Flavors of non-random meiotic segregation of autosomes and sex chromosomes

Segregation of chromosomes is a multistep process occurring both at mitosis and meiosis to ensure that daughter cells receive a complete set of genetic information. Critical components in the chromosome segregation include centromeres, kinetochores, components of sister chromatid and homologous chromosomes cohesion, microtubule organizing centres, and spindles. Based on the cytological work in the grasshopper Brachystola, it has been accepted for decades that segregation of homologs at meiosis is fundamentally random. This ensures that alleles on chromosomes have equal chance to be transmitted to progeny. At the same time mechanisms of meiotic drive and an increasing number of other examples of non-random segregation of autosomes and sex chromosomes provide insights into the underlying mechanisms of chromosome segregation but also question the textbook dogma of random chromosome segregation. Recent advances provide a better understanding of meiotic drive as a prominent force where cellular and chromosomal changes allow autosomes to bias their segregation. Less understood are mechanisms explaining observations that autosomal heteromorphism may cause biased segregation and regulate alternating segregation of multiple sex chromosome systems or translocation heterozygotes as an extreme case of non-random segregation. We speculate that molecular and cytological mechanisms of non-random segregation might be common in these cases and that there might be a continuous transition between random and non-random segregation which may play a role in the evolution of sexually antagonistic genes and sex chromosome evolution

Platypus and echidna genomes reveal mammalian biology and evolution

Egg-laying mammals (monotremes) are the only extant mammalian outgroup to therians (marsupial and eutherian animals) and provide key insights into mammalian evolution1,2. Here we generate and analyse reference genomes of the platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus), which represent the only two extant monotreme lineages. The nearly complete platypus genome assembly has anchored almost the entire genome onto chromosomes, markedly improving the genome continuity and gene annotation. Together with our echidna sequence, the genomes of the two species allow us to detect the ancestral and lineage-specific genomic changes that shape both monotreme and mammalian evolution. We provide evidence that the monotreme sex chromosome complex originated from an ancestral chromosome ring configuration. The formation of such a unique chromosome complex may have been facilitated by the unusually extensive interactions between the multi-X and multi-Y chromosomes that are shared by the autosomal homologues in humans. Further comparative genomic analyses unravel marked differences between monotremes and therians in haptoglobin genes, lactation genes and chemosensory receptor genes for smell and taste that underlie the ecological adaptation of monotremes.We thank members of BGI-Shenzhen, China National GeneBank and VGP, and P. Baybayan, R. Hall and J. Howard for help carrying out the sequencing of the platypus and echidna genomes, M. Asahara for discussion, and D. Charlesworth for comments. Work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB31020000), the National Key R&D Program of China (MOST) grant 2018YFC1406901, International Partnership Program of Chinese Academy of Sciences (152453KYSB20170002), Carlsberg foundation (CF16-0663) and Villum Foundation (25900) to G.Z. Q.Z. is supported by the National Natural Science Foundation of China (31722050, 31671319 and 32061130208), Natural Science Foundation of Zhejiang Province (LD19C190001), European Research Council Starting Grant (grant agreement 677696) and start-up funds from Zhejiang University.T.H. was financed by JSPS KAKENHI grant numbers 16K18630 and 19K16241 and the Sasakawa Scientific Research Grant from the Japan Science Society. The echidna RNA-sequencing analysis was supported by H.K.’s grant from the European Research Council (615253, OntoTransEvol). This work was supported by Guangdong Provincial Academician Workstation of BGI Synthetic Genomics No. 2017B090904014 (H.Y.), Robert and Rosabel Osborne Endowment, Howard Hughes Medical Institute (E.D.J.), Rockefeller University start-up funds (E.D.J.), Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (A.R. and A.M.P.), Korea Health Technology R&D Project through the Korea Health Industry Development Institute HI17C2098 (A.R.). This work used the computational resources of BGI-Shenzhen and the NIH HPC Biowulf cluster (https://hpc.nih.gov). Animal icons are from https://www.flaticon.com/ (made by Freepik) and http://phylopic.org/

Incomplete transcriptional dosage compensation of chicken and platypus sex chromosomes is balanced by post-transcriptional compensation

Heteromorphic sex chromosomes (XY or ZW) present problems of gene dosage imbalance between sexes and with autosomes. A need for dosage compensation has long been thought to be critical in vertebrates. However, this was questioned by findings of unequal mRNA abundance measurements in monotreme mammals and birds. Here, we demonstrate unbalanced mRNA levels of X genes in platypus males and females and a correlation with differential loading of histone modifications. We also observed unbalanced transcripts of Z genes in chicken. Surprisingly, however, we found that protein abundance ratios were 1:1 between the sexes in both species, indicating a post-transcriptional layer of dosage compensation. We conclude that sex chromosome output is maintained in chicken and platypus (and perhaps many other non therian vertebrates) via a combination of transcriptional and post-transcriptional control, consistent with a critical importance of sex chromosome dosage compensation

Chimeric caspase molecules with potent cell killing activity in apoptosis-resistant cells

Copyright © 2001 Academic Press. All rights reserved.Cellular defects which prevent apoptotic cell death can result in the generation of hyperproliferative disorders and can prevent the effective treatment of such diseases. The majority of cellular defects which result in apoptosis resistance lie upstream of caspase activation. We have described chimeric caspase molecules consisting of the prodomain of caspase-2 fused to the amino terminus of caspase-3, and which are tagged at the carboxyl terminus with green fluorescent protein (GFP) to allow direct visualisation of transfected cells. Here we show that these chimeric caspase molecules possess potent, rapid cell-killing activity in cell lines which display a range of defects resulting in apoptosis resistance.Linda Shearwin-Whyatt, Belinda Baliga, Joanna Doumanis and Sharad Kumarhttp://www.elsevier.com/wps/find/journaldescription.cws_home/622790/description#descriptio

N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel golgi-associated protein

Nedd4 belongs to a family of ubiquitin-protein ligases that is characterized by 2--4 WW domains, a carboxyl-terminal Hect (homologous to E6-AP Carboxyl terminus)domain and in most cases an amino-terminal C2 domain. We had previously identified a series of proteins that associates with the WW domains of Nedd4. In this paper, we demonstrate that one of the Nedd4-binding proteins, N4WBP5, belongs to a small group of evolutionarily conserved proteins with three transmembrane domains. N4WBP5 binds Nedd4 WW domains via the two PPXY motifs present in the amino terminus of the protein. In addition to Nedd4, N4WBP5 can interact with the WW domains of a number of Nedd4 family members and is ubiquitinated. Endogenous N4WBP5 localizes to the Golgi complex. Ectopic expression of the protein disrupts the structure of the Golgi, suggesting that N4WBP5 forms part of a family of integral Golgi membrane proteins. Based on previous observations in yeast, we propose that N4WBP5 may act as an adaptor for Nedd4-like proteins and their putative targets to control ubiquitin-dependent protein sorting and trafficking.Kieran F. Harvey, Linda M. Shearwin-Whyatt, Andrew Fotia, Robert G. Parton and Sharad Kuma

Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein

The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of α, β, and γ subunits. The carboxyl terminus of each ENaC subunit contains a PPXY motif that is believed to be important for interaction with the WW domains of the ubiquitin-protein ligases, Nedd4 and Nedd4-2. Disruption of this interaction, as in Liddle’s syndrome where mutations delete or alter the PPXY motif of either the β or γ subunits, has been shown to result in increased ENaC activity and arterial hypertension. Here we present evidence that N4WBP5A, a novel Nedd4/Nedd4-2-binding protein, is a potential regulator of ENaC. In Xenopus laevis oocytes N4WBP5A increases surface expression of ENaC by reducing the rate of ENaC retrieval. We further demonstrate that N4WBP5A prevents sodium feedback inhibition of ENaC possibly by interfering with the xNedd4-2-mediated regulation of ENaC. As N4WBP5A binds Nedd4/Nedd4-2 via PPXY motif/WW domain interactions and appears to be associated with specific intracellular vesicles, we propose that N4WBP5A functions by regulating Nedd4/ Nedd4-2 availability and trafficking. Because N4WBP5A is highly expressed in native renal collecting duct and other tissues that express ENaC, it is a likely candidate to modulate ENaC function in vivo.Angelos-Aristeidis Konstas, Linda M. Shearwin-Whyatt, Andrew B. Fotia, Brian Degger, Daniela Riccardi, David I. Cook, Christoph Korbmacher and Sharad Kuma

Platypus and echidna genomes reveal mammalian biology and evolution

Work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB31020000), the National Key R&D Program of China (MOST) grant 2018YFC1406901, International Partnership Program of Chinese Academy of Sciences (152453KYSB20170002), Carlsberg foundation (CF16-0663) and Villum Foundation (25900) to G.Z. Q.Z. is supported by the National Natural Science Foundation of China (31722050, 31671319 and 32061130208), Natural Science Foundation of Zhejiang Province (LD19C190001), European Research Council Starting Grant (grant agreement 677696) and start-up funds from Zhejiang University. F.G., L.S.-W. and T.D. are supported by Australian Research Council (FT160100267, DP170104907 and DP110105396). M.B.R., J.C.F. and S.D.J. are supported by the Australian Research Council (LP160101728). We acknowledge the Kyoto University Research Administration Office for support and Human Genome Center, the Institute of Medical Science, the University of Tokyo for the super-computing resource for supporting T.H.’s research facilities. T.H. was financed by JSPS KAKENHI grant numbers 16K18630 and 19K16241 and the Sasakawa Scientific Research Grant from the Japan Science Society. The echidna RNA-sequencing analysis was supported by H.K.’s grant from the European Research Council (615253, OntoTransEvol). This work was supported by Guangdong Provincial Academician Workstation of BGI Synthetic Genomics No. 2017B090904014 (H.Y.), Robert and Rosabel Osborne Endowment, Howard Hughes Medical Institute (E.D.J.), Rockefeller University start-up funds (E.D.J.), Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (A.R. and A.M.P.), Korea Health Technology R&D Project through the Korea Health Industry Development Institute HI17C2098 (A.R.). This work used the computational resources of BGI-Shenzhen and the NIH HPC Biowulf cluster (https://hpc.nih.gov). Animal icons are from https://www.flaticon.com/ (made by Freepik) and http://phylopic.org/