The Cyprinodon variegatus genome reveals gene expression changes underlying differences in skull morphology among closely related species

Genes in durophage intersection set at 15 dpf. This is a comma separated table of the genes in the 15 dpf durophage intersection set. Given are edgeR results for each pairwise comparison. Columns indicating whether a gene is included in the intersection set at a threshold of 1.5 or 2 fold are provided. (CSV 13 kb

Evidence for Transcript Networks Composed of Chimeric RNAs in Human Cells

The classic organization of a gene structure has followed the Jacob and Monod bacterial gene model proposed more than 50 years ago. Since then, empirical determinations of the complexity of the transcriptomes found in yeast to human has blurred the definition and physical boundaries of genes. Using multiple analysis approaches we have characterized individual gene boundaries mapping on human chromosomes 21 and 22. Analyses of the locations of the 5′ and 3′ transcriptional termini of 492 protein coding genes revealed that for 85% of these genes the boundaries extend beyond the current annotated termini, most often connecting with exons of transcripts from other well annotated genes. The biological and evolutionary importance of these chimeric transcripts is underscored by (1) the non-random interconnections of genes involved, (2) the greater phylogenetic depth of the genes involved in many chimeric interactions, (3) the coordination of the expression of connected genes and (4) the close in vivo and three dimensional proximity of the genomic regions being transcribed and contributing to parts of the chimeric RNAs. The non-random nature of the connection of the genes involved suggest that chimeric transcripts should not be studied in isolation, but together, as an RNA network

The mutational impact of culturing human pluripotent and adult stem cells

Genetic changes acquired during in vitro culture pose a risk for the successful application of stem cells in regenerative medicine. To assess the genetic risks induced by culturing, we determined all mutations in individual human stem cells by whole genome sequencing. Individual pluripotent, intestinal, and liver stem cells accumulate 3.5 ± 0.5, 7.2 ± 1.1 and 8.3 ± 3.6 base substitutions per population doubling, respectively. The annual in vitro mutation accumulation rate of adult stem cells is nearly 40-fold higher than the in vivo mutation accumulation rate. Mutational signature analysis reveals that in vitro induced mutations are caused by oxidative stress. Reducing oxygen tension in culture lowers the mutational load. We use the mutation rates, spectra, and genomic distribution to model the accumulation of oncogenic mutations during typical in vitro expansion, manipulation or screening experiments using human stem cells. Our study provides empirically defined parameters to assess the mutational risk of stem cell based therapies

Evolution of a supergene that regulates a trans-species social polymorphism

Supergenes are clusters of linked genetic loci that jointly affect the expression of complex phenotypes, such as social organization. Little is known about the origin and evolution of these intriguing genomic elements. Here we analyse whole-genome sequences of males from native populations of six fire ant species and show that variation in social organization is under the control of a novel supergene haplotype (termed Sb), which evolved by sequential incorporation of three inversions spanning half of a 'social chromosome'. Two of the inversions interrupt protein-coding genes, resulting in the increased expression of one gene and modest truncation in the primary protein structure of another. All six socially polymorphic species studied harbour the same three inversions, with the single origin of the supergene in their common ancestor inferred by phylogenomic analyses to have occurred half a million years ago. The persistence of Sb along with the ancestral SB haplotype through multiple speciation events provides a striking example of a functionally important trans-species social polymorphism presumably maintained by balancing selection. We found that while recombination between the Sb and SB haplotypes is severely restricted in all species, a low level of gene flux between the haplotypes has occurred following the appearance of the inversions, potentially mitigating the evolutionary degeneration expected at genomic regions that cannot freely recombine. These results provide a detailed picture of the structural genomic innovations involved in the formation of a supergene controlling a complex social phenotype

Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade

Immune checkpoints blockade (ICB) is a viable anti-cancer strategy. Here the authors show that nuclear receptor NR2F6 acts as an immune checkpoint in T cells and, using mouse models and human T cells, they show NR2F6 inhibition might improve current ICB therapy or work as an alternative therapeutic strategy

Genomic analysis of Sparus aurata reveals the evolutionary dynamics of sex-biased genes in a sequential hermaphrodite fish

Sexual dimorphism is a fascinating subject in evolutionary biology and mostly results from sex-biased expression of genes, which have been shown to evolve faster in gonochoristic species. We report here genome and sex-specific transcriptome sequencing of Sparus aurata, a sequential hermaphrodite fish. Evolutionary comparative analysis reveals that sex-biased genes in S. aurata are similar in number and function, but evolved following strikingly divergent patterns compared with gonochoristic species, showing overall slower rates because of stronger functional constraints. Fast evolution is observed only for highly ovary-biased genes due to female-specific patterns of selection that are related to the peculiar reproduction mode of S. aurata, first maturing as male, then as female. To our knowledge, these findings represent the first genome-wide analysis on sex-biased loci in a hermaphrodite vertebrate species, demonstrating how having two sexes in the same individual profoundly affects the fate of a large set of evolutionarily relevant genes.European Union KBBE.2013.1.2-10 European Community 311920 Fondazione Cassa di Risparmio Padova e Rovigo FCT - Foundation for Science and Technology research grant SPARCOMP under the Call ARISTEIA I of the National Strategic Reference Framework - by the EU 36 Hellenic Republic through the European Social Fundinfo:eu-repo/semantics/publishedVersio

The first transcriptome of Italian wall lizard, a new tool to infer about the Island Syndrome

Some insular lizards show a high degree of differentiation from their conspecific mainland populations, like Licosa island lizards, which are described as affected by Reversed Island Syndrome (RIS). In previous works, we demonstrated that some traits of RIS, as melanization, depend on a differential expression of gene encoding melanocortin receptors. To better understand the basis of syndrome, and providing raw data for future investigations, we generate the first de novo transcriptome of the Italian wall lizard. Comparing mainland and island transcriptomes, we link differences in life-traits to differential gene expression. Our results, taking together testis and brain sequences, generated 275,310 and 269,885 transcripts, 18,434 and 21,606 proteins in Gene Ontology annotation, for mainland and island respectively. Variant calling analysis identified about the same number of SNPs in island and mainland population. Instead, through a differential gene expression analysis we found some putative genes involved in syndrome more expressed in insular samples like Major Histocompatibility Complex class I, Immunoglobulins, Melanocortin 4 receptor, Neuropeptide Y and Proliferating Cell Nuclear Antigen

Author Correction: Expanded encyclopaedias of DNA elements in the human and mouse genomes

Online Correction for: https://doi.org/10.1038/s41586-020-2493-4 | Erratum for https://bura.brunel.ac.uk/handle/2438/21299In the version of this article initially published, two members of the ENCODE Project Consortium were missing from the author list. Rizi Ai (Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA) and Shantao Li (Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA) are now included in the author list. These errors have been corrected in the online version of the article : 'Expanded encyclopaedias of DNA elements in the human and mouse genomes'.https://www.nature.com/articles/s41586-021-04226-3https://www.nature.com/articles/s41586-021-04226-

DDX5 plays essential transcriptional and post-transcriptional roles in the maintenance and function of spermatogonia

Mammalian spermatogenesis is sustained by mitotic germ cells with self-renewal potential known as undifferentiated spermatogonia. Maintenance of undifferentiated spermatogonia and spermatogenesis is dependent on tightly co-ordinated transcriptional and post-transcriptional mechanisms. The RNA helicase DDX5 is expressed by spermatogonia but roles in spermatogenesis are unexplored. Using an inducible knockout mouse model, we characterise an essential role for DDX5 in spermatogonial maintenance and show that Ddx5 is indispensable for male fertility. We demonstrate that DDX5 regulates appropriate splicing of key genes necessary for spermatogenesis. Moreover, DDX5 regulates expression of cell cycle genes in undifferentiated spermatogonia post-transcriptionally and is required for cell proliferation and survival. DDX5 can also act as a transcriptional co-activator and we demonstrate that DDX5 interacts with PLZF, a transcription factor required for germline maintenance, to co-regulate select target genes. Combined, our data reveal a critical multifunctional role for DDX5 in regulating gene expression programmes and activity of undifferentiated spermatogonia