Biology subjects

Molaro, A.

Publications and source records attributed to Molaro, A..

5 recordsLinked to original sources

bioRxiv2024

Recurrent Evolutionary Innovations in Rodent and Primate Schlafen Genes

SCHLAFEN 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.

evolutionary biology↗

bioRxiv2022

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

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 findingsO_LIEvolutionary 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. C_LIO_LIIdentification 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. C_LIO_LIEvidence of primate specific adaptation of the entry factor TMPRSS2 pointing to its host- specific in vivo importance and predicting molecular interfaces. C_LIO_LIFYCO1 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. C_LIO_LIIdentification of adaptive evolution in the bats multifunctional RIPK1 at residues that may differentially regulate inflammation. C_LI

evolutionary biology↗

bioRxiv2021

Novel classes and evolutionary turnover of histone H2B variants in the mammalian germline

Histones and their post-translational modifications facilitate diverse chromatin functions in eukaryotes. Core histones (H2A, H2B, H3, and H4) package genomes after DNA replication. In contrast, variant histones promote specialized chromatin functions, including DNA repair, genome stability, and epigenetic inheritance. Previous studies have identified only a few H2B variants in animals; their roles and evolutionary origins remain largely unknown. Here, using phylogenomic analyses, we reveal the presence of five H2B variants broadly present in mammalian genomes. In addition to three previously described variants (H2B.1, subH2B, and H2B.W), we identify and describe two new variants, H2B.L and H2B.N. Four of these five H2B variants originated in mammals, whereas H2B.L arose prior to the last common ancestor of bony vertebrates. We find that though mammalian H2B variants are subject to high gene turnover, most are broadly retained in mammals, including humans. Despite an overall signature of purifying selection, H2B variants evolve more rapidly than core H2B with considerable divergence in sequence and length. All five H2B variants are expressed in the germline. H2B.L and H2B.N are predominantly expressed in oocytes, an atypical expression site for mammalian histone variants. Our findings suggest that H2B variants likely encode potentially redundant but vital functions via unusual chromatin packaging or non-chromatin functions in mammalian germline cells. Our discovery of novel histone variants highlights the advantages of comprehensive phylogenomic analyses and provides unique opportunities to study how innovations in chromatin function evolve.

evolutionary biology↗

bioRxiv2019

Dynamic evolution of de novo DNA methyltransferases in rodent and primate genomes

Transcriptional 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 DNMT3Cs unique function are unknown. Using a phylogenomic approach, we confirm here that Dnmt3C arose through a single duplication of Dnmt3B that occurred between 45-71Mya in the last common ancestor of muroid rodents. Most importantly, we reveal that DNMT3C is composed of two independently evolving segments: the latter two-thirds has undergone recurrent gene conversion with Dnmt3B, whereas the N-terminus has not undergone gene conversion and has evolved under strong diversifying selection. We hypothesize that positive selection of Dnmt3C is the result on 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 DNMT 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 DNMTs in mammals.

evolutionary biology↗

bioRxiv2017

Evolutionary origins and diversification of testis-specific short histone H2A variants in mammals

Eukaryotic genomes must accomplish the tradeoff between compact packaging for genome stability and inheritance, and accessibility for gene expression. They do so using post-translational modifications of four ancient canonical histone proteins (H2A, H2B, H3 and H4), and by deploying histone variants with specialized chromatin functions. While some histone variants are highly conserved across eukaryotes, others carry out lineage-specific functions. Here, we characterize the evolution of male germline-specific \"short H2A variants\", which wrap shorter DNA fragments than canonical H2A. In addition to three previously described H2A.B, H2A.L and H2A.P variants, we describe a novel, extremely short H2A histone variant: H2A.Q. We show that H2A.B, H2A.L, H2A.P and H2A.Q are most closely related to a novel, more canonical mmH2A variant found only in monotremes and marsupials. Using phylogenomics, we trace the origins and early diversification of short histone variants into four distinct clades to the ancestral X chromosome of placental mammals. We show that short H2A variants further diversified by repeated lineage-specific amplifications and losses, including pseudogenization of H2A.L in many primates. We also uncover evidence for concerted evolution of H2A.B and H2A.L genes by gene conversion in many species, involving loci separated by large distances. Finally, we find that short H2As evolve more rapidly than any other histone variant, with evidence that positive selection has acted upon H2A.P in primates. Based on their X chromosomal location and pattern of genetic innovation, we speculate that short H2A histone variants are engaged in a form of genetic conflict involving the mammalian sex chromosomes.

evolutionary biology↗