Sex and suicide : the curious case of Toll-like receptors

Copyright: © 2020 Navarro-Costa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.During in vitro fertilisation (IVF), pharmacological activation of the murine X chromosome–encoded receptor proteins Toll-like receptor (TLR) 7 and TLR8 reportedly results in male-biased litters by selectively disrupting the motility of X-bearing sperm cells. Thus—in the context of agonist treatment during IVF—these receptors act as ‘suicidal’ segregation distorters that impair their own transmission to the next generation. Such behaviour would, from an evolutionary perspective, be strongly selected against if present during natural fertilisation. Consequently, TLR7/8 biology in vivo must differ significantly from this in vitro situation to allow these genes to persist in the genome. Here, we use our current understanding of male germ cell biology and TLR function as a starting point to explore the mechanistic and evolutionary aspects of this apparent paradox.The following funding sources are acknowledged: PAN-C, Fundação para a Ciência e a Tecnologia (PTDC/MEC-AND/30221/2017); AM, Damon Runyon Cancer Research Foundation (DRG:2192-14) and NIH (R01 GM074108); CSM, Fundação para a Ciência e a Tecnologia doctoral scholarship (PD/BD/114362/2016); CDM, NIH R01-GM123194; and PJE, the UK Higher Education Funding Council for England (HEFCE), the Biotechnology and Biological Sciences Research Council (BBSRC, BB/N000463/1), and the Leverhulme Trust (RPG-2019-414 194). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Production of artificial piRNAs in flies and mice

In animals a discrete class of small RNAs, the piwi-interacting RNAs (piRNAs), guard germ cell genomes against the activity of mobile genetic elements. piRNAs are generated, via an unknown mechanism, from apparently single-stranded precursors that arise from discrete genomic loci, termed piRNA clusters. Presently, little is known about the signals that distinguish a locus as a source of piRNAs. It is also unknown how individual piRNAs are selected from long precursor transcripts. To address these questions, we inserted new artificial sequence information into piRNA clusters and introduced these marked clusters as transgenes into heterologous genomic positions in mice and flies. Profiling of piRNA from transgenic animals demonstrated that artificial sequences were incorporated into the piRNA repertoire. Transgenic piRNA clusters are functional in non-native genomic contexts in both mice and flies, indicating that the signals that define piRNA generative loci must lie within the clusters themselves rather than being implicit in their genomic position. Comparison of transgenic animals that carry insertions of the same artificial sequence into different ectopic piRNA-generating loci showed that both local and long-range sequence environments inform the generation of individual piRNAs from precursor transcripts

Hératabilité et avolution de la reprogrammation epigénétique des cellules germinales chez les Mammiferes

During mammalian post-implantation development, germ cells are induced from the somatic tissues of the embryo. Following their induction, primordial germ cells undergo a genome-wide erasure and de novo re-establishment of DNA methylation marks. This epigenetic reprogramming re-instates pluripotency and allows parental imprints to be deposited. In the male germ line, a unique RNAi pathway involving PIWI proteins and their associated small RNAs (piRNAs) is necessary for proper de novo methylation. PIWI mutant mice are infertile and display methylation defects over transposon sequences. Using a transgenic approach, we investigated the signals necessary for piRNA production. We show that artificial piRNAs can be produced from reprogrammed loci outside of their native context. We then studied the genome-wide impact of piRNA loss on germ cell methylation. Whereas most of the genome is properly methylated, only a small group of transposons transiently reactivated in primordial germ cells is affected. Also we identified important structural differences in de novo methylation profiles between human sperm and ES cells. Finally, we compared sperm methylation profiles between human and chimpanzee and showed that the genome and the epigenome can evolve independently. Taken together, our results highlight the surprising plasticity of genome and epigenome interactions during development and evolutionChez les mammifères, les cellules germinales sont induites à partir des tissus somatiques de l'embryon post-implantatoire. Les cellules germinales primordiales nouvellement induites voient l'ensemble de leurs marques de méthylation de l'ADN intégralement effacées puis rétablies de novo. Cette reprogrammation épigénétique rétablit leur pluripotence et leur permet d'acquérir les marques d'empreintes parentales. Chez les mâles, la méthylation de novo nécessite une voie d'ARN interférence impliquant les protéines PIWI et leurs petits ARNs associés (piRNAs). Les souris mutantes pour les protéines PIWIs sont stériles et présentent une méthylation incomplète des transposons. Nous avons généré des souris transgéniques permettant d'étudier les signaux nécessaires à la production des piRNAs. Nous montrons que des loci reprogrammés sont capable de produire des piRNAs exogènes. Nous avons ensuite étudié l'impact de la perte des piRNAs sur les profils de méthylation des spermatocytes : alors que la majorité du génome reste correctement méthylé, seul un nombre réduit de transposons, transitoirement réactivés dans les cellules germinales primordiales, semble être affecté. Troisièmement, nous avons identifié chez l'Homme des différences structurelles entre les profils de méthylation de novo des cellules ES et du sperme. Enfin, la comparaison des profils de méthylation du sperme d'Homme et de Chimpanzé a révélé que le génome et l'épigénome évoluent de manière distincte ou concertée selon les régions. Dans leur ensemble, nos résultats illustrent l'étonnante plasticité des interactions existantes entre le génome et l'épigenome au cours du développement et de l'évolutio

Hératabilité et avolution de la reprogrammation epigénétique des cellules germinales chez les Mammiferes

Chez les mammifères, les cellules germinales sont induites à partir des tissus somatiques de l embryon post-implantatoire. Les cellules germinales primordiales nouvellement induites voient l ensemble de leurs marques de méthylation de l ADN intégralement effacées puis rétablies de novo. Cette reprogrammation épigénétique rétablit leur pluripotence et leur permet d acquérir les marques d empreintes parentales. Chez les mâles, la méthylation de novo nécessite une voie d ARN interférence impliquant les protéines PIWI et leurs petits ARNs associés (piRNAs). Les souris mutantes pour les protéines PIWIs sont stériles et présentent une méthylation incomplète des transposons. Nous avons généré des souris transgéniques permettant d étudier les signaux nécessaires à la production des piRNAs. Nous montrons que des loci reprogrammés sont capable de produire des piRNAs exogènes. Nous avons ensuite étudié l impact de la perte des piRNAs sur les profils de méthylation des spermatocytes : alors que la majorité du génome reste correctement méthylé, seul un nombre réduit de transposons, transitoirement réactivés dans les cellules germinales primordiales, semble être affecté. Troisièmement, nous avons identifié chez l Homme des différences structurelles entre les profils de méthylation de novo des cellules ES et du sperme. Enfin, la comparaison des profils de méthylation du sperme d Homme et de Chimpanzé a révélé que le génome et l épigénome évoluent de manière distincte ou concertée selon les régions. Dans leur ensemble, nos résultats illustrent l étonnante plasticité des interactions existantes entre le génome et l épigenome au cours du développement et de l évolutionDuring mammalian post-implantation development, germ cells are induced from the somatic tissues of the embryo. Following their induction, primordial germ cells undergo a genome-wide erasure and de novo re-establishment of DNA methylation marks. This epigenetic reprogramming re-instates pluripotency and allows parental imprints to be deposited. In the male germ line, a unique RNAi pathway involving PIWI proteins and their associated small RNAs (piRNAs) is necessary for proper de novo methylation. PIWI mutant mice are infertile and display methylation defects over transposon sequences. Using a transgenic approach, we investigated the signals necessary for piRNA production. We show that artificial piRNAs can be produced from reprogrammed loci outside of their native context. We then studied the genome-wide impact of piRNA loss on germ cell methylation. Whereas most of the genome is properly methylated, only a small group of transposons transiently reactivated in primordial germ cells is affected. Also we identified important structural differences in de novo methylation profiles between human sperm and ES cells. Finally, we compared sperm methylation profiles between human and chimpanzee and showed that the genome and the epigenome can evolve independently. Taken together, our results highlight the surprising plasticity of genome and epigenome interactions during development and evolutionPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Dynamic Evolution of De Novo DNA Methyltransferases in Rodent and Primate Genomes

International audienceTranscriptional silencing of retrotransposons via DNA methylation is paramount for mammalian fertility and reproductive fitness. During germ cell development, most mammalian species utilize the de novo DNA methyltransferases DNMT3A and DNMT3B to establish DNA methylation patterns. However, many rodent species deploy a third enzyme, DNMT3C, to selectively methylate the promoters of young retrotransposon insertions in their germline. The evolutionary forces that shaped DNMT3C's unique function are unknown. Using a phylogenomic approach, we confirm here that Dnmt3C arose through a single duplication of Dnmt3B that occurred 60 Ma in the last common ancestor of muroid rodents. Importantly, we reveal that DNMT3C is composed of two independently evolving segments: the latter two-thirds have undergone recurrent gene conversion with Dnmt3B, whereas the N-terminus has instead evolved under strong diversifying selection. We hypothesize that positive selection of Dnmt3C is the result of an ongoing evolutionary arms race with young retrotransposon lineages in muroid genomes. Interestingly, although primates lack DNMT3C, we find that the N-terminus of DNMT3A has also evolved under diversifying selection. Thus, the N-termini of two independent de novo methylation enzymes have evolved under diversifying selection in rodents and primates. We hypothesize that repression of young retrotransposons might be driving the recurrent innovation of a functional domain in the N-termini on germline DNMT3s in mammals

Recurrent Evolutionary Innovations in Rodent and Primate Schlafen Genes

Posted January 13, 2024 on bioRxiv.International audienceSCHLAFEN proteins are a large family of RNase-related enzymes carrying essential immune and developmental functions. Despite these important roles, Schlafen genes display varying degrees of evolutionary conservation in mammals. While this appears to influence their molecular activities, a detailed understanding of these evolutionary innovations is still lacking. Here, we used in depth phylogenomic approaches to characterize the evolutionary trajectories and selective forces shaping mammalian Schlafen genes. We traced lineage-specific Schlafen amplifications and found that recent duplicates evolved under distinct selective forces, supporting repeated sub-functionalization cycles. Codon-level natural selection analyses in primates and rodents, identified recurrent positive selection over Schlafen protein domains engaged in viral interactions. Combining crystal structures with machine learning predictions, we discovered a novel class of rapidly evolving residues enriched at the contact interface of SCHLAFEN protein dimers. Our results suggest that inter Schlafen compatibilities are under strong selective pressures and are likely to impact their molecular functions. We posit that cycles of genetic conflicts with pathogens and between paralogs drove Schlafens’ recurrent evolutionary innovations in mammals

Short H2A histone variants are expressed in cancer

International audienceShort H2A (sH2A) histone variants are primarily expressed in the testes of placental mammals. Their incorporation into chromatin is associated with nucleosome destabilization and modulation of alternate splicing. Here, we show that sH2As innately possess features similar to recurrent oncohistone mutations associated with nucleosome instability. Through analyses of existing cancer genomics datasets, we find aberrant sH2A upregulation in a broad array of cancers, which manifest splicing patterns consistent with global nucleosome destabilization. We posit that short H2As are a class of "ready-made" oncohistones, whose inappropriate expression contributes to chromatin dysfunction in cancer

Distinct evolutionary trajectories of SARS-CoV-2 interacting proteins in bats and primates identify important host determinants of COVID-19

Abstract The COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus that spilled from the bat reservoir. Despite numerous clinical trials and vaccines, the burden remains immense, and the host determinants of SARS-CoV-2 susceptibility and COVID-19 severity remain largely unknown. Signatures of positive selection detected by comparative functional-genetic analyses in primate and bat genomes can uncover important and specific adaptations that occurred at virus-host interfaces. Here, we performed high-throughput evolutionary analyses of 334 SARS- CoV-2 interacting proteins to identify SARS-CoV adaptive loci and uncover functional differences between modern humans, primates and bats. Using DGINN (Detection of Genetic INNovation), we identified 38 bat and 81 primate proteins with marks of positive selection. Seventeen genes, including the ACE2 receptor, present adaptive marks in both mammalian orders, suggesting common virus-host interfaces and past epidemics of coronaviruses shaping their genomes. Yet, 84 genes presented distinct adaptations in bats and primates. Notably, residues involved in ubiquitination and phosphorylation of the inflammatory RIPK1 have rapidly evolved in bats but not primates, suggesting different inflammation regulation versus humans. Furthermore, we discovered residues with typical virus-host arms-race marks in primates, such as in the entry factor TMPRSS2 or the autophagy adaptor FYCO1, pointing to host-specific in vivo important interfaces that may be drug targets. Finally, we found that FYCO1 sites under adaptation in primates are those associated with severe COVID-19, supporting their importance in pathogenesis and replication. Overall, we identified functional adaptations involved in SARS- CoV-2 infection in bats and primates, critically enlightening modern genetic determinants of virus susceptibility and severity. Key findings: Evolutionary history of 334 SARS-CoV-2 interacting proteins (VIPs) in bats and primates identifying how the past has shaped modern viral reservoirs and humans – results publicly-available in an online resource. Identification of 81 primate and 38 bat VIPs with signatures of adaptive evolution. The common ones among species delineate a core adaptive interactome, while the ones displaying distinct evolutionary trajectories enlighten host lineage-specific determinants. Evidence of primate specific adaptation of the entry factor TMPRSS2 pointing to its host- specific in vivo importance and predicting molecular interfaces. FYCO1 sites associated with severe COVID-19 in human (GWAS) display hallmarks of ancient adaptive evolution in primates, highlighting its importance in SARS-CoV-2 replication or pathogenesis and differences with the bat reservoir. Identification of adaptive evolution in the bat’s multifunctional RIPK1 at residues that may differentially regulate inflammation

Distinct evolutionary trajectories of SARS-CoV-2-interacting proteins in bats and primates identify important host determinants of COVID-19

International audienceThe coronavirus disease 19 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a coronavirus that spilled over from the bat reservoir. Despite numerous clinical trials and vaccines, the burden remains immense, and the host determinants of SARS-CoV-2 susceptibility and COVID-19 severity remain largely unknown. Signatures of positive selection detected by comparative functional genetic analyses in primate and bat genomes can uncover important and specific adaptations that occurred at virus–host interfaces. We performed high-throughput evolutionary analyses of 334 SARS-CoV-2-interacting proteins to identify SARS-CoV adaptive loci and uncover functional differences between modern humans, primates, and bats. Using DGINN (Detection of Genetic INNovation), we identified 38 bat and 81 primate proteins with marks of positive selection. Seventeen genes, including the ACE2 receptor, present adaptive marks in both mammalian orders, suggesting common virus–host interfaces and past epidemics of coronaviruses shaping their genomes. Yet, 84 genes presented distinct adaptations in bats and primates. Notably, residues involved in ubiquitination and phosphorylation of the inflammatory RIPK1 have rapidly evolved in bats but not primates, suggesting different inflammation regulation versus humans. Furthermore, we discovered residues with typical virus–host arms race marks in primates, such as in the entry factor TMPRSS2 or the autophagy adaptor FYCO1, pointing to host-specific in vivo interfaces that may be drug targets. Finally, we found that FYCO1 sites under adaptation in primates are those associated with severe COVID-19, supporting their importance in pathogenesis and replication. Overall, we identified adaptations involved in SARS-CoV-2 infection in bats and primates, enlightening modern genetic determinants of virus susceptibility and severity