stemlines arising in the same number of patients. Each stemline is assumed to derive from a diploid cell (having 0 numerical aberrations) and is allowed to proliferate for a maximum of 2000 generations (G), when the overall distribution of numerical aberrations is sampled. Stemlines accumulate numerical aberrations at a certain mis-segregation rate (<i>p</i>) and are subject to aneuploidy-dependent selection at a certain degree (<i>s</i>), which may in turn result in termination of the stemline (horizontal dumbbell), corresponding to the end of clonal expansion. Because this may result in regression of tumorigenesis at an early stage, cases where stemlines were thus terminated were removed from sampling. (C) Simulated distribution of tumour cases with a certain number of numerical aberrations as the tumour cohort is sampled at generations 1–2000 in a setting where tumours harbour an elevated mis-segregation rate in the absence of negative selection against aneuploid cells (see main text for details). This will result in a binomial-like distribution already after 100 generations, the modal value of which increases with time, in contrast to the actual distribution in human tumours (compare to 6A).</p