Sex chromosomes generally evolve from a homomorphic to heteromorphic state. Once a heteromorphic system is established, the sex chromosome system may remain stable for an extended period. Here, we ...show the opposite case of sex chromosome evolution from a heteromorphic to a homomorphic system in the Japanese frog
Glandirana rugosa.
One geographic group, Neo-ZW, has ZZ-ZW type heteromorphic sex chromosomes. We found that its western edge populations, which are geographically close to another West-Japan group with homomorphic sex chromosomes of XX-XY type, showed homozygous genotypes of sex-linked genes in both sexes. Karyologically, no heteromorphic sex chromosomes were identified. Sex-reversal experiments revealed that the males were heterogametic in sex determination. In addition, we identified another similar population around at the southwestern edge of the Neo-ZW group in the Kii Peninsula: the frogs had homomorphic sex chromosomes under male heterogamety, while shared mitochondrial haplotypes with the XY group, which is located in the east and bears heteromorphic sex chromosomes. In conclusion, our study revealed that the heteromorphic sex chromosome systems independently reversed back to or turned over to a homomorphic system around each of the western and southwestern edges of the Neo-ZW group through hybridization with the West-Japan group bearing homomorphic sex chromosomes.
This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part II)’.
The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the ...biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10(-9) (95% confidence interval = 4.6 × 10(-9)-6.5 × 10(-9)) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population.
A contribution of epigenetic modifications to B cell tolerance has been proposed but not directly tested. Here we report that deficiency of ten-eleven translocation (Tet) DNA demethylase family ...members Tet2 and Tet3 in B cells led to hyperactivation of B and T cells, autoantibody production and lupus-like disease in mice. Mechanistically, in the absence of Tet2 and Tet3, downregulation of CD86, which normally occurs following chronic exposure of self-reactive B cells to self-antigen, did not take place. The importance of dysregulated CD86 expression in Tet2- and Tet3-deficient B cells was further demonstrated by the restriction, albeit not complete, on aberrant T and B cell activation following anti-CD86 blockade. Tet2- and Tet3-deficient B cells had decreased accumulation of histone deacetylase 1 (HDAC1) and HDAC2 at the Cd86 locus. Thus, our findings suggest that Tet2- and Tet3-mediated chromatin modification participates in repression of CD86 on chronically stimulated self-reactive B cells, which contributes, at least in part, to preventing autoimmunity.
Sleep is conserved from invertebrates to vertebrates, and is tightly regulated in a homeostatic manner. The molecular and cellular mechanisms that determine the amount of rapid eye movement sleep ...(REMS) and non-REMS (NREMS) remain unknown. Here we identify two dominant mutations that affect sleep and wakefulness by using an electroencephalogram/electromyogram-based screen of randomly mutagenized mice. A splicing mutation in the Sik3 protein kinase gene causes a profound decrease in total wake time, owing to an increase in inherent sleep need. Sleep deprivation affects phosphorylation of regulatory sites on the kinase, suggesting a role for SIK3 in the homeostatic regulation of sleep amount. Sik3 orthologues also regulate sleep in fruitflies and roundworms. A missense, gain-of-function mutation in the sodium leak channel NALCN reduces the total amount and episode duration of REMS, apparently by increasing the excitability of REMS-inhibiting neurons. Our results substantiate the use of a forward-genetics approach for studying sleep behaviours in mice, and demonstrate the role of SIK3 and NALCN in regulating the amount of NREMS and REMS, respectively.
The canonical model of sex-chromosome evolution predicts that, as recombination is suppressed along sex chromosomes, gametologs will progressively differentiate, eventually becoming heteromorphic. ...However, there are numerous examples of homomorphic sex chromosomes across the tree of life. This homomorphy has been suggested to result from frequent sex-chromosome turnovers, yet we know little about which forces drive them. Here, we describe an extremely fast rate of turnover among 28 species of Ranidae. Transitions are not random, but converge on several chromosomes, potentially due to genes they harbour. Transitions also preserve the ancestral pattern of male heterogamety, in line with the 'hot-potato' model of sex-chromosome transitions, suggesting a key role for mutation-load accumulation in non-recombining genomic regions. The importance of mutation-load selection in frogs might result from the extreme heterochiasmy they exhibit, making frog sex chromosomes differentiate immediately from emergence and across their entire length.
The introduction of lenalidomide has significantly improved clinical outcomes in myelodysplastic syndrome (MDS) with isolated interstitial deletion of the long arm of chromosome 5 (del(5q)) (5q– ...syndrome). These days, MDS with isolated del(5q) includes cases with one additional chromosome abnormality other than monosomy 7 or del(7q), and so we need a better way to monitor tumor cells in each patient than the clinical parameters used to date. An 82-year-old woman with MDS with isolated del(5q) was treated with lenalidomide daily for 21 days in a 4-week cycle. Fluorescence in situ hybridization with CSF1R located at 5q was applied to the peripheral blood samples. Because mature lymphocytes are not involved in the MDS clone, based on the nuclear morphology, polymorphonuclear cells (PMNs) and round-shaped nuclear cells (RSNs) were separately evaluated during treatment. After a single course of treatment, the number of PMNs with del(5q) decreased; by the end of the second course of treatment, both PMNs and RSNs with del(5q) had disappeared. The dynamics of 5q– PMNs is a simple but rapid and reliable indicator to confirm the effect of lenalidomide in MDS with del(5q).
Amphibians have highly diverse sex-determining modes leading to a notable interest in vertebrate sex determination and sex chromosome evolution. The identification of sex-determining systems in ...amphibians, however, is often difficult as a vast majority consist of homomorphic sex chromosomes making them hard to distinguish. In this study, we used Diversity Array Technology sequencing (DArTseq) to identify the sex-determining system in the ornate burrowing frog from Australia, Platyplectrum ornatum. We applied DArTseq to 44 individuals, 19 males and 25 females, collected from two locations to develop sex-linked markers. Unexpectedly, these 44 individuals were classified into two distinct population clusters based on our SNP analyses, 36 individuals in cluster 1, and 8 individuals in cluster 2. We then performed sex-linkage analyses separately in each cluster. We identified 35 sex-linked markers from cluster 1, which were all associated with maleness. Therefore, P. ornatum cluster 1 is utilising a male heterogametic (XX/XY) sex-determining system. On the other hand, we identified 210 sex-linked markers from cluster 2, of which 89 were male specific, i.e., identifying XX/XY sex determining system and 111 were female specific, i.e., identifying ZZ/ZW sex determining system, suggesting existence of either male or female heterogametic sex determining system in cluster 2. We also performed cytogenetic analyses in 1 male and 1 female from cluster 1; however, we did not detect any visible differentiation between the X and Y sex chromosomes. We also mapped sex-linked markers from the two clusters against the P. ornatum genome and our comparative analysis indicated that the sex chromosomes in both clusters shared homologies to chromosome 10 (autosome) of Rana temporaria and ZWY sex chromosome of Xenopus tropicalis. Our preliminary data suggest that it is plausible that the cluster 2 has a potential to be either male or female heterogamety in sex determination, requiring further investigation.
We uncovered the phylogenetic origins of the Japanese red-bellied newt (Cynops pyrrhogaster) population newly found in Yokohama city and 11 neighboring populations in Kanagawa Prefecture based on ...mitochondrial NADH6-tRNAGlu-cytochrome b DNA sequences. The Yokohama city population was found to be an alien population introduced from Western Japan. On the other hand, the other populations we investigated belong to either of two genetic lineages of the newt (CENTRAL and NORTHERN), and they are distributed parapatrically around the foot of the Tanzawa Mountains.
The so-called "double-hit" and "double-protein-expression" lymphoma with
and
rearrangements is a rare, mature B-cell neoplasm characterized by a germinal center B-cell phenotype, abundant protein ...expression of MYC and BCL2, rapid disease progression, and a poor prognosis. In this study, we showed the potential benefit of the BCL2 inhibitor venetoclax in the treatment of this disease. Immunohistochemical studies of the lymphoma tissues confirmed that overexpression of MYC and BCL2 was observed more frequently in this subtype than in other germinal center B-cell-like diffuse large B-cell lymphomas. In contrast, another pro-survival protein MCL1 was less expressed in this subtype, even when compared with its expression in the non-"double-hit" and "double-protein-expression" type. Furthermore,
studies using two "double-hit" and "double-protein-expression" lymphoma-derived cell lines, Karpas231 and OCI-Ly8, clearly showed that a low concentration of venetoclax, but not the MCL1 inhibitor S63845, was sufficient to induce apoptosis in the two lines, compared with in other germinal center B-cell-derived cell lines, BJAB and SU-DHL10. These results indicate that the survival of this type of lymphoma depends predominantly on BCL2 rather than on MCL1. Unexpectedly, we found that venetoclax not only disrupts the interaction between BCL2 and the pro-apoptotic protein BIM, but also leads to dephosphorylation of BCL2 and further downregulates MCL1 protein expression, probably through modulation of the protein phosphatase 2A B56α activity in Karpas231 and OCI-Ly8. Indeed, a low concentration of venetoclax induced substantial apoptosis in the primary lymphoma cells, regardless of high protein expression of MCL1 associated with venetoclax resistance. Venetoclax clearly triggers the signal transduction related to BCL2 and MCL1 in "double-hit" and "double-protein-expression" lymphoma cells.
Mouse models of red blood cell abnormalities are important for understanding the underlying molecular mechanisms of human erythrocytic diseases. DBA.B6-Mha (Microcytic hypochromic anemia) congenic ...mice were generated from the cross between N-ethyl-N-nitrosourea (ENU)-mutagenized male C57BL/6J and female DBA/2J mice as part of the RIKEN large-scale ENU mutagenesis project. The mice were established by backcrossing with DBA/2J mice for more than 20 generations. These mice showed autosomal-dominant microcytic hypochromic anemia with decreased mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) levels and increased red blood cell distribution width (RDW) and plasma ferritin levels. Linkage analysis indicated that the Mha locus was located within an interval of approximately 1.95-Mb between D16Nut1 (58.35 Mb) and D16Mit185 (60.30 Mb) on mouse chromosome 16. Mutation analysis revealed that DBA.B6-Mha mice had a point mutation (c.921-2A>G) at the acceptor site of intron 4 in the coproporphyrinogen oxidase (Cpox) gene, a heme-synthesizing gene. RT-PCR revealed that the Cpox mRNA in DBA.B6-Mha mice caused splicing errors. Our results suggest that microcytic hypochromic anemia in DBA.B6-Mha mice is owing to impaired heme synthesis caused by splice mutations in Cpox. Therefore, the DBA.B6-Mha mice may be used to elucidate the molecular mechanisms underlying microcytic hypochromic anemia caused by mutations in Cpox. Although low MCV levels are known to confer malarial resistance to the host, there were no marked changes in the susceptibility of DBA.B6-Mha mice to rodent malarial (Plasmodium yoelii 17XL) infection.
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